Chlamydia pneumoniae polynucleotides and uses thereof

[0001] The Sequence Listing for this application is on duplicate compact discs labeled “Copy 1” and “Copy 2”. Copy 1 and Copy 2 each contain only one file named “seqlist-28July2001.txt” which was created on Jul. 30, 2001. The file is 5,284 KB. The entire contents of each of the computer discs are incorporated herein by reference in their entireties.

[0002] The subject of the invention is the genomic sequence and the nucleotide sequences encoding polypeptides of Chlamydia pneumoniae, such as cellular envelope polypeptides, which are secreted or specific, or which are involved in metabolism, in the replication process or in virulence, polypeptides encoded by such sequences, as well as vectors including the said sequences and cells or animals transformed with these vectors. The invention also relates to transcriptional gene products of the Chlamydia pneumoniae genome, such as, for example, antisense and ribozyme molecules, which can be used to control growth of the microorganism. The invention also relates to methods of detecting these nucleic acids or polypeptides and kits for diagnosing Chlamydia pneumoniae infection. The invention also relates to a method of selecting compounds capable of modulating bacterial infection and a method for the biosynthesis or biodegradation of molecules of interest using the said nucleotide sequences or the said polypeptides. The invention finally comprises, pharmaceutical, in particular vaccine, compositions for the prevention and/or treatment of bacterial, in particular Chlamydia pneumoniae, infections.

[0003] Comparative analysis of the sequence of the gene encoding the ribosomal 16S RNA has been widely used for the phylogenetic study of prokaryotes. This approach has made it possible to classify the Chlamydiae among the eubacteria, among which they represent a well-isolated group, with, nevertheless, a very weak link with the planctomyces. The Chlamydiae thus exhibit some unique characteristics within the eubacteria, in particular their development cycle and the structure of their membranes. They have a unique two-phase cell cycle: the elementary body, a small extracellular form, attaches to the host and is phagocytosed; in the phagosome, it is converted to the replicative intracellular form, the reticulate body. The Chlamydiae are obligate intracellular bacteria which multiply in eukaryotic cells at the expense of their energy reserves and nucleotide pools; they are responsible for a wide variety of diseases in mammals and birds. The Chlamydiae are the only members of the order Chlamydiales, of the family Chlamydiaceae and of the genus Chlamydia. Within the genus Chlamydia, four species are currently described: Chlamydia trachomatis, Chlamydia psittaci, Chlamydia pneumoniae and Chlamydia pecorum. These bacteria are grouped together and share biological and biochemical properties. Among them, only the first three infect humans, Chlamydia pecorum being a pathogen of ruminants.

[0004] The species Chlamydia psittaci infects many animals, in particular birds, and is transmissible to humans. It is responsible for a typical pneumonia, for hepatic and renal dysfunction, for endocarditis and for conjunctivitis.

[0005] The species Chlamydia trachomatis is the best characterized. Besides a murine strain, it is divided into two groups which are distinguishable by the nature of the diseases for which they are responsible: trachoma, genital attack and venereal lymphogranulomatosis. There are fifteen human serotypes of Chlamydia trachomatis (A, K) and LGV (L1, L2, L3). Strains A to C are mainly found in eye infections, whereas strains D to K and LGV are essentially responsible for genital entry infections. It should be mentioned that the LGV strains are responsible for systemic diseases. Historically, it was in 1906 that Halberstaeder and Von Provaseck discovered, in trachoma patients, the presence of inclusions in the cytoplasm of the cells derived from conjunctival scrapings. In 1940, Rake and Jones described these same inclusions in certain cells obtained by puncturing the ganglia from a patient suffering from venereal granulomatosis. Characterization of the Chlamydia trachomatis microorganism was only successfully carried out in 1957, after a series of isolations in cell cultures.

[0006] It was in 1983 that Chlamydia pneumoniae was recognized as a human pathogen (Grayston J T et al., 1986); since then, special attention has been paid to this bacterium and it is estimated (Gaydos C A et al., 1994) that 10% of pneumonias, and 5% of bronchitides and sinusites are attributable to Chlamydia pneumoniae (Aldous M B et al., 1992). More recently, the association of this bacterium with the pathogenesis of asthmatic disease and of cardiovascular impairments is increasingly of interest.

[0007] Serological studies have made it possible to observe that Chlamydia pneumoniae infection is common in children between 5 and 16 years of age. Before this age, it is rare to find antibodies; the increase in the number of individuals carrying antibodies is then correlated with age up to 20 years. Accordingly, 50% of adults are carriers of antibodies, it being possible for this prevalence to be as high as 75%. These figures are all the more striking since a first infection induces antibody levels of which the persistence over time is limited to 3 or at most 5 years, which suggests frequent reinfection during the entire lifespan. The annual seroconversion rate is about 8% between 8 and 12 years and about 6% between 12 and 16 years (Haidl et al., 1994). Before the age of 15 years, the seroprevalence of the disease is identical between both sexes. After this age, men are more frequently infected than women; this is true in all regions worldwide where such studies have been carried out.

[0008] These infections are geographically highly widespread, as shown by numerous studies carried out throughout the world (Kanamoto Y et al., 1991; Tong C Y et al., 1993). Developed countries of the north such as Canada, Denmark and Norway have the lowest infection rates; conversely, the highest prevalence rates are found in the less developed countries of tropical regions where the infection may occur before the age of 5 years.

[0009] Humans are the only known reservoir for Chlamydia pneumoniae and it is probable that the infection is caused by direct transmission, respiratory secretions probably being responsible for this low-yield transmission (Aldous et al., 1992). The chain of transmission may also appear to be indirect (Kleemola M et al., 1988), suggesting that the infection is caused by an effective transmission, but also that asymptomatic carriers exist, which could explain the high prevalence of the disease. Other studies (Mordhorst C H et al., 1992) show that the efficiency of the transmission varies according to the individuals and list cases of infection affecting all or the majority of members of one family or of a group of families. The period of incubation is several weeks, significantly longer in this regard than that of many other respiratory pathogenic agents. Although under conditions of high relative humidity the infectivity of Chlamydia pneumoniae in the open air decreases rapidly, suggesting a direct mode of transmission under these conditions, it is probable that the transmission occurs in some cases indirectly since the microorganism can survive for up to 30 hours in a hostile environment (Falsey et al., 1993).

[0010] Clinical manifestations due to Chlamydia pneumoniae are essentially respiratory diseases. Pneumonia and bronchitis are the most frequent because they are clinically patent: since etiological diagnosis is evoked in this case, the infectious agent is identified. The asymptomatic diseases are probably numerous (Grayston J T et al., 1992; Grayston J T et al., 1986; Thom D H et al., 1990). The disease then progresses via bronchitis or pneumonia; fever is absent at the time of examination but is sometimes reported by the patient. The degree of seriousness of the disease is variable and in hospitalized patients, it is common to observe pleural effusion; a generalized infection may also be observed and, in severe cases, anatomicopathological examination shows Chlamydia pneumoniae diseases.

[0011] Other syndromes such as sinusitis (Hashiguchi K et al., 1992), purulent otitis media (Ogawa H et al., 1992), or pharyngitis (Huovinen P et al., 1989) have been described, as well as infections with respiratory impairments similar to asthma (Hahn D L et al., 1991). Chlamydia pneumoniae has also been associated with sarcoidosis, with erythema nodosum (Sundelof et al., 1993) and one case of Guillain-Barre syndrome has even been described (Haidl et al., 1992). The involvement of Chlamydia pneumoniae in Reiter's syndrome has also been evaluated (Braun J et al., 1994).

[0012] The association of Chlamydia pneumoniae with coronary diseases and with myocardial infarction was first suspected from the observation of the high antibody level in 71% of patients having a heart disease (Shor A et al., 1992; Kuo C C et al., 1993; Puolakkainen M et al., 1993; Thomas G N et al., 1997). Studies carried out in several countries have shown similar results in patients with atheromatous impairments (Shor A et al., 1992; Kuo C C et al., 1993; Puolakkainen M et al., 1993; Grayston J T et al., 1996; Casas-Ciria J et al., 1996; Thomas G N et al., 1997; Jackson L A et al., 1997) and in patients with carotid impairments. Anatomicopathological and microbiological studies have detected Chlamydia pneumoniae in the vessels. The electron microscope has made it possible to visualize the bacterium (Ladany S et al., 1989), which has in fact been demonstrated by other techniques such as PCR (Campbell L A et al., 1992; Kuo C C et al., 1993; Kuo C C et al., 1988). It also appears that the bacterium is more frequently found in old atheromatous lesions. Other studies carried out on young subjects from 15 to 35 years have given the opportunity to study the coronary arteries of people without atherosclerosis, this observation not being possible in older subjects (the onset of the atheromatous disease is early). In these young subjects, the PCR studies did not find Chlamydia pneumoniae in subjects free of atheromatous disease, but revealed the presence of Chlamydia pneumoniae in two of the eleven subjects who showed early lesions and in six of the seven subjects who developed atheroma plaques. These studies therefore show that the atheroma plaque is very strongly correlated with the presence of Chlamydia pneumoniae, but the role played by the bacterium in vascular pathology is not yet defined.

[0013] The data relating to controlled clinical studies analysing the effect of treatments in Chlamydia pneumoniae infections are limited in number. Unlike penicillin, ampicillin or the sulphamides, erythromycin, tetracycline or doxycycline show an antibiotic activity in vitro against Chlamydia pneumoniae. However, a treatment at high doses should be continued for several weeks in order to avoid a recurrence of the infection. Accordingly, the use of two new macrolides, clarithromycin and azithromycin, whose diffusion, bioavailability and half-life allow shorter and better tolerated cures, is nowadays preferred. In the absence of definitive proof based on the results of clinical studies, an effective, without recurrences, and well-tolerated treatment of Chlamydia pneumoniae infections therefore remains desirable.

[0014] An even more important need up until now relates to a specific and sensitive diagnosis, which can be carried out conveniently and rapidly, allowing early screening for the infection. Methods based on Chlamydia pneumoniae culture are slow and require a considerable know-how because of the difficulty involved in the collection, preservation and storage of the strain under appropriate conditions. Methods based on antigen detection (EIA, DFA) or on nucleic acid amplification (PCR) provide tests which are more suitable for laboratory practice. A reliable, sensitive and convenient test, which allows distinction between serogroups and a fortiori between Chlamydia pneumoniae species is therefore highly desirable.

[0015] This is all the more important since the symptoms of Chlamydia pneumoniae infection appear slowly, since all the pathologies associated with these infections have not yet been identified, and since, as has been mentioned above, an association is suspected between these infections and serious chronic infections, asthma or atherosclerosis.

[0016] No vaccine is yet available against Chlamydia pneumoniae: this is due to the labile nature of the antigens specific to the strain, which has so far prevented their specific identification.

[0017] Although the number of studies and of animal models developed is high, the antigens used have not induced sufficient protective immunity to lead to the development of human vaccines. In the case of Chlamydia pneumoniae, the role of the immune defense in the physiology and pathology of the disease should probably be understood in order to develop satisfactory vaccines.

[0018] More detailed information relating to the biology of these strains, their interactions with their hosts, the associated phenomena of infectivity and those of escaping the immune defenses of the host in particular, and finally their involvement in the development of the these associated pathologies, will allow a better understanding of these mechanisms. In the light of the preceding text which shows in particular the limitations of the means of controlling Chlamydia pneumoniae infection, it is therefore at present essential, on the one hand, to develop molecular tools, in particular from a better genetic knowledge of Chlamydia pneumoniae, but also to develop new preventive and therapeutic treatments, new diagnostic methods and new vaccine strategies which are specific, effective and tolerated. This is precisely the object of the present invention.

[0019] The subject of the present invention is the nucleotide sequence having the sequence SEQ ID No. 1 of the Chlamydia pneumoniae genome. However, the invention is not limited to SEQ ID No. 1, but encompasses genomes and nucleotides encoding polypeptides of strain variants, polymorphisms, allelic variants, and mutants.

[0020] Thus, the subject of the present invention encompasses nucleotide sequences characterized in that they are chosen from:

[0021] a) the nucleotide sequence of SEQ ID No. 1, a nucleotide sequence exhibiting at least 99.9% identity with the sequence SEQ ID No. 1, the nucleotide sequence of the genomic DNA contained within ATCC Deposit No.VR2634, the nucleotide sequence of a clone insert within ATCC Deposit No. 207000; 207001; and 207002;

[0022] b) a nucleotide sequence homologous to the sequence SEQ ID No. 1;

[0023] c) a polynucleotide sequence that hybridizes to the nucleotide sequence of a) under conditions of high or intermediate stringency as described below:

[0024] (i) By way of example and not limitation, procedures using conditions of high stringency are as follows: Prehybridization of filters containing DNA is carried out for 8 h to overnight at 65° C. in buffer composed of 6×SSC, 50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 μg/ml denatured salmon sperm DNA. Filters are hybridized for 48 h at 65° C., the preferred hybridization temperature, in prehybridization mixture containing 100 μg/ml denatured salmon sperm DNA and 5-20×106 cpm of 32P-labeled probe. Alternatively, the hybridization step can be performed at 65° C. in the presence of SSC buffer, 1×SSC corresponding to 0.15M NaCl and 0.05 M Na citrate. Subsequently, filter washes can be done at 37° C. for 1 h in a solution containing 2×SSC, 0.01% PVP, 0.01% Ficoll, and 0.01% BSA, followed by a wash in 0.1×SSC at 50° C. for 45 min. Alternatively, filter washes can be performed in a solution containing 2×SSC and 0.1% SDS, or 0.5×SSC and 0.1% SDS, or 0.1×SSC and 0.1% SDS at 68° C. for 15 minute intervals. Following the wash steps, the hybridized probes are detectable by autoradiography. Other conditions of high stringency which may be used are well known in the art and as cited in Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Press, N.Y., pp. 9.47-9.57; and Ausubel et al., 1989, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N.Y. are incorporated herein in their entirety.

[0025] (ii) By way of example and not limitation, procedures using conditions of intermediate stringency are as follows: Filters containing DNA are prehybridized, and then hybridized at a temperature of 60° C. in the presence of a 5×SSC buffer and labeled probe. Subsequently, filters washes are performed in a solution containing 2×SSC at 50° C. and the hybridized probes are detectable by autoradiography. Other conditions of intermediate stringency which may be used are well known in the art and as cited in Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Press, N.Y., pp. 9.47-9.57; and Ausubel et al., 1989, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N.Y. are incorporated herein in their entirety.

[0026] d) a nucleotide sequence complementary to the sequence SEQ ID No. 1 or complementary to a nucleotide sequence as defined in a), b) or c) and a nucleotide sequence of their corresponding RNA;

[0027] e) a nucleotide sequence of a representative fragment of the sequence SEQ ID No. 1, or of a representative fragment of the nucleotide sequence as defined in a), b), c) or d);

[0028] f) a nucleotide sequence comprising a sequence as defined in a), b), c), d) or e);

[0029] g) a nucleotide sequence capable of being obtained from a nucleotide sequence as defined in a), b), c), d), e) or f); and

[0030] h) a modified nucleotide sequence of a nucleotide sequence as defined in a), b), c), d), e), f) or g).

[0031] Nucleotide sequence, polynucleotide or nucleic acid are understood to mean, according to the present invention, either a double-stranded DNA, a single-stranded DNA or products of transcription of the said DNAs.

[0032] It should be understood that the present invention does not relate to the genomic nucleotide sequences of Chlamydia pneumoniae taken in their natural environment, that is to say in the natural state. They are sequences which may have been isolated, purified or partially purified, by separation methods such as, for example, ion-exchange chromatography, molecular size exclusion chromatography or affinity chromatography, or alternatively fractionation techniques based on solubility in various solvents, or by genetic engineering methods such as amplification, cloning or subcloning, it being possible for the sequences of the invention to be carried by vectors.

[0033] The nucleotide sequence SEQ ID No. 1 was obtained by sequencing the Chlamydia pneumoniae genome by the method of directed sequencing after fluorescent automated sequencing of the inserts of clones and assembling of these sequences of nucleotide fragments (inserts) by means of softwares (cf. Examples). In spite of the high precision of the sequence SEQ ID No. 1, it is possible that it does not perfectly, 100% represent the nucleotide sequence of the Chlamydia pneumoniae genome and that a few rare sequencing errors or uncertainties still remain in the sequence SEQ ID No. 1. In the present invention, the presence of an uncertainty for an amino acid is designated by “Xaa” and that for a nucleotide is designated by “N” in the sequence listing below. These few rare errors or uncertainties could be easily detected and corrected by persons skilled in the art using the entire chromosome and/or its representative fragments according to the invention and standard amplification, cloning and sequencing methods, it being possible for the sequences obtained to be easily compared, in particular by means of a computer software and using computer-readable media for recording the sequences according to the invention as described, for example, below. After correcting these possible rare errors or uncertainties, the corrected nucleotide sequence obtained would still exhibit at least 99.9% identity with the sequence SEQ ID No. 1. Such rare sequencing uncertainties are not present within the DNA contained within ATCC Deposit No. VR2634; 207000; 207001; or 207002, and whatever rare sequence uncertainties that exist within SEQ ID No. 1 can routinely be corrected utilizing the DNA of the ATCC deposits.

[0034] Homologous nucleotide sequence for the purposes of the present invention is understood to mean a nucleotide sequence having a percentage identity with the bases of the nucleotide sequence SEQ ID No. 1 of at least 80%, preferably 90% and 95%, this percentage being purely statistical and it being possible for the differences between the two nucleotide sequences to be distributed randomly and over their entire length. The said homologous sequences exhibiting a percentage identity with the bases of the nucleotide sequence SEQ ID No. 1 of at least 80%, preferably 90% and 95%, may comprise, for example, the sequences corresponding to the genomic sequence or to the sequences of its representative fragments of a bacterium belonging to the Chlamydia family, including the species Chlamydia trachomatis, Chlamydia psittaci and Chlamydia pecorum mentioned above, as well as the sequences corresponding to the genomic sequence or to the sequences of its representative fragments of a bacterium belonging to the variants of the species Chlamydia pneumoniae. In the present invention, the terms family and genus are mutually interchangeable, the terms variant, serotype, strain and subspecies are also mutually interchangeable. These homologous sequences may thus correspond to variations linked to mutations within the same species or between species and may correspond in particular to truncations, substitutions, deletions and/or additions of at least one nucleotide. The said homologous sequences may also correspond to variations linked to the degeneracy of the genetic code or to a bias in the genetic code which is specific to the family, to the species or to the variant and which are likely to be present in Chlamydia.

[0035] Protein and/or nucleic acid sequence homologies may be evaluated using any of the variety of sequence comparison algorithms and programs known in the art. Such algorithms and programs include, but are by no means limited to, TBLASTN, BLASTP, FASTA, TFASTA, and CLUSTALW (Pearson and Lipman, 1988, Proc. Natl. Acad. Sci. USA 85(8):2444-2448; Altschul et al., 1990, J. Mol. Biol. 215(3):403-410; Thompson et al., 1994, Nucleic Acids Res. 22(2):4673-4680; Higgins et al., 1996, Methods Enzymol. 266:383-402; Altschul et al., 1990, J. Mol. Biol. 215(3):403-410; Altschul et al., 1993, Nature Genetics 3:266-272).

[0036] In a particularly preferred embodiment, protein and nucleic acid sequence homologies are evaluated using the Basic Local Alignment Search Tool (“BLAST”) which is well known in the art (see, e.g., Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. USA 87:2267-2268; Altschul et al., 1990, J. Mol. Biol. 215:403-410; Altschul et al., 1993, Nature Genetics 3:266-272; Altschul et al., 1997, Nuc. Acids Res. 25:3389-3402). In particular, five specific BLAST programs are used to perform the following task:

[0037] (1) BLASTP and BLAST3 compare an amino acid query sequence against a protein sequence database;

[0038] (2) BLASTN compares a nucleotide query sequence against a nucleotide sequence database;

[0039] (3) BLASTX compares the six-frame conceptual translation products of a query nucleotide sequence (both strands) against a protein sequence database;

[0040] (4) TBLASTN compares a query protein sequence against a nucleotide sequence database translated in all six reading frames (both strands); and

[0041] (5) TBLASTX compares the six-frame translations of a nucleotide query sequence against the six-frame translations of a nucleotide sequence database.

[0042] The BLAST programs identify homologous sequences by identifying similar segments, which are referred to herein as “high-scoring segment pairs,” between a query amino or nucleic acid sequence and a test sequence which is preferably obtained from a protein or nucleic acid sequence database. High-scoring segment pairs are preferably identified (i.e., aligned) by means of a scoring matrix, many of which are known in the art. Preferably, the scoring matrix used is the BLOSUM62 matrix (Gonnet et al., 1992, Science 256:1443-1445; Henikoff and Henikoff, 1993, Proteins 17:49-61). Less preferably, the PAM or PAM250 matrices may also be used (see, e.g., Schwartz and Dayhoff, eds., 1978, Matrices for Detecting Distance Relationships: Atlas of Protein Sequence and Structure, Washington: National Biomedical Research Foundation)

[0043] The BLAST programs evaluate the statistical significance of all high-scoring segment pairs identified, and preferably selects those segments which satisfy a user-specified threshold of significance, such as a user-specified percent homology. Preferably, the statistical significance of a high-scoring segment pair is evaluated using the statistical significance formula of Karlin (see, e.g., Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. USA 87:2267-2268).

[0044] Nucleotide sequence complementary to a sequence of the invention is understood to mean any DNA whose nucleotides are complementary to those of the sequence of the invention, and whose orientation is reversed (antiparallel sequence).

[0045] The present invention further comprises fragments of the sequences of a) through f), above. Representative fragments of the sequences according to the invention will be understood to mean any nucleotide fragment having at least 8 successive nucleotides, preferably at least 12 successive nucleotides, and still more preferably at least 15 or at least 20 successive nucleotides of the sequence from which it is derived. It is understood that such fragments refer only to portions of SEQ ID No. 1 that are not currently listed in a publicly available database.

[0046] Among these representative fragments, those capable of hybridizing under stringent conditions with a nucleotide sequence according to the invention are preferred. Hybridization under stringent conditions means that the temperature and ionic strength conditions are chosen such that they allow hybridization to be maintained between two complementary DNA fragments.

[0047] By way of illustration, high stringency conditions for the hybridization step for the purposes of defining the nucleotide fragments described above, are advantageously the following.

[0048] The hybridization is carried out at a preferred temperature of 65° C. in the presence of SSC buffer, 1×SSC corresponding to 0.15 M NaCl and 0.05 M Na citrate. The washing steps may be, for example, the following:

[0049] 2×SSC, 0.1% SDS at room temperature followed by three washes with 1×SSC, 0.1% SDS;

[0050] 0.5×SSC, 0.1% SDS; 0.11×SSC, 0.1% SDS at 68° C. for 15 minutes.

[0051] Intermediate stringency conditions, using, for example, a temperature of 60° C. in the presence of a 5×SSC buffer, or of low stringency, for example a temperature of 50° C. in the presence of a 5×SSC buffer, respectively require a lower overall complementarity for the hybridization between the two sequences.

[0052] The stringent hybridization conditions described above for a polynucleotide of about 300 bases in size will be adapted by persons skilled in the art for larger- or smaller-sized oligonucleotides, according to the teaching of Sambrook et al., 1989.

[0053] Among the representative fragments according to the invention, those which can be used as primer or probe in methods which make it possible to obtain homologous sequences or their representative fragments according to the invention, or to reconstitute a genomic fragment found to be incomplete in the sequence SEQ ID No. 1 or carrying an error or an uncertainty, are also preferred, these methods, such as the polymerase chain reaction (PCR), cloning and sequencing of nucleic acid being well known to persons skilled in the art. These homologous nucleotide sequences corresponding to mutations or to inter- or intra-species variations, as well as the complete genomic sequence or one of its representative fragments capable of being reconstituted, of course form part of the invention.

[0054] Among the said representative fragments, those which can be used as primer or probe in methods allowing diagnosis of the presence of Chlamydia pneumoniae or one of its associated microorganisms as defined below are also preferred.

[0055] The representative fragments capable of modulating, regulating, inhibiting or inducing the expression of a gene of Chlamydia pneumoniae or one of its associated microorganisms, and/or capable of modulating the replication cycle of Chlamydia pneumoniae or one of its associated microorganisms in the host cell and/or organism, are also preferred. Replication cycle is intended to designate invasion, multiplication, intracellular localization, in particular retention in the vacuole and inhibition of the process of fusion to the lysosome, and propagation of Chlamydia pneumoniae or one of its associated microorganisms from host cells to host cells.

[0056] Among the said representative fragments, those corresponding to nucleotide sequences corresponding to open reading frames, called ORF sequences (ORF for open reading frame), and encoding polypeptides, such as for example, but without being limited thereto, the ORF sequences which will be later described, are finally preferred.

[0057] The representative fragments according to the invention may be obtained, for example, by specific amplification, such as PCR, or after digestion, with appropriate restriction enzymes, of nucleotide sequences according to the invention; these methods are in particular described in the manual by Sambrook et al., 1989. The said representative fragments may also be obtained by chemical synthesis when they are not too large in size and according to methods well known to persons skilled in the art. For example, such fragments can be obtained by isolating fragments of the genomic DNA of ATCC Deposit No. VR2634 or a clone insert present at this ATCC Deposit No. 207000; 207001; or 207002.

[0058] The representative fragments according to the invention may be used, for example, as primer, to reconstitute some of the said representative fragments, in particular those in which a portion of the sequence is likely to be missing or imperfect, by methods well known to persons skilled in the art such as amplification, cloning or sequencing techniques.

[0059] Modified nucleotide sequence will be understood to mean any nucleotide sequence obtained by mutagenesis according to techniques well known to persons skilled in the art, and exhibiting modifications in relation to the normal sequences, for example mutations in the regulatory and/or promoter sequences for the expression of a polypeptide, in particular leading to a modification of the level of expression of the said polypeptide or to a modulation of the replicative cycle.

[0060] Modified nucleotide sequence will also be understood to mean any nucleotide sequence encoding a modified polypeptide as defined below.

[0061] The subject of the present invention also includes Chlamydia pneumoniae nucleotide sequences characterized in that they are chosen from a nucleotide sequence of an open reading frame (ORF), that is, the ORF2 to ORF1297 sequences.

[0062] The ORF2 to ORF1297 nucleotide sequences are defined in Tables 1 and 2, infra, by their position on the sequence SEQ ID No. 1. For example, the ORF2 sequence is defined by the nucleotide sequence between the nucleotides at position 42 and 794 on the sequence SEQ ID No. 1, ends included. ORF2 to ORF1297 have been identified via homology analyses as well as via analyses of potential ORF start sites, as discussed in the examples below. It is to be understood that each identified ORF of the invention comprises a nucleotide sequence that spans the contiguous nucleotide sequence from the ORF stop codon immediately 3′ to the stop codon of the preceding ORF and through the 5′ codon to the next stop codon of SEQ ID No.:1 in-frame to the ORF nucleotide sequence. Table 2, infra, lists the beginning, end and potential start site of each of ORFs 1-1297. In one embodiment, the ORF comprises the contiguous nucleotide sequence spanning from the potential ORF start site downstream (that is, 3′) to the ORF stop codon (or the ORF codon immediately adjacent to and upstream of the ORF stop codon). ORF2 to ORF1297 encode the polypeptides of SEQ ID No. 2 to SEQ ID No. 1291 and of SEQ ID No. 6844 to SEQ ID No. 6849, respectively.

[0063] Upon introduction of minor frameshifts, certain individual ORFs can comprise larger “combined” ORFs. A list of such putative “combined” ORFs is shown in Table 3, below. For example, a combined ORF can comprise ORF 25, ORF 26 and ORF 27, including intervening in-frame, nucleotide sequences. The order of ORFs (5′ to 3′), within each “combined” ORF is as listed. It is to be understood that when ORF2 to ORF1297 are referred to herein, such reference is also meant to include “combined” ORFs. Polypeptide sequences encoded by such “combined” ORFs are also part of the present invention.

[0064] Table 1 also depicts the results of homology searches that compared the sequences of the polypeptides encoded by each of the ORFs to sequences present in public published databases. It is understood that those polypeptides listed in Table 1 as exhibiting greater than about 95% identity to a polypeptide present in a publicly disclosed database are not considered part of the present invention; likewise in this embodiment, those nucleotide sequences encoding such polypeptides are not considered part of the invention. In another embodiment, it is understood that those polypeptides listed in Table 1 as exhibiting greater than about 99% identity to a polypeptide present in a publicly disclosed database are not considered part of the invention; likewise, in this embodiment, those nucleotide sequences encoding such polypeptides are not considered part of the invention.

[0065] The invention also relates to the nucleotide sequences characterized in that they comprise a nucleotide sequence chosen from:

[0066] a) an ORF2 to ORF1297, a “combined” ORF nucleotide sequence, the nucleotide sequence of the genomic DNA contained within ATCC Deposit No. VR2634 or a clone insert present at this ATCC Deposit No. 207000; 207001; or according to the invention;

[0067] b) a homologous nucleotide sequence exhibiting at least 80% identity across an entire ORF2 to ORF1297 nucleotide sequence according to the invention or as defined in a);

[0068] c) a polynucleotide sequence that hybridizes to ORF2 to ORF1297 under conditions of high or intermediate stringency as described below:

[0069] (i) By way of example and not limitation, procedures using conditions of high stringency are as follows: Prehybridization of filters containing DNA is carried out for 8 h to overnight at 65° C. in buffer composed of 6×SSC, 50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 μg/ml denatured salmon sperm DNA. Filters are hybridized for 48 h at 65EC, the preferred hybridization temperature, in prehybridization mixture containing 100 μg/ml denatured salmon sperm DNA and 5-20×106 cpm of 32P-labeled probe. Alternatively, the hybridization step can be performed at 65EC in the presence of SSC buffer, 1×SSC corresponding to 0.15M NaCl and 0.05 M Na citrate. Subsequently, filter washes can be done at 37EC for 1 h in a solution containing 2×SSC, 0.01% PVP, 0.01% Ficoll, and 0.01% BSA, followed by a wash in 0.1×SSC at 50EC for 45 min. Alternatively, filter washes can be performed in a solution containing 2×SSC and 0.1% SDS, or 0.5×SSC and 0.1% SDS, or 0.1×SSC and 0.1% SDS at 68EC for 15 minute intervals. Following the wash steps, the hybridized probes are detectable by autoradiography. Other conditions of high stringency which may be used are well known in the art and as cited in Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Press, N.Y., pp. 9.47-9.57; and Ausubel et al., 1989, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N.Y. are incorporated herein in their entirety. Preferably, such sequences encode a homolog of a polypeptide encoded by one of ORF2 to ORF1297. In one embodiment, such sequences encode a Chlamydia pneumoniae polypeptide.

[0070] (ii) By way of example and not limitation, procedures using conditions of intermediate stringency are as follows: Filters containing DNA are prehybridized, and then hybridized at a temperature of 60EC in the presence of a 5×SSC buffer and labeled probe. Subsequently, filters washes are performed in a solution containing 2×SSC at 50EC and the hybridized probes are detectable by autoradiography. Other conditions of intermediate stringency which may be used are well known in the art and as cited in Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Press, N.Y., pp. 9.47-9.57; and Ausubel et al., 1989, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N.Y. are incorporated herein in their entirety. Preferably, such sequences encode a homolog of a polypeptide encoded by one of ORF2 to ORF1297. In one embodiment, such sequences encode a Chlamydia pneumoniae polypeptide.

[0071] d) complementary or RNA nucleotide sequence corresponding to an ORF2 to ORF1297 sequence according to the invention or as defined in a), b) or c);

[0072] e) a nucleotide sequence of a representative fragment of an ORF2 to ORF1297 sequence according to the invention or of a sequence as defined in a), b), c) or d);

[0073] f) a nucleotide sequence capable of being obtained from an ORF2 to ORF1297 sequence according to the invention or as defined in a), b), c), d) or e); and

[0074] g) a modified nucleotide sequence of an ORF2 to ORF1297 sequence according to the invention or as defined in a), b), c), d), e) or f).

[0075] As regards the homology with the ORF2 to ORF1297 nucleotide sequences, the homologous sequences exhibiting a percentage identity with the bases of one of the ORF2 to ORF1297 nucleotide sequences of at least 80%, preferably 90% and 95%, are preferred. Such homologous sequences are identified routinely via, for example, the algorithms described above and in the examples below. The said homologous sequences correspond to the homologous sequences as defined above and may comprise, for example, the sequences corresponding to the ORF sequences of a bacterium belonging to the Chlamydia family, including the species Chlamydia trachomatis, Chlamydia psittaci and Chlamydia pecorum mentioned above, as well as the sequences corresponding to the ORF sequences of a bacterium belonging to the variants of the species Chlamydia pneumoniae. These homologous sequences may likewise correspond to variations linked to mutations within the same species or between species and may correspond in particular to truncations, substitutions, deletions and/or additions of at least one nucleotide. The said homologous sequences may also correspond to variations linked to the degeneracy of the genetic code or to a bias in the genetic code which is specific to the family, to the species or to the variant and which are likely to be present in Chlamydia.

[0076] The invention comprises polypeptides encoded by a nucleotide sequence according to the invention, preferably by a representative fragment of the sequence SEQ ID No. 1 and corresponding to an ORF sequence, in particular the Chlamydia pneumoniae polypeptides, characterized in that they are chosen from the sequences SEQ ID No. 2 to SEQ ID No. 1291 or SEQ ID No. 6844 to SEQ ID No. 6849 and representative fragments thereof. However, the invention is not limited to polypeptides encoded by ORFs in SEQ ID No. 1 and its corresponding ORF sequences, but encompasses polypeptides of strain variants, polymorphisms, allelic variants, and mutants.

[0077] Thus, the invention also comprises the polypeptides characterized in that they comprise a polypeptide chosen from:

[0078] a) a polypeptide encoded by a polynucleotide sequence in SEQ ID No. 1 (e.g., any polypeptide encoded by a polynucleotide sequence corresponding to ORF2 to ORF1297 and/or representative fragments thereof) according to the invention;

[0079] b) a polypeptide homologous to a polypeptide according to the invention, or as defined in a);

[0080] c) a polypeptide encoded by a polynucleotide sequence that hybridizes to SEQ ID No. 1 or ORF2 to ORF1297 under high or intermediate stringency as described below:

[0081] (i) By way of example and not limitation, procedures using conditions of high stringency are as follows: Prehybridization of filters containing DNA is carried out for 8 h to overnight at 65EC in buffer composed of 6×SSC, 50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 μg/ml denatured salmon sperm DNA. Filters are hybridized for 48 h at 65EC, the preferred hybridization temperature, in prehybridization mixture containing 100 μg/ml denatured salmon sperm DNA and 5-20×106 cpm of 32P-labeled probe. Alternatively, the hybridization step can be performed at 65EC in the presence of SSC buffer, 1×SSC corresponding to 0.15M NaCl and 0.05 M Na citrate. Subsequently, filter washes can be done at 37EC for 1 h in a solution containing 2×SSC, 0.01% PVP, 0.01% Ficoll, and 0.01% BSA, followed by a wash in 0.1×SSC at 50EC for 45 min. Alternatively, filter washes can be performed in a solution containing 2×SSC and 0.1% SDS, or 0.5×SSC and 0.1% SDS, or 0.1×SSC and 0.1% SDS at 68EC for 15 minute intervals. Following the wash steps, the hybridized probes are detectable by autoradiography. Other conditions of high stringency which may be used are well known in the art and as cited in Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Press, N.Y., pp. 9.47-9.57; and Ausubel et al., 1989, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N.Y. are incorporated herein in their entirety. Preferably such polypeptide represents a homolog of a polypeptide encoded by ORF2 to ORF1297. Preferably, such sequences encode a homolog of a polypeptide encoded by one of ORF2 to ORF1297. In one embodiment, such sequences encode a Chlamydia pneumoniae polypeptide.

[0082] (ii) By way of example and not limitation, procedures using conditions of intermediate stringency are as follows: Filters containing DNA are prehybridized, and then hybridized at a temperature of 60EC in the presence of a 5×SSC buffer and labeled probe. Subsequently, filters washes are performed in a solution containing 2×SSC at 50EC and the hybridized probes are detectable by autoradiography. Other conditions of intermediate stringency which may be used are well known in the art and as cited in Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Press, N.Y., pp. 9.47-9.57; and Ausubel et al., 1989, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N.Y. are incorporated herein in their entirety. Preferably, such sequences encode a homolog of a polypeptide encoded by one of ORF2 to ORF1297. In one embodiment, such sequences encode a Chlamydia pneumoniae polypeptide.

[0083] d) a fragment of at least 5 amino acids of a polypeptide according to the invention, or as defined in a), b) or c);

[0084] e) a biologically active fragment of a polypeptide according to the invention, or as defined in a), b), c) or d); and

[0085] f) a modified polypeptide of a polypeptide according to the invention, as defined in a), b), c),d) ore).

[0086] In the present description, the terms polypeptide, peptide and protein are interchangeable.

[0087] It should be understood that the invention does not relate to the polypeptides in natural form, that is to say that they are not taken in their natural environment but that they may have been isolated or obtained by purification from natural sources, or alternatively obtained by genetic recombination, or else by chemical synthesis and that they may, in this case, comprise nonnatural amino acids, as will be described below.

[0088] Homologous polypeptide will be understood to designate the polypeptides exhibiting, in relation to the natural polypeptide, certain modifications such as in particular a deletion, addition or substitution of at least one amino acid, a truncation, an extension, a chimeric fusion, and/or a mutation, or polypeptides exhibiting post-translational modifications. Among the homologous polypeptides, those whose amino acid sequence exhibits at least 80%, preferably 90%, homology or identity with the amino acid sequences of the polypeptides according to the invention are preferred. In the case of a substitution, one or more consecutive or nonconsecutive amino acids are replaced by “equivalent” amino acids. The expression “equivalent” amino acid is intended here to designate any amino acid capable of being substituted for one of the amino acids in the basic structure without, however, essentially modifying the biological activities of the corresponding peptides and as will be defined later.

[0089] Protein and/or nucleic acid sequence homologies may be evaluated using any of the variety of sequence comparison algorithms and programs known in the art. Such algorithms and programs include, but are by no means limited to, TBLASTN, BLASTP, FASTA, TFASTA, and CLUSTALW (Pearson and Lipman, 1988, Proc. Natl. Acad. Sci. USA 85(8):2444-2448; Altschul et al., 1990, J. Mol. Biol. 215(3):403-410; Thompson et al., 1994, Nucleic Acids Res. 22(2):4673-4680; Higgins et al., 1996, Methods Enzymol. 266:383-402; Altschul et al., 1990, J. Mol. Biol. 215(3):403-410; Altschul et al., 1993, Nature Genetics 3:266-272).

[0090] In a particularly preferred embodiment, protein and nucleic acid sequence homologies are evaluated using the Basic Local Alignment Search Tool (“BLAST”) which is well know in the art (see, e.g., Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. USA 87:2267-2268; Altschul et al., 1990, J. Mol. Biol. 215:403-410; Altschul et al., 1993, Nature Genetics 3:266-272; Altschul et al., 1997, Nuc. Acids Res. 25:3389-3402). In particular, five specific BLAST programs are used to perform the following task:

[0091] (1) BLASTP and BLAST3 compare an amino acid query sequence against a protein sequence database;

[0092] (2) BLASTN compares a nucleotide query sequence against a nucleotide sequence database;

[0093] (3) BLASTX compares the six-frame conceptual translation products of a query nucleotide sequence (both strands) against a protein sequence database;

[0094] (4) TBLASTN compares a query protein sequence against a nucleotide sequence database translated in all six reading frames (both strands); and

[0095] (5) TBLASTX compares the six-frame translations of a nucleotide query sequence against the six-frame translations of a nucleotide sequence database.

[0096] The BLAST programs identify homologous sequences by identifying similar segments, which are referred to herein as “high-scoring segment pairs,” between a query amino or nucleic acid sequence and a test sequence which is preferably obtained from a protein or nucleic acid sequence database. High-scoring segment pairs are preferably identified (i.e., aligned) by means of a scoring matrix, many of which are known in the art. Preferably, the scoring matrix used is the BLOSUM62 matrix (Gonnet et al., 1992, Science 256:1443-1445; Henikoff and Henikoff, 1993, Proteins 17:49-61). Less preferably, the PAM or PAM250 matrices may also be used (see, e.g., Schwartz and Dayhoff, eds., 1978, Matrices for Detecting Distance Relationships: Atlas of Protein Sequence and Structure, Washington: National Biomedical Research Foundation)

[0097] The BLAST programs evaluate the statistical significance of all high-scoring segment pairs identified, and preferably selects those segments which satisfy a user-specified threshold of significance, such as a user-specified percent homology. Preferably, the statistical significance of a high-scoring segment pair is evaluated using the statistical significance formula of Karlin (see, e.g., Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. USA 87:2267-2268).

[0098] Equivalent amino acids may be determined either based on their structural homology with the amino acids for which they are substituted, or on results of comparative tests of biological activity between the various polypeptides which may be carried out.

[0099] By way of example, there may be mentioned the possibilities of substitutions which may be carried out without resulting in a substantial modification of the biological activity of the corresponding modified polypeptides; the replacements, for example, of leucine with valine or isoleucine, of aspartic acid with glutamic acid, of glutamine with asparagine, of arginine with lysine, and the like, the reverse substitutions naturally being feasible under the same conditions.

[0100] The homologous polypeptides also correspond to the polypeptides encoded by the homologous nucleotide sequences as defined above and thus comprise in the present definition the mutated polypeptides or polypeptides corresponding to inter- or intra-species variations which may exist in Chlamydia, and which correspond in particular to truncations, substitutions, deletions and/or additions of at least one amino acid residue.

[0101] Biologically active fragment of a polypeptide according to the invention will be understood to designate in particular a polypeptide fragment, as defined below, exhibiting at least one of the characteristics of the polypeptides according to the invention, in particular in that it is:

[0102] capable of eliciting an immune response directed against Chlamydia pneumoniae; and/or

[0103] capable of being recognized by an antibody specific for a polypeptide according to the invention; and/or

[0104] capable of binding to a polypeptide or to a nucleotide sequence of Chlamydia pneumoniae; and/or

[0105] capable of modulating, regulating, inducing or inhibiting the expression of a gene of Chlamydia pneumoniae or one of its associated microorganisms, and/or capable of modulating the replication cycle of Chlamydia pneumoniae or one of its associated microorganisms in the host cell and/or organism; and/or

[0106] capable of generally exerting an even partial physiological activity, such as for example a structural activity (cellular envelope, ribosome), an enzymatic (metabolic) activity, a transport activity, an activity in the secretion or in the virulence.

[0107] A polypeptide fragment according to the invention is understood to designate a polypeptide comprising a minimum of 5 amino acids, preferably 10 amino acids or preferably 15 amino acids. It is to be understood that such fragments refer only to portions of polypeptides encoded by ORF2 to ORF1297 that are not currently listed in a publicly available database.

[0108] The polypeptide fragments according to the invention may correspond to isolated or purified fragments which are naturally present in Chlamydia pneumoniae or which are secreted by Chlamydia pneumoniae, or may correspond to fragments capable of being obtained by cleaving the said polypeptide with a proteolytic enzyme, such as trypsin or chymotrypsin or collagenase, or with a chemical reagent, such as cyanogen bromide (CNBr) or alternatively by placing the said polypeptide in a highly acidic environment, for example at pH 2.5. Such polypeptide fragments may be equally well prepared by chemical synthesis, using hosts transformed with an expression vector according to the invention containing a nucleic acid allowing the expression of the said fragments, placed under the control of appropriate elements for regulation and/or expression.

[0109] “Modified polypeptide” of a polypeptide according to the invention is understood to designate a polypeptide obtained by genetic recombination or by chemical synthesis as will be described below, exhibiting at least one modification in relation to the normal sequence. These modifications may in particular affect amino acids responsible for a specificity or for the efficiency of the activity, or responsible for the structural conformation, for the charge or for the hydrophobicity, and for the capacity for multimerization and for membrane insertion of the polypeptide according to the invention. It is thus possible to create polypeptides with an equivalent, an increased or a reduced activity, and with an equivalent, a narrower or a broader specificity. Among the modified polypeptides, there may be mentioned the polypeptides in which up to 5 amino acids may be modified, truncated at the N- or C-terminal end, or alternatively deleted, or else added.

[0110] As is indicated, the modifications of the polypeptide may have in particular the objective:

[0111] of making it capable of modulating, regulating, inhibiting or inducing the expression of a gene of Chlamydia, in particular of Chlamydia pneumoniae and its variants, or one of its associated microorganisms, and/or capable of modulating the replication cycle of Chlamydia, in particular of Chlamydia pneumoniae and its variants, or one of its associated microorganisms, in the host cell and/or organism,

[0112] of allowing its use in methods of biosynthesis or of biodegradation, or its incorporation into vaccine compositions,

[0113] of modifying its bioavailability as a compound for therapeutic use.

[0114] The said modified polypeptides may also be used on any cell or microorganism for which the said modified polypeptides will be capable of modulating, regulating, inhibiting or inducing gene expression, or of modulating the growth or the replication cycle of the said cell or of the said microorganism. The methods allowing demonstration of the said modulations on eukaryotic or prokaryotic cells are well known to persons skilled in the art. The said cells or microorganisms will be chosen, in particular, from tumour cells or infectious microorganisms and the said modified polypeptides may be used for the prevention or treatment of pathologies linked to the presence of the said cells or of the said microorganisms. It is also clearly understood that the nucleotide sequences encoding the said modified polypeptides may be used for the said modulations, for example by the intermediacy of vectors according to the invention and which are described below, so as to prevent or to treat the said pathologies.

[0115] The above modified polypeptides may be obtained using combinatory chemistry, in which it is possible to systematically vary portions of the polypeptide before testing them on models, cell cultures or microorganisms for example, so as to select the compounds which are the most active or which exhibit the desired properties.

[0116] Chemical synthesis also has the advantage of being able to use:

[0117] nonnatural amino acids, or

[0118] nonpeptide bonds.

[0119] Accordingly, in order to extend the life of the polypeptides according to the invention, it may be advantageous to use nonnatural amino acids, for example in the D form, or alternatively amino acid analogues, in particular sulphur-containing forms for example.

[0120] Finally, the structure of the polypeptides according to the invention, its homologous or modified forms, as well as the corresponding fragments may be integrated into chemical structures of the polypeptide type and the like. Accordingly, it may be advantageous to provide at the N- and C-terminal ends compounds which are not recognized by proteases.

[0121] Also forming part of the invention are the nucleotide sequences encoding a polypeptide according to the invention. Described below are ORF nucleotide sequences encoding polypeptides exhibiting particularly preferable characteristics. For each group of preferred ORFS described below, it is to be understood that in addition to the individual ORFs listed, in instances wherein such ORFS are present as part of “combined” ORFs, the “combined” ORFs are also to be included within the preferred group.

[0122] More particularly, the subject of the invention is nucleotide sequences, characterized in that they encode a polypeptide of the cellular envelope, preferably of the outer cellular envelope of Chlamydia pneumoniae or one of its representative fragments, such as for example the predominant proteins of the outer membrane, the adhesion proteins or the proteins entering into the composition of the Chlamydia wall. Among these sequences, the sequences comprising a nucleotide sequence chosen from the following sequences are most preferred:

[0123] ORF15; ORF25; ORF26; ORF27; ORF28; ORF29; ORF30; ORF31; ORF32; ORF33; ORF35; ORF68; ORF124; ORF275; ORF291; ORF294; ORF327; ORF342; ORF364; ORF374; ORF380; ORF414; ORF439; ORF466; ORF467; ORF468; ORF469; ORF470; ORF472; ORF474; ORF476; ORF477; ORF478; ORF479; ORF480; ORF482; ORF485; ORF500; ORF501; ORF503; ORF504; ORF505; ORF506; ORF520; ORF578; ORF580; ORF581; ORF595; ORF596; ORF597; ORF737; ORF830; ORF834; ORF836; ORF893; ORF917; ORF932; ORF976; ORF1035; ORF1045; ORF1090 and one of their representative fragments.

[0124] The structure of the cytoplasmic membranes and of the wall of bacteria is dependent on the associated proteins. The structure of the cytoplasmic membrane makes it impermeable to water, to water-soluble substances and to small-sized molecules (ions, small inorganic molecules, peptides or proteins). To enter into or to interfere with a cell or a bacterium, a ligand must establish a special relationship with a protein anchored in the cytoplasmic membrane (the receptor). These proteins which are anchored on the membrane play an important role in metabolism since they control the exchanges in the bacterium. These exchanges apply to molecules of interest for the bacterium (small molecules such as sugars and small peptides) as well as undesirable molecules for the bacterium such as antibiotics or heavy metals.

[0125] The double lipid layer structure of the membrane requires the proteins which are inserted therein to have hydrophobic domains of about twenty amino acids forming an alpha helix. Predominantly hydrophobic and potentially transmembrane regions may be predicted from the primary sequence of the proteins, itself deduced from the nucleotide sequence. The presence of one or more putative transmembrane domains raises the possibility for a protein to be associated with the cytoplasmic membrane and to be able to play an important metabolic role therein or alternatively for the protein thus exposed to be able to exhibit potentially protective epitopes.

[0126] If the proteins inserted into the membrane exhibit several transmembrane domains capable of interacting with one another via electrostatic bonds, it then becomes possible for these proteins to form pores which go across the membrane which becomes permeable for a number of substances. It should be noted that proteins which do not have transmembrane domains may also be anchored by the intermediacy of fatty acids in the cytoplasmic membrane, it being possible for the breaking of the bond between the protein and its anchor in some cases to be responsible for the release of the peptide outside the bacterium.

[0127] Preferably, the invention relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae transmembrane polypeptide or one of its representative fragments, having between 1 and 3 transmembrane domains and in that they comprise a nucleotide sequence chosen from the following sequences: ORF2; ORF3; ORF6; ORF9; ORF10; ORF11; ORF13; ORF14; ORF16; ORF18; ORF19; ORF20; ORF21; ORF22; ORF25; ORF27; ORF28; ORF29; ORF30; ORF31; ORF32; ORF33; ORF34; ORF35; ORF37; ORF39; ORF41; ORF42; ORF44; ORF45; ORF46; ORF47; ORF48; ORF49; ORF50; ORF53; ORF54; ORF56; ORF57; ORF59; ORF60; ORF61; ORF62; ORF63; ORF64; ORF65; ORF66; ORF 69; ORF72; ORF73; ORF74; ORF76; ORF77; ORF78; ORF79; ORF80; ORF82; ORF84; ORF85; ORF86; ORF88; ORF89; ORF90; ORF91; ORF92; ORF93; ORF95; ORF96; ORF98; ORF99; ORF100; ORF101; ORF102; ORF103; ORF104; ORF105; ORF106; ORF107; ORF108; ORF114; ORF117; ORF118; ORF122; ORF123; ORF124; ORF125; ORF129; ORF130; ORF131; ORF132; ORF133; ORF134; ORF135; ORF137; ORF138; ORF139; ORF140; ORF141; ORF142; ORF143; ORF 145; ORF146; ORF147; ORF150; ORF151; ORF152; ORF 156; ORF157; ORF158; ORF159; ORF160; ORF161; ORF162; ORF164; ORF166; ORF167; ORF170; ORF173; ORF175; ORF176; ORF178; ORF179; ORF180; ORF182; ORF183; ORF184; ORF185; ORF186; ORF187; ORF188; ORF189; ORF190; ORF191; ORF192; ORF194; ORF195; ORF 196; ORF197; ORF198; ORF199; ORF200; ORF201; ORF202; ORF205; ORF207; ORF208; ORF209; ORF210; ORF212; ORF215; ORF219; ORF220; ORF224; ORF226; ORF227; ORF228; ORF231; ORF232; ORF233; ORF234; ORF235; ORF236; ORF238; ORF239; ORF240; ORF241; ORF242; ORF244; ORF247; ORF251; ORF252; ORF253; ORF255; ORF256; ORF257; ORF258; ORF260; ORF262; ORF263; ORF266; ORF267; ORF268; ORF269; ORF270; ORF273; ORF274; ORF276; ORF278; ORF279; ORF280; ORF281; ORF282; ORF283; ORF284; ORF286; ORF287; ORF289; ORF290; ORF291; ORF293; ORF294; ORF297; ORF304; ORF305; ORF307; ORF308; ORF309; ORF310; ORF311; ORF313; ORF314; ORF315; ORF316; ORF318; ORF319; ORF320; ORF321; ORF322; ORF323; ORF324; ORF325; ORF326; ORF331; ORF332; ORF336; ORF338; ORF339; ORF341; ORF344; ORF345; ORF346; ORF350; ORF352; ORF353; ORF356; ORF357; ORF358; ORF359; ORF360; ORF362; ORF365; ORF366; ORF367; ORF370; ORF372; ORF373; ORF376; ORF377; ORF378; ORF379; ORF381; ORF382; ORF383; ORF384; ORF385; ORF386; ORF387; ORF390; ORF392; ORF393; ORF394; ORF396; ORF398; ORF399; ORF400; ORF404; ORF408; ORF410; ORF411; ORF413; ORF416; ORF417; ORF418; ORF420; ORF422; ORF424; ORF427; ORF428; ORF429; ORF430; ORF431; ORF433; ORF434; ORF437; ORF440; ORF441; ORF442; ORF443; ORF444; ORF445; ORF447; ORF450; ORF451; ORF452; ORF455; ORF456; ORF459; ORF460; ORF461; ORF462; ORF463; ORF464; ORF465; ORF467; ORF469; ORF471; ORF474; ORF475; ORF476; ORF477; ORF479; ORF482; ORF483; ORF484; ORF485; ORF486; ORF487; ORF488; ORF491; ORF493; ORF494; ORF497; ORF498; ORF499; ORF503; ORF508; ORF509; ORF510; ORF512; ORF514; ORF515; ORF516; ORF517; ORF518; ORF520; ORF521; ORF523; ORF525; ORF527; ORF528; ORF529; ORF530; ORF531; ORF533; ORF534; ORF535; ORF536; ORF537; ORF540; ORF541; ORF543; ORF544; ORF545; ORF546; ORF548; ORF549; ORF551; ORF553; ORF554; ORF555; ORF556; ORF557; ORF558; ORF559; ORF560; ORF562; ORF563; ORF564; ORF565; ORF566; ORF569; ORF571; ORF573; ORF576; ORF577; ORF581; ORF583; ORF584; ORF585; ORF586; ORF588; ORF591; ORF592; ORF594; ORF595; ORF596; ORF597; ORF599; ORF600; ORF603; ORF605; ORF608; ORF614; ORF615; ORF620; ORF621; ORF622; ORF623; ORF624; ORF625; ORF629; ORF630; ORF631; ORF633; ORF634; ORF637; ORF642; ORF644; ORF645; ORF647; ORF648; ORF652; ORF654; ORF655; ORF657; ORF658; ORF659; ORF660; ORF661; ORF664; ORF665; ORF666; ORF667; ORF670; ORF671; ORF672; ORF673; ORF674; ORF676; ORF679; ORF681; ORF684; ORF687; ORF688; ORF689; ORF690; ORF693; ORF694; ORF695; ORF696; ORF697; ORF698; ORF699; ORF700; ORF701; ORF703; ORF705; ORF706; ORF707; ORF708; ORF710; ORF712; ORF715; ORF716; ORF717; ORF718; ORF719; ORF721; ORF722; ORF723; ORF725; ORF726; ORF727; ORF728; ORF729; ORF730; ORF731; ORF733; ORF736; ORF737; ORF738; ORF740; ORF741; ORF742; ORF743; ORF747; ORF748; ORF750; ORF752; ORF754; ORF755; ORF756; ORF757; ORF759; ORF760; ORF761; ORF762; ORF763; ORF764; ORF765; ORF766; ORF767; ORF768; ORF772; ORF774; ORF775; ORF777; ORF781; ORF783; ORF788; ORF791; ORF792; ORF793; ORF794; ORF795; ORF796; ORF797; ORF798; ORF799; ORF802; ORF803; ORF806; ORF807; ORF808; ORF809; ORF810; ORF811; ORF813; ORF814; ORF815; ORF816; ORF817; ORF819; ORF820; ORF821; ORF823; ORF824; ORF827; ORF829; ORF830; ORF831; ORF833; ORF834; ORF835; ORF837; ORF844; ORF845; ORF846; ORF847; ORF848; ORF849; ORF850; ORF851; ORF852; ORF854; ORF855; ORF856; ORF857; ORF859; ORF860; ORF862; ORF865; ORF866; ORF868; ORF869; ORF870; ORF871; ORF872; ORF874; ORF877; ORF878; ORF879; ORF880; ORF881; ORF882; ORF884; ORF885; ORF888; ORF889; ORF890; ORF891; ORF892; ORF894; ORF895; ORF896; ORF897; ORF899; ORF900; ORF902; ORF903; ORF904; ORF905; ORF909; ORF910; ORF912; ORF913; ORF914; ORF915; ORF917; ORF918; ORF919; ORF921; ORF923; ORF924; ORF926; ORF927; ORF928; ORF929; ORF930; ORF931; ORF937; ORF938; ORF939; ORF941; ORF943; ORF948; ORF951; ORF952; ORF953; ORF958; ORF960; ORF963; ORF964; ORF965; ORF968; ORF970; ORF974; ORF975; ORF977; ORF979; ORF980; ORF981; ORF983; ORF984; ORF985; ORF987; ORF989; ORF992; ORF993; ORF997; ORF998; ORF999; ORF1001; ORF1002; ORF1004; ORF1005; ORF1009; ORF1013; ORF1014; ORF1015; ORF1016; ORF1019; ORF1021; ORF1023; ORF1024; ORF1029; ORF1031; ORF1033; ORF1034; ORF1039; ORF1041; ORF1042; ORF1045; ORF1047; ORF1049; ORF1051; ORF1052; ORF1053; ORF1054; ORF1056; ORF1059; ORF1061; ORF1062; ORF1063; ORF1064; ORF1065; ORF1067; ORF1075; ORF1077; ORF1078; ORF1079; ORF1080; ORF1081; ORF1089; ORF1095; ORF1097; ORF1098; ORF1099; ORF1101; ORF1102; ORF1103; ORF1106; ORF1107; ORF1108; ORF1109; ORF1110; ORF1113; ORF1116; ORF1118; ORF1119; ORF1121; ORF1123; ORF1124; ORF1126; ORF1128; ORF1130; ORF1131; ORF1133; ORF1134; ORF1136; ORF 1137 and one of their representative fragments.

[0128] Preferably, the invention relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae transmembrane polypeptide or one of its representative fragments, having between 4 and 6 transmembrane domains and in that they comprise a nucleotide sequence chosen from the following sequences:

[0129] ORF5; ORF7; ORF8; ORF15; ORF36; ORF38; ORF51; ORF55; ORF58; ORF67; ORF70; ORF81; ORF97; ORF110; ORF111; ORF115; ORF119; ORF126; ORF128; ORF148; ORF155; ORF163; ORF165; ORF168; ORF169; ORF171; ORF172; ORF174; ORF177; ORF181; ORF193; ORF203; ORF213; ORF214; ORF216; ORF217; ORF221; ORF222; ORF225; ORF229; ORF243; ORF246; ORF248; ORF254; ORF261; ORF285; ORF288; ORF292; ORF296; ORF298; ORF299; ORF301; ORF303; ORF317; ORF328; ORF329; ORF351; ORF354; ORF355; ORF364; ORF371; ORF374; ORF375; ORF391; ORF395; ORF401; ORF403; ORF405; ORF409; ORF414; ORF419; ORF421; ORF423; ORF425; ORF438; ORF448; ORF453; ORF458; ORF466; ORF468; ORF470; ORF480; ORF489; ORF490; ORF496; ORF501; ORF504; ORF505; ORF506; ORF511; ORF513; ORF519; ORF526; ORF532; ORF538; ORF539; ORF547; ORF550; ORF561; ORF568; ORF570; ORF574; ORF578; ORF579; ORF580; ORF582; ORF589; ORF593; ORF598; ORF601; ORF604; ORF610; ORF613; ORF617; ORF626; ORF632; ORF635; ORF638; ORF640; ORF641; ORF646; ORF649; ORF650; ORF651; ORF686; ORF711; ORF724; ORF732; ORF734; ORF744; ORF745; ORF749; ORF751; ORF769; ORF770; ORF771; ORF773; ORF776; ORF779; ORF780; ORF785; ORF787; ORF789; ORF801; ORF805; ORF812; ORF822; ORF825; ORF826; ORF839; ORF841; ORF843; ORF853;:ORF861; ORF875; ORF876; ORF886; ORF893; ORF898; ORF906; ORF907; ORF908; ORF920; ORF922; ORF925; ORF933; ORF935; ORF936; ORF944; ORF946; ORF947; ORF954; ORF959; ORF961; ORF966; ORF967; ORF972; ORF978; ORF995; ORF996; ORF1000; ORF1003; ORF1010; ORF1011; ORF1012; ORF1017; ORF1020; ORF1030; ORF1036; ORF1038; ORF1043; ORF1046; ORF1048; ORF1050; ORF1058; ORF1071; ORF1073; ORF1084; ORF1085; ORF1086; ORF1087; ORF1091; ORF1092; ORF1094; ORF1096; ORF110; ORF1104; ORF1111; ORF1112; ORF1114; ORF1117; ORF1122; ORF1125 and one of their representative fragments.

[0130] Preferably, the invention also relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae transmembrane polypeptide or one of its representative fragments, having at least 7 transmembrane domains and in that they comprise a nucleotide sequence chosen from the following sequences:

[0131] ORF17; ORF52; ORF68; ORF83; ORF87; ORF109; ORF112; ORF113; ORF120; ORF121; ORF127; ORF153; ORF204; ORF211; ORF218; ORF223; ORF275; ORF277; ORF295; ORF300; ORF302; ORF306; ORF327; ORF335; ORF342; ORF343; ORF347; ORF349; ORF361; ORF363; ORF369; ORF380; ORF388; ORF389; ORF397; ORF415; ORF432; ORF439; ORF446; ORF449; ORF472; ORF478; ORF500; ORF522; ORF524; ORF567; ORF575; ORF602; ORF606; ORF609; ORF636; ORF639; ORF643; ORF653; ORF668; ORF692; ORF702; ORF704; ORF713; ORF720; ORF778; ORF784; ORF800; ORF836; ORF838; ORF842; ORF864; ORF867; ORF883; ORF901; ORF916; ORF932; ORF934; ORF940; ORF942; ORF950; ORF956; ORF971; ORF973; ORF976; ORF988; ORF994; ORF1018; ORF1028; ORF1035; ORF1037; ORF1044; ORF1055; ORF1057; ORF1068; ORF1069; ORF1070; ORF1072; ORF1082; ORF1088; ORF1105; ORF1132; ORF1135 and one of their representative fragments.

[0132] Preferably, the invention relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae surface exposed polypeptide (e.g., an outer membrane protein) or one of its representative fragments, said nucleotide sequences comprising a nucleotide sequence chosen from the following sequences:

[0133] ORF 15, ORF 25, ORF 26, ORF 27, ORF 28, ORF 29, ORF 30, ORF 31, ORF 32, ORF 33, ORF 35, ORF 36, ORF 1257, ORF 280, ORF 291, ORF 314, ORF 354, ORF 380, ORF 1266, ORF 466, ORF 467, ORF 468, ORF 469, ORF 470, ORF 472, ORF 474, ORF 476, ORF 477, ORF 478, ORF 479, ORF 480, ORF 482, ORF 483, ORF 485, ORF 486, ORF 500, ORF 501, ORF 503, ORF 504, ORF 505, ORF 506, ORF 507, ORF 1268, ORF 1269, ORF 543, ORF 544, ORF 578, ORF 579, ORF 580, ORF 581, ORF 595, ORF 596, ORF 597, ORF 1271, ORF 633, ORF 637, ORF 699, ORF 706, ORF 737, ORF 744, ORF 1273, ORF 751, ORF 775, ORF 776, ORF 777, ORF 793, ORF 815, ORF 830, ORF 1221, ORF 849, ORF 851, ORF 852, ORF 874, ORF 891, ORF 922, ORF 940, ORF 1231, ORF 1281, ORF 1035, ORF 1079, ORF 1087, ORF 1108, and one of their representative fragments.

[0134] Preferably, the invention relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae lipoprotein or one of its representative fragments, said nucleotide sequences comprising a nucleotide sequence chosen from the following sequences:

[0135] ORF 3, ORF 10, ORF 11, ORF 16, ORF 1254, ORF 1255, ORF 38, ORF 1256, ORF 62, ORF 85, ORF 1258, ORF 115, ORF 1151, ORF 151, ORF 1259, ORF 173, ORF 1261, ORF 186, ORF 194, ORF 205, ORF 214, ORF 216, ORF 217, ORF 238, ORF 1177, ORF 280, ORF 291, ORF 317, ORF 327, ORF 354, ORF 364, ORF 367, ORF 414, ORF 432, ORF 1192, ORF 460, ORF 1267, ORF 1268, ORF 520, ORF 536, ORF 1270, ORF 576, ORF 597, ORF 603, ORF 609, ORF 637, ORF 1272, ORF 652, ORF 1213, ORF 699, ORF 705, ORF 706, ORF 708, ORF 711, ORF 727, ORF 1274, ORF 800, ORF 814, ORF 825, ORF 829, ORF 830, ORF 831, ORF 844, ORF 849, ORF 1275, ORF 1276, ORF 1277, ORF 872, ORF 878, ORF 880, ORF 891, ORF 892, ORF 1278, ORF 1279, ORF 1280, ORF 941, ORF 942, ORF 1282, ORF 1283, ORF 952, ORF 988, ORF 998, ORF 1009, ORF 1285, ORF 1235, ORF 1028, ORF 1056, ORF 1070, ORF 1287, ORF 1087, ORF 1288, ORF 1289, ORF 1098, ORF 1246, ORF 1291, ORF 1108, ORF 1109, ORF 1112, ORF 1133, and one of their representative fragments.

[0136] Preferably, the invention relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae polypeptide involved in lipopolysaccharide (LPS) biosynthesis, said nucleotide sequences comprising a nucleotide sequence chosen from the following sequences: ORF 316, ORF 564, ORF 610, ORF 647, ORF 1211, ORF 688, ORF 924, and one of their representative fragments.

[0137] Preferably the invention relates to additional LPS-related nucleotide sequences according to the invention, characterized in that they encode:

[0138] (a) a Chlamydia pneumoniae KDO (3-deoxy-D-manno-octulosonic acid)-related polypeptide or one of its representative fragments, said nucleotide sequences comprising a nucleotide sequence chosen from the following sequences: ORF 177, ORF 1156, ORF 245, ORF 767, and one of their representative fragments;

[0139] (b) a Chlamydia pneumoniae phosphomannomutase-related polypeptide or one of its representative fragments, said nucleotide sequences comprising a nucleotide sequence chosen from the following sequences: ORF 74, and one of its representative fragments;

[0140] (c) a Chlamydia pneumoniae phosphoglucomutase-related polypeptide or one of its representative fragments, said nucleotide sequences comprising a nucleotide sequence chosen from the following sequences: ORF 1286, ORF 1039, and one of their representative fragments; and

[0141] (d) a Chlamydia pneumoniae lipid A component-related polypeptide or one of its representative fragments, said nucleotide sequences comprising a nucleotide sequence chosen from the following sequences: ORF 689, ORF 690, ORF 691, ORF 1037, and one of their representative fragments.

[0142] Preferably, the invention relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae polypeptide containing RGD (Arg-Gly-Asp) attachment sites or one of its representative fragments.

[0143] (a) RGD-containing proteins that are outer membrane proteins, are more likely to play a role in cell attachment. ORFs that encoded a protein containing an RGD sequence and also were classified as outer membrane proteins are ORF 468 and its representative fragments.

[0144] An RGD-encoding ORF that showed homology to cds1, cds2, and copN type III virulence loci in Chlamydia psittaci (Hsia, R. et al. (1997), Type III secretion genes identity a putative virulence locus of Chlamydia. Molecular Microbiology 25:351-359) is ORF 350, and its representative fragments.

[0145] (c) The outer membrane of Chlamydia is made of cysteine-rich proteins that form a network of both intra and inter molecular disulfide links. This contributes to the integrity of the membrane since Chlamydia lacks the peptidoglycan layer that other gram-negative bacteria have. Cysteine-rich proteins that have the RGD sequence are also considered to be potential vaccine candidates. Cysteine-rich proteins were defined as proteins that had more than 3.0% cysteine in their primary amino acid sequence, above the mean genomic ORF cysteine content. The corresponding ORFs are: ORF 1290, ORF 1294, ORF 1296, and one of their representative fragments.

[0146] (d) The outer membrane of Chlamydia may also contain small proteins that have cysteines in their N- and C-terminus that may contribute to the network formed by disulfide linkages. These proteins may be anchored in the outer membrane via their N-terminus and may have their C-terminus exposed, which then can interact with the host cells. Alternatively, these proteins may be anchored in the outer membrane via both N- and C-terminus and may have regions in the middle that may be exposed which can in turn interact with the host cells. ORFs encoding polypeptides that contain cysteines in their first 30 amino acids and also contain an RGD sequence are:

[0147] ORF 105, ORF 106, ORF 114, ORF 170, ORF 171, ORF 1264, ORF 268, ORF 1265, ORF 350, ORF 393, ORF 394, ORF 451, ORF 452, ORF 453, ORF 473, ORF 499, ORF 515, ORF 519, ORF 525, ORF 526, ORF 538, ORF 611, ORF 645, ORF 686, ORF 700, ORF 746, ORF 755, ORF 756, ORF 757, ORF 789, ORF 814, ORF 855, ORF 856, ORF 878, ORF 957, ORF 958, ORF 989, ORF 1290, and one of their representative fragments.

[0148] (e) RGD-containing ORFs homologous to RGD-containing ORFs from Chlamydia trachomatis are:

[0149] ORF 114, ORF 468, ORF 755, ORF 756, ORF 757, ORF 855, ORF 856, ORF 905, ORF 913, ORF 914, ORF 915, and one of their representative fragments.

[0150] Preferably, the invention relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae Type III or other, non-type III secreted polypeptide or one of its representative fragments, said nucleotide sequences comprising a nucleotide sequence chosen from the following sequences:

[0151] ORF 25, ORF 28, ORF 29, ORF 33, ORF 308, ORF 309, ORF 343, ORF 344, ORF 345, ORF 367, ORF 414, ORF 415, ORF 480, ORF 550, ORF 579, ORF 580, ORF 581, ORF 597, ORF 699, ORF 744, ORF 751, ORF 776, ORF 866, ORF 874, ORF 883, ORF 884, ORF 888, ORF 891, ORF 1293, and one of their representative fragments.

[0152] Preferably, the invention relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae cell wall anchored surface polypeptide or one of its representative fragments, said nucleotide sequences comprising a nucleotide sequence chosen from the following sequences: ORF 267, ORF 271, ORF 419, ORF 590, ORF 932, ORF 1292, ORF 1295, and one of their representative fragments.

[0153] Preferably, the invention relates to the nucleotide sequences according to the invention, characterized in that they encode Chlamydia pneumoniae polypeptides not found in Chlamydia trachomatis (Blastp. P>e−10), said nucleotide sequences comprising a nucleotide sequence chosen from the following sequences: ORF 7, ORF 8, ORF 9, ORF 16, ORF 17, ORF 18, ORF 19, ORF 20, ORF 21, OR 22, ORF 1254, ORF 23, ORE 1255, ORE 24, ORF 1139, ORF 1140, ORF 46, ORF 47, ORF 51, ORE 60, ORE 1256, ORE 61, ORE 62, ORF 63, ORE 64, ORF 1257, ORE 65, ORF 66, ORF 67, ORF 68, ORF 1143, ORF 1145, ORF 83, ORE 84, ORE 1146, ORF 85, ORF 86, ORE 87, ORE 1258, ORE 116, ORE 117, ORE 125, ORE 1148, ORE 143, ORF 1150, ORF 1151, ORF 144, ORE 145, ORF 147, ORF 148, ORE 149, ORF 150, ORF 152, ORE 1259, ORE 162, ORF 166, ORF 1154, ORF 167, ORF 1261, ORE 1156, ORF 1157, ORF 178, ORE 179, ORF 1158, ORF 182, ORF 183, ORE 184, ORE 185, ORF 1159, ORF 186, ORE 1160, ORF 187, ORF 188, ORF 189,ORE 190, ORE 1161, ORF 1162, ORE 191, ORF 192, ORF 194, ORE 195, ORE 1163, ORF 196, ORE 201, ORE 202, ORF 209, ORE 212, ORF 221, ORF 224, ORF 1167, ORF 226, ORE 227, ORE 228, ORF 229, ORE 230, ORF 231, ORF 232, ORF 1169, ORF 1170, ORE 1171, ORF 234, ORF 235, ORE 236, ORE 1172, ORF 243, ORF 251, ORE 252, ORE 1176, ORE 253, ORF 255, ORF 254, ORE 256, ORE 1177, ORF 1178, ORF 262, ORF 263, ORF 1264, ORF 278, ORF 279, ORF 1180, ORF 280, ORF 290, ORF 291, ORF 292, ORF 296, ORF 1181, ORF 297, ORF 298, ORF 300, ORF 1265, ORF 322, ORF 324, ORF 325, ORF 370, ORF 1186, ORF 371, ORF 372, ORF 1187, ORF 373, ORF 378, ORF 1266, ORF 382, ORF 383, ORF 384, ORF 385, ORF 386, ORF 1188, ORF 1189, ORF 391, ORF 392, ORF 398, ORF 400, ORF 403, ORF 1191, ORF 423, ORF 435, ORF 445, ORF 450, ORF 1193, ORF 456, ORF 460, ORF 461, ORF 465, ORF 1196, ORF 471, ORF 473, ORF 475, ORF 481, ORF 484, ORF 487, ORF 488, ORF 489, ORF 490, ORF 491, ORF 492, ORF 493, ORF 494, ORF 495, ORF 496, ORF 497, ORF 498, ORF 499, ORF 502, ORF 1267, ORF 1268, ORF 508, ORF 510, ORF 509, ORF 512, ORF 515, ORF 519, ORF 1197, ORF 521, ORF 1198, ORF 522, ORF 524, ORF 528, ORF 534, ORF 537, ORF 1269, ORF 1270, ORF 548, ORF 551, ORF 557, ORF 1201, ORF 1203, ORF 562, ORF 566, ORF 593, ORF 595, ORF 600, ORF 1271, ORF 604, ORF 611, ORF 612, ORF 614, ORF 616, ORF 625, ORF 627, ORF 628, ORF 629, ORF 631, ORF 641, ORF 1272, ORE 648, ORF 1212, ORF 663, ORF 685, ORF 707, ORF 714, ORF 715, ORF 716, ORF 717, ORF 722, ORF 746, ORF 1273, ORF 761, ORF 764, ORF 770, ORF 1217, ORF 783, ORF 1274, ORF 803, ORF 815, ORF 1220, ORF 835, ORF 1221, ORE 844, ORF 845, ORF 846, ORF 847, ORF 848, ORF 849, ORF 850, ORF 851, ORF 1275, ORF 852, ORF 862, ORF 1276, ORF 1277, ORF 873, ORF 1223, ORF 892, ORF 919, ORF 1225, ORF 1278, ORF 926, ORF 1228, ORF 1229, ORF 1230, ORF 1279, ORF 1281, ORF 1282, ORF 1283, ORF 948, ORF 950, ORF 949, ORF 951, ORF 980, ORF 982, ORF 1233, ORF 999, ORF 1000, ORF 1001, ORF 1002, ORF 1008, ORF 1285, ORF 1235, ORF 1016, ORF 1019, ORF 1027, ORF 1036, ORF 1241, ORF 1048, ORF 1049, ORF 1050, ORF 1053, ORF 1054, ORF 1064, ORF 1076, ORF 1091, ORF 1288, ORF 1093, ORF 1289, ORF 1101, ORF 1103, ORF 1245, ORF 1246, ORF 1247, ORF 1290, ORF 1291, ORF 1115, ORF 1116, ORF 1118, ORF 1120, ORF 1249, ORF 1121, ORF 1250, ORF 1126, ORF 1125, ORF 1127, ORF 1128, ORF 1130, ORF 1129, ORF 1131, ORF 1136, ORF 1253, ORF 1292, ORF 1294, ORF 1295, ORF 1296, and one of their representative fragments.

[0154] Preferably, the invention also relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the intermediate metabolism, in particular in the metabolism of sugars and/or of cofactors, such as for example triose phosphate isomerase or pyruvate kinase, and in that they comprise a nucleotide sequence chosen from the following sequences:

[0155] ORF2; ORF55; ORF56; ORF69; ORF75; ORF80; ORF100; ORF110; ORF114; ORF120; ORF121; ORF157; ORF160; ORF161; ORF172; ORF180; ORF181; ORF198; ORF200; ORF225; ORF248; ORF249; ORF276; ORF277; ORF318; ORF319; ORF320; ORF323; ORF331; ORF347; ORF375; ORF376; ORF381; ORF393; ORF394; ORF395; ORF396; ORF409; ORF446; ORF447; ORF448; ORF449; ORF513; ORF516; ORF571; ORF647; ORF662; ORF697; ORF718; ORF793; ORF794; ORF808; ORF809; ORF838; ORF839; ORF840; ORF853; ORF854; ORF918; ORF923; ORF929; ORF931; ORF938; ORF939; ORF958; ORF959; ORF960; ORF966; ORF995; ORF1021; ORF1040; ORF1041; ORF1042; ORF1085; ORF1100; ORF1102; ORF1117; ORF1118; ORF1119; ORF1120; ORF1135 and one of their representative fragments.

[0156] Preferably, the invention also relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the intermediate metabolism of nucleotides or nucleic acids, such as for example CTP synthetase or GMP synthetase, and in that they comprise a nucleotide sequence chosen from the following sequences:

[0157] ORF77; ORF78; ORF138; ORF189; ORF190; ORF233; ORF246; ORF338; ORF412; ORF421; ORF438; ORF607; ORF648; ORF657; ORF740; ORF783; ORF967; ORF989; ORF990; ORF992; ORF1011; ORF1058; ORF1059; ORF1073; ORF1074 and one of their representative fragments.

[0158] Preferably, the invention also relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the metabolism of nucleic acids, such as for example DNA polymerases or DNA topoisomerases, and in that they comprise a nucleotide sequence chosen from the following sequences:

[0159] ORF14; ORF59; ORF70; ORF71; ORF97; ORF113; ORF137; ORF141; ORF169; ORF285; ORF287; ORF288; ORF313; ORF326; ORF358; ORF411; ORF443; ORF548; ORF569; ORF601; ORF651; ORF654; ORF658; ORF659; ORF664; ORF665; ORF694; ORF698; ORF704; ORF760; ORF762; ORF763; ORF786; ORF787; ORF788; ORF801; ORF802; ORF812; ORF819; ORF822; ORF870; ORF897; ORF898; ORF902; ORF908; ORF916; ORF954; ORF955; ORF961; ORF983; ORF996; ORF1007; ORF1012; ORF1013; ORF1014; ORF1015; ORF1038; ORF1137 and one of their representative fragments.

[0160] Preferably, the invention also relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the metabolism of amino acids or polypeptides, such as for example serine hydroxymethyl transferase or the proteins which load amino acids onto transfer RNAs, and in that they comprise a nucleotide sequence chosen from the following sequences:

[0161] ORF99; ORF111; ORF127; ORF134; ORF140; ORF174; ORF175; ORF176; ORF353; ORF377; ORF404; ORF523; ORF539; ORF559; ORF561; ORF586; ORF598; ORF609; ORF636; ORF687; ORF700; ORF701; ORF759; ORF790; ORF857; ORF861; ORF904; ORF936; ORF952; ORF962; ORF963; ORF964; ORF965; ORF991; ORF1003; ORF1004; ORF1005; ORF1018; ORF1067; ORF1110; ORF1111; ORF1112; ORF1114; ORF1121; ORF1122; ORF1123; ORF1124; ORF1125 and one of their representative fragments.

[0162] Preferably, the invention also relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the metabolism of polypeptides, such as for example protein kinases or proteases, and in that they comprise a nucleotide sequence chosen from the following sequences:

[0163] ORF4; ORF44; ORF45; ORF48; ORF54; ORF112; ORF130; ORF155; ORF163; ORF212; ORF257; ORF307; ORF343; ORF405; ORF416; ORF458; ORF540; ORF541; ORF542; ORF543; ORF544; ORF560; ORF594; ORF652; ORF699; ORF723; ORF747; ORF817; ORF827; ORF871; ORF909; ORF910; ORF911; ORF912; ORF1023; ORF1051; ORF1052; ORF1081 and one of their representative fragments.

[0164] Preferably, the invention also relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the metabolism of fatty acids, such as for example succinyl-CoA-synthesizing proteins or phosphatidylserine synthetase, and in that they comprise a nucleotide sequence chosen from the following sequences:

[0165] ORF76; ORF284; ORF308; ORF309; ORF310; ORF311; ORF312; ORF425; ORF433; ORF565; ORF688; ORF690; ORF691; ORF767; ORF797; ORF894; ORF895; ORF994; ORF1020; ORF1030; ORF1033; ORF1034; ORF1046; ORF1047; ORF1057 and one of their representative fragments.

[0166] Preferably, the invention also relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the synthesis of the wall, such as for example KDO transferase, and the proteins responsible for the attachment of certain sugars onto the exposed proteins, and in that they comprise a nucleotide sequence chosen from the following sequences:

[0167] ORF49; ORF50; ORF177; ORF178; ORF245; ORF610; ORF972; ORF974; ORF978; ORF1037 and one of their representative fragments.

[0168] Preferably, the invention also relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the transcription, translation and/or maturation process, such as for example initiation factors, RNA polymerases or certain chaperone proteins, and in that they comprise a nucleotide sequence chosen from the following sequences:

[0169] ORF90; ORF92; ORF131; ORF151; ORF199; ORF333; ORF334; ORF336; ORF379; ORF589; ORF590; ORF619; ORF630; ORF649; ORF739; ORF741; ORF806; ORF821; ORF843; ORF968; ORF971; ORF1061 and one of their representative fragments.

[0170] Preferably, the invention also relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae ribosomal polypeptide or one of its representative fragments, such as for example the ribosomal proteins L21, L27 and S10, and in that they comprise a nucleotide sequence chosen from the following sequences:

[0171] ORF93; ORF94; ORF95; ORF136; ORF259; ORF332; ORF348; ORF583; ORF584; ORF588; ORF591; ORF592; ORF663; ORF666; ORF667; ORF669; ORF670; ORF671; ORF672; ORF673; ORF674; ORF675; ORF676; ORF677; ORF678; ORF679; ORF680; ORF681; ORF683; ORF684; ORF738; ORF781; ORF1008; ORF1024; ORF1025; ORF1066 and one of their representative fragments.

[0172] Preferably, the invention also relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae transport polypeptide or one of its representative fragments, such as for example the proteins for transporting amino acids, sugars and certain oligopeptides, and in that they comprise a nucleotide sequence chosen from the following sequences:

[0173] ORF40; ORF41; ORF52; ORF105; ORF106; ORF107; ORF109; ORF133; ORF210; ORF211; ORF214; ORF215; ORF216; ORF217; ORF218; ORF219; ORF220; ORF223; ORF242; ORF260; ORF293; ORF299; ORF366; ORF369; ORF575; ORF602; ORF638; ORF639; ORF640; ORF643; ORF653; ORF702; ORF703; ORF724; ORF732; ORF855; ORF856; ORF901; ORF906; ORF933; ORF942; ORF1043; ORF1086; ORF1105 and one of their representative fragments.

[0174] Preferably, the invention also relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the virulence process, such as for example the proteins analogous to the Escherichia coli vacB protein, and in that they comprise a nucleotide sequence chosen from the following sequences:

[0175] ORF546; ORF550; ORF778; ORF779; ORF886 and one of their representative fragments.

[0176] Preferably, the invention also relates to the nucleotide sequences according to the invention, characterized in that they encode a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the secretory system and/or which is secreted, such as for example proteins homologous to proteins in the secretory system of certain bacteria such as the Salmonellae or the Yersiniae, and in that they comprise a nucleotide sequence chosen from the following sequences:

[0177] ORF751; ORF874; ORF875; ORF876; ORF883; ORF884; ORF885 and one of their representative fragments.

[0178] Preferably, the invention also relates to a nucleotide sequence according to the invention, characterized in that they encode a polypeptide specific to Chlamydia pneumoniae or one of its representative fragments (with a Blast E value of >10−5), and in that they comprise a nucleotide sequence chosen from the following sequences:

[0179] ORF7; ORF8; ORF17; ORF18; ORF19; ORF20; ORF22; ORF23; ORF24; ORF51; ORF60; ORF63; ORF65; ORF66; ORF67; ORF83; ORF84; ORF86; ORF87; ORF125; ORF143; ORF144; ORF179; ORF182; ORF184; ORF185; ORF187; ORF221; ORF252; ORF254; ORF278; ORF279; ORF387; ORF388; ORF397; ORF1048; ORF1049; ORF1050; ORF1128; ORF1130; ORF1131 and one of their representative fragments.

[0180] Also forming part of the invention are polypeptides encoded by the polynucleotides of the invention, as well as fusion polypeptides comprising such polypeptides. In one embodiment, the polypeptides and fusion polypeptides immunoreact with seropositive serum of an individual infected with Chlamydia pneumoniae. For example, described below, are polypeptide sequences exhibiting particularly preferable characteristics. For each group of preferred polypeptides described below, it is to be understood that in addition to the individual polypeptides listed, in instances wherein such polypeptides are encoded as part of “combined” ORFs, such “combined” polypeptides are also to be included within the preferred group.

[0181] The subject of the invention is also a polypeptide according to the invention, characterized in that it is a polypeptide of the cellular envelope, preferably of the outer cellular envelope, of Chlamydia pneumoniae or one of its representative fragments. According to the invention, the said polypeptide is preferably chosen from the polypeptides having the following sequences:

[0182] SEQ ID No. 15; SEQ ID No. 25; SEQ ID No. 26; SEQ ID No. 27; SEQ ID No. 28; SEQ ID No. 29; SEQ ID No. 30; SEQ ID No. 31; SEQ ID No. 32; SEQ ID No. 33; SEQ ID No. 35; SEQ ID No. 68; SEQ ID No. 124; SEQ ID No. 275; SEQ ID No. 291; SEQ ID No. 294; SEQ ID No. 327; SEQ ID No. 342; SEQ ID No. 364; SEQ ID No. 374; SEQ ID No. 380; SEQ ID No. 414; SEQ ID No. 439; SEQ ID No. 466; SEQ ID No. 467; SEQ ID No. 468; SEQ ID No. 469; SEQ ID No. 470; SEQ ID No. 472; SEQ ID No. 474; SEQ ID No. 476; SEQ ID No. 477; SEQ ID No. 478; SEQ ID No. 479; SEQ ID No. 480; SEQ ID No. 482; SEQ ID No. 485; SEQ ID No. 500; SEQ ID No. 501; SEQ ID No. 503; SEQ ID No. 504; SEQ ID No. 505; SEQ ID No. 506; SEQ ID No. 520; SEQ ID No. 578; SEQ ID No. 580; SEQ ID No. 581; SEQ ID No. 595; SEQ ID No. 596; SEQ ID No. 597; SEQ ID No. 737; SEQ ID No. 830; SEQ ID No. 834; SEQ ID No. 836; SEQ ID No. 893; SEQ ID No. 917; SEQ ID No. 932; SEQ ID No. 976; SEQ ID No. 1035; SEQ ID No. 1045; SEQ ID No. 1090 and one of their representative fragments.

[0183] Preferably, the invention relates to a polypeptide according to the invention, characterized in that it is a Chlamydia pneumoniae transmembrane polypeptide or one of its representative fragments, having between 1 and 3 transmembrane domains, and in that it is chosen from the polypeptides having the following sequences:

[0184] SEQ ID No. 2; SEQ ID No. 3; SEQ ID No. 6; SEQ ID No. 9; SEQ ID No. 10; SEQ ID No. 11; SEQ ID No. 13; SEQ ID No. 14; SEQ ID No. 16; SEQ ID No. 18; SEQ ID No. 19; SEQ ID No. 20; SEQ ID No. 21; SEQ ID No. 22; SEQ ID No. 25; SEQ ID No. 27; SEQ ID No. 28; SEQ ID No. 29; SEQ ID No. 30; SEQ ID No. 31; SEQ ID No. 32; SEQ ID No. 33; SEQ ID No. 34; SEQ ID No. 35; SEQ ID No. 37; SEQ ID No. 39; SEQ ID No. 41; SEQ ID No. 42; SEQ ID No. 44; SEQ ID No. 45; SEQ ID No. 46; SEQ ID No. 47; SEQ ID No. 48; SEQ ID No. 49; SEQ ID No. 50; SEQ ID No. 53; SEQ ID No. 54; SEQ ID No. 56; SEQ ID No. 57; SEQ ID No. 59; SEQ ID No. 60; SEQ ID No. 61; SEQ ID No. 62; SEQ ID No. 63; SEQ ID No. 64; SEQ ID No. 65; SEQ ID No. 66; SEQ ID No. 69; SEQ ID No. 72; SEQ ID No. 73; SEQ ID No. 74; SEQ ID No. 76; SEQ ID No. 77; SEQ ID No. 78; SEQ ID No. 79; SEQ ID No. 80; SEQ ID No. 82; SEQ ID No. 84; SEQ ID No. 85; SEQ ID No. 86; SEQ ID No. 88; SEQ ID No. 89; SEQ ID No. 90; SEQ ID No. 91; SEQ ID No. 92; SEQ ID No. 93; SEQ ID No. 95; SEQ ID No. 96; SEQ ID No. 98; SEQ ID No. 99; SEQ ID No. 100; SEQ ID No. 101; SEQ ID No. 102; SEQ ID No. 103; SEQ ID No. 104; SEQ ID No. 105; SEQ ID No. 106; SEQ ID No. 107; SEQ ID No. 108; SEQ ID No. 114; SEQ ID No. 117; SEQ ID No. 118; SEQ ID No. 122; SEQ ID No. 123; SEQ ID No. 124; SEQ ID No. 125; SEQ ID No. 129; SEQ ID No. 130; SEQ ID No. 131; SEQ ID No. 132; SEQ ID No. 133; SEQ ID No. 134; SEQ ID No. 135; SEQ ID No. 137; SEQ ID No. 138; SEQ ID No. 139; SEQ ID No. 140; SEQ ID No. 141; SEQ ID No. 142; SEQ ID No. 143; SEQ ID No. 145; SEQ ID No. 146; SEQ ID No. 147; SEQ ID No. 150; SEQ ID No. 151; SEQ ID No. 152; SEQ ID No. 156; SEQ ID No. 157; SEQ ID No. 158; SEQ ID No. 159; SEQ ID No. 160; SEQ ID No. 161; SEQ ID No. 162; SEQ ID No. 164; SEQ ID No. 166; SEQ ID No. 167; SEQ ID No. 170; SEQ ID No. 173; SEQ ID No. 175; SEQ ID No. 176; SEQ ID No. 178; SEQ ID No. 179; SEQ ID No. 180; SEQ ID No. 182; SEQ ID No. 183; SEQ ID No. 184; SEQ ID No. 185; SEQ ID No. 186; SEQ ID No. 187; SEQ ID No. 188; SEQ ID No. 189; SEQ ID No. 190; SEQ ID No. 191; SEQ ID No. 192; SEQ ID No. 194; SEQ ID No. 195; SEQ ID No. 196; SEQ ID No. 197; SEQ ID No. 198; SEQ ID No. 199; SEQ ID No. 200; SEQ ID No. 201; SEQ ID No. 202; SEQ ID No. 205; SEQ ID No. 207; SEQ ID No. 208; SEQ ID No. 209; SEQ ID No. 210; SEQ ID No. 212; SEQ ID No. 215; SEQ ID No. 219; SEQ ID No. 220; SEQ ID No. 224; SEQ ID No. 226; SEQ ID No. 227; SEQ ID No. 228; SEQ ID No. 231; SEQ ID No. 232; SEQ ID No. 233; SEQ ID No. 234; SEQ ID No. 235; SEQ ID No. 236; SEQ ID No. 238; SEQ ID No. 239; SEQ ID No. 240; SEQ ID No. 241; SEQ ID No. 242; SEQ ID No. 244; SEQ ID No. 247; SEQ ID No. 251; SEQ ID No. 252; SEQ ID No. 253; SEQ ID No. 255; SEQ ID No. 256; SEQ ID No. 257; SEQ ID No. 258; SEQ ID No. 260; SEQ ID No. 262; SEQ ID No. 263; SEQ ID No. 266; SEQ ID No. 267; SEQ ID No. 268; SEQ ID No. 269; SEQ ID No. 270; SEQ ID No. 273; SEQ ID No. 274; SEQ ID No. 276; SEQ ID No. 278; SEQ ID No. 279; SEQ ID No. 280; SEQ ID No. 281; SEQ ID No. 282; SEQ ID No. 283; SEQ ID No. 284; SEQ ID No. 286; SEQ ID No. 287; SEQ ID No. 289; SEQ ID No. 290; SEQ ID No. 291; SEQ ID No. 293; SEQ ID No. 294; SEQ ID No. 297; SEQ ID No. 304; SEQ ID No. 305; SEQ ID No. 307; SEQ ID No. 308; SEQ ID No. 309; SEQ ID No. 310; SEQ ID No. 311; SEQ ID No. 313; SEQ ID No. 314; SEQ ID No. 315; SEQ ID No. 316; SEQ ID No. 318; SEQ ID No. 319; SEQ ID No. 320; SEQ ID No. 321; SEQ ID No. 322; SEQ ID No. 323; SEQ ID No. 324; SEQ ID No. 325; SEQ ID No. 326; SEQ ID No. 331; SEQ ID No. 332; SEQ ID No. 336; SEQ ID No. 338; SEQ ID No. 339; SEQ ID No. 341; SEQ ID No. 344; SEQ ID No. 345; SEQ ID No. 346; SEQ ID No. 350; SEQ ID No. 352; SEQ ID No. 353; SEQ ID No. 356; SEQ ID No. 357; SEQ ID No. 358; SEQ ID No. 359; SEQ ID No. 360; SEQ ID No. 362; SEQ ID No. 365; SEQ ID No. 366; SEQ ID No. 367; SEQ ID No. 370; SEQ ID No. 372; SEQ ID No. 373; SEQ ID No. 376; SEQ ID No. 377; SEQ ID No. 378; SEQ ID No. 379; SEQ ID No. 381; SEQ ID No. 382; SEQ ID No. 383; SEQ ID No. 384; SEQ ID No. 385; SEQ ID No. 386; SEQ ID No. 387; SEQ ID No. 390; SEQ ID No. 392; SEQ ID No. 393; SEQ ID No. 394; SEQ ID No. 396; SEQ ID No. 398; SEQ ID No. 399; SEQ ID No. 400; SEQ ID No. 404; SEQ ID No. 408; SEQ ID No. 410; SEQ ID No. 411; SEQ ID No. 413; SEQ ID No. 416; SEQ ID No. 417; SEQ ID No. 418; SEQ ID No. 420; SEQ ID No. 422; SEQ ID No. 424; SEQ ID No. 427; SEQ ID No. 428; SEQ ID No. 429; SEQ ID No. 430; SEQ ID No. 431; SEQ ID No. 433; SEQ ID No. 434; SEQ ID No. 437; SEQ ID No. 440; SEQ ID No. 441; SEQ ID No. 442; SEQ ID No. 443; SEQ ID No. 444; SEQ ID No. 445; SEQ ID No. 447; SEQ ID No. 450; SEQ ID No. 451; SEQ ID No. 452; SEQ ID No. 455; SEQ ID No. 456; SEQ ID No. 459; SEQ ID No. 460; SEQ ID No. 461; SEQ ID No. 462; SEQ ID No. 463; SEQ ID No. 464; SEQ ID No. 465; SEQ ID No. 467; SEQ ID No. 469; SEQ ID No. 471; SEQ ID No. 474; SEQ ID No. 475; SEQ ID No. 476; SEQ ID No. 477; SEQ ID No. 479; SEQ ID No. 482; SEQ ID No. 483; SEQ ID No. 484; SEQ ID No. 485; SEQ ID No. 486; SEQ ID No. 487; SEQ ID No. 488; SEQ ID No. 491; SEQ ID No. 493; SEQ ID No. 494; SEQ ID No. 497; SEQ ID No. 498; SEQ ID No. 499; SEQ ID No. 503; SEQ ID No. 508; SEQ ID No. 509; SEQ ID No. 510; SEQ ID No. 512; SEQ ID No. 514; SEQ ID No. 515; SEQ ID No. 516; SEQ ID No. 517; SEQ ID No. 518; SEQ ID No. 520; SEQ ID No. 521; SEQ ID No. 523; SEQ ID No. 525; SEQ ID No. 527; SEQ ID No. 528; SEQ ID No. 529; SEQ ID No. 530; SEQ ID No. 531; SEQ ID No. 533; SEQ ID No. 534; SEQ ID No. 535; SEQ ID No. 536; SEQ ID No. 537; SEQ ID No. 540; SEQ ID No. 541; SEQ ID No. 543; SEQ ID No. 544; SEQ ID No. 545; SEQ ID No. 546; SEQ ID No. 548; SEQ ID No. 549; SEQ ID No. 551; SEQ ID No. 553; SEQ ID No. 554; SEQ ID No. 555; SEQ ID No. 556; SEQ ID No. 557; SEQ ID No. 558; SEQ ID No. 559; SEQ ID No. 560; SEQ ID No. 562; SEQ ID No. 563; SEQ ID No. 564; SEQ ID No. 565; SEQ ID No. 566; SEQ ID No. 569; SEQ ID No. 571; SEQ ID No. 573; SEQ ID No. 576; SEQ ID No. 577; SEQ ID No. 581; SEQ ID No. 583; SEQ ID No. 584; SEQ ID No. 585; SEQ ID No. 586; SEQ ID No. 588; SEQ ID No. 591; SEQ ID No. 592; SEQ ID No. 594; SEQ ID No. 595; SEQ ID No. 596; SEQ ID No. 597; SEQ ID No. 599; SEQ ID No. 600; SEQ ID No. 603; SEQ ID No. 605; SEQ ID No. 608; SEQ ID No. 614; SEQ ID No. 615; SEQ ID No. 620; SEQ ID No. 621; SEQ ID No. 622; SEQ ID No. 623; SEQ ID No. 624; SEQ ID No. 625; SEQ ID No. 629; SEQ ID No. 630; SEQ ID No. 631; SEQ ID No. 633; SEQ ID No. 634; SEQ ID No. 637; SEQ ID No. 642; SEQ ID No. 644; SEQ ID No. 645; SEQ ID No. 647; SEQ ID No. 648; SEQ ID No. 652; SEQ ID No. 654; SEQ ID No. 655; SEQ ID No. 657; SEQ ID No. 658; SEQ ID No. 659; SEQ ID No. 660; SEQ ID No. 661; SEQ ID No. 664; SEQ ID No. 665; SEQ ID No. 666; SEQ ID No. 667; SEQ ID No. 670; SEQ ID No. 671; SEQ ID No. 672; SEQ ID No. 673; SEQ ID No. 674; SEQ ID No. 676; SEQ ID No. 679; SEQ ID No. 681; SEQ ID No. 684; SEQ ID No. 687; SEQ ID No. 688; SEQ ID No. 689; SEQ ID No. 690; SEQ ID No. 693; SEQ ID No. 694; SEQ ID No. 695; SEQ ID No. 696; SEQ ID No. 697; SEQ ID No. 698; SEQ ID No. 699; SEQ ID No. 700; SEQ ID No. 701; SEQ ID No. 703; SEQ ID No. 705; SEQ ID No. 706; SEQ ID No. 707; SEQ ID No. 708; SEQ ID No. 710; SEQ ID No. 712; SEQ ID No. 715; SEQ ID No. 716; SEQ ID No. 717; SEQ ID No. 718; SEQ ID No. 719; SEQ ID No. 721; SEQ ID No. 722; SEQ ID No. 723; SEQ ID No. 725; SEQ ID No. 726; SEQ ID No. 727; SEQ ID No. 728; SEQ ID No. 729; SEQ ID No. 730; SEQ ID No. 731; SEQ ID No. 733; SEQ ID No. 736; SEQ ID No. 737; SEQ ID No. 738; SEQ ID No. 740; SEQ ID No. 741; SEQ ID No. 742; SEQ ID No. 743; SEQ ID No. 747; SEQ ID No. 748; SEQ ID No. 750; SEQ ID No. 752; SEQ ID No. 754; SEQ ID No. 755; SEQ ID No. 756; SEQ ID No. 757; SEQ ID No. 759; SEQ ID No. 760; SEQ ID No. 761; SEQ ID No. 762; SEQ ID No. 763; SEQ ID No. 764; SEQ ID No. 765; SEQ ID No. 766; SEQ ID No. 767; SEQ ID No. 768; SEQ ID No. 772; SEQ ID No. 774; SEQ ID No. 775; SEQ ID No. 777; SEQ ID No. 781; SEQ ID No. 783; SEQ ID No. 788; SEQ ID No. 791; SEQ ID No. 792; SEQ ID No. 793; SEQ ID No. 794; SEQ ID No. 795; SEQ ID No. 796; SEQ ID No. 797; SEQ ID No. 798; SEQ ID No. 799; SEQ ID No. 802; SEQ ID No. 803; SEQ ID No. 806; SEQ ID No. 807; SEQ ID No. 808; SEQ ID No. 809; SEQ ID No. 810; SEQ ID No. 811; SEQ ID No. 813; SEQ ID No. 814; SEQ ID No. 815; SEQ ID No. 816; SEQ ID No. 817; SEQ ID No. 819; SEQ ID No. 820; SEQ ID No. 821; SEQ ID No. 823; SEQ ID No. 824; SEQ ID No. 827; SEQ ID No. 829; SEQ ID No. 830; SEQ ID No. 831; SEQ ID No. 833; SEQ ID No. 834; SEQ ID No. 835; SEQ ID No. 837; SEQ ID No. 844; SEQ ID No. 845; SEQ ID No. 846; SEQ ID No. 847; SEQ ID No. 848; SEQ ID No. 849; SEQ ID No. 850; SEQ ID No. 851; SEQ ID No. 852; SEQ ID No. 854; SEQ ID No. 855; SEQ ID No. 856; SEQ ID No. 857; SEQ ID No. 859; SEQ ID No. 860; SEQ ID No. 862; SEQ ID No. 865; SEQ ID No. 866; SEQ ID No. 868; SEQ ID No. 869; SEQ ID No. 870; SEQ ID No. 871; SEQ ID No. 872; SEQ ID No. 874; SEQ ID No. 877; SEQ ID No. 878; SEQ ID No. 879; SEQ ID No. 880; SEQ ID No. 881; SEQ ID No. 882; SEQ ID No. 884; SEQ ID No. 885; SEQ ID No. 888; SEQ ID No. 889; SEQ ID No. 890; SEQ ID No. 891; SEQ ID No. 892; SEQ ID No. 894; SEQ ID No. 895; SEQ ID No. 896; SEQ ID No. 897; SEQ ID No. 899; SEQ ID No. 900; SEQ ID No. 902; SEQ ID No. 903; SEQ ID No. 904; SEQ ID No. 905; SEQ ID No. 909; SEQ ID No. 910; SEQ ID No. 912; SEQ ID No. 913; SEQ ID No. 914; SEQ ID No. 915; SEQ ID No. 917; SEQ ID No. 918; SEQ ID No. 919; SEQ ID No. 921; SEQ ID No. 923; SEQ ID No. 924; SEQ ID No. 926; SEQ ID No. 927; SEQ ID No. 928; SEQ ID No. 929; SEQ ID No. 930; SEQ ID No. 931; SEQ ID No. 937; SEQ ID No. 938; SEQ ID No. 939; SEQ ID No. 941; SEQ ID No. 943; SEQ ID No. 948; SEQ ID No. 951; SEQ ID No. 952; SEQ ID No. 953; SEQ ID No. 958; SEQ ID No. 960; SEQ ID No. 963; SEQ ID No. 964; SEQ ID No. 965; SEQ ID No. 968; SEQ ID No. 970; SEQ ID No. 974; SEQ ID No. 975; SEQ ID No. 977; SEQ ID No. 979; SEQ ID No. 980; SEQ ID No. 981; SEQ ID No. 983; SEQ ID No. 984; SEQ ID No. 985; SEQ ID No. 987; SEQ ID No. 989; SEQ ID No. 992; SEQ ID No. 993; SEQ ID No. 997; SEQ ID No. 998; SEQ ID No. 999; SEQ ID No. 1001; SEQ ID No. 1002; SEQ ID No. 1004; SEQ ID No. 1005; SEQ ID No. 1009; SEQ ID No. 1013; SEQ ID No. 1014; SEQ ID No. 1015; SEQ ID No. 1016; SEQ ID No. 1019; SEQ ID No. 1021; SEQ ID No. 1023; SEQ ID No. 1024; SEQ ID No. 1029; SEQ ID No. 1031; SEQ ID No. 1033; SEQ ID No. 1034; SEQ ID No. 1039; SEQ ID No. 1041; SEQ ID No. 1042; SEQ ID No. 1045; SEQ ID No. 1047; SEQ ID No. 1049; SEQ ID No. 1051; SEQ ID No. 1052; SEQ ID No. 1053; SEQ ID No. 1054; SEQ ID No. 1056; SEQ ID No. 1059; SEQ ID No. 1061; SEQ ID No. 1062; SEQ ID No. 1063; SEQ ID No. 1064; SEQ ID No. 1065; SEQ ID No. 1067; SEQ ID No. 1075; SEQ ID No. 1077; SEQ ID No. 1078; SEQ ID No. 1079; SEQ ID No. 1080; SEQ ID No. 1081; SEQ ID No. 1089; SEQ ID No. 1095; SEQ ID No. 1097; SEQ ID No. 1098; SEQ ID No. 1099; SEQ ID No. 1101; SEQ ID No. 1102; SEQ ID No. 1103; SEQ ID No. 1106; SEQ ID No. 1107; SEQ ID No. 1108; SEQ ID No. 1109; SEQ ID No. 1110; SEQ ID No. 1113; SEQ ID No. 1116; SEQ ID No. 1118; SEQ ID No. 1119; SEQ ID No. 1121; SEQ ID No. 1123; SEQ ID No. 1124; SEQ ID No. 1126; SEQ ID No. 1128; SEQ ID No. 1130; SEQ ID No. 1131; SEQ ID No. 1133; SEQ ID No. 1134; SEQ ID No. 1136; SEQ ID No. 1137 and one of their representative fragments.

[0185] Preferably, the invention relates to a polypeptide according to the invention, characterized in that it is a Chlamydia pneumoniae transmembrane polypeptide or one of its respective fragments, having between 4 and 6 transmembrane domains, and in that it is chosen from the polypeptides having the following sequences:

[0186] SEQ ID No. 5; SEQ ID No. 7; SEQ ID No. 8; SEQ ID No. 15; SEQ ID No. 36; SEQ ID No. 38; SEQ ID No. 51; SEQ ID No. 55; SEQ ID No. 58; SEQ ID No. 67; SEQ ID No. 70; SEQ ID No. 81; SEQ ID No. 97; SEQ ID No. 110; SEQ ID No. 111; SEQ ID No. 115; SEQ ID No. 119; SEQ ID No. 126; SEQ ID No. 128; SEQ ID No. 148; SEQ ID No. 155; SEQ ID No. 163; SEQ ID No. 165; SEQ ID No. 168; SEQ ID No. 169; SEQ ID No. 171; SEQ ID No. 172; SEQ ID No. 174; SEQ ID No. 177; SEQ ID No. 181; SEQ ID No. 193; SEQ ID No. 203; SEQ ID No. 213; SEQ ID No. 214; SEQ ID No. 216; SEQ ID No. 217; SEQ ID No. 221; SEQ ID No. 222; SEQ ID No. 225; SEQ ID No. 229; SEQ ID No. 243; SEQ ID No. 246; SEQ ID No. 248; SEQ ID No. 254; SEQ ID No. 261; SEQ ID No. 285; SEQ ID No. 288; SEQ ID No. 292; SEQ ID No. 296; SEQ ID No. 298; SEQ ID No. 299; SEQ ID No. 301; SEQ ID No. 303; SEQ ID No. 317; SEQ ID No. 328; SEQ ID No. 329; SEQ ID No. 351; SEQ ID No. 354; SEQ ID No. 355; SEQ ID No. 364; SEQ ID No. 371; SEQ ID No. 374; SEQ ID No. 375; SEQ ID No. 391; SEQ ID No. 395; SEQ ID No. 401; SEQ ID No. 403; SEQ ID No. 405; SEQ ID No. 409; SEQ ID No. 414; SEQ ID No. 419; SEQ ID No. 421; SEQ ID No. 423; SEQ ID No. 425; SEQ ID No. 438; SEQ ID No. 448; SEQ ID No. 453; SEQ ID No. 458; SEQ ID No. 466; SEQ ID No. 468; SEQ ID No. 470; SEQ ID No. 480; SEQ ID No. 489; SEQ ID No. 490; SEQ ID No. 496; SEQ ID No. 501; SEQ ID No. 504; SEQ ID No. 505; SEQ ID No. 506; SEQ ID No. 511; SEQ ID No. 513; SEQ ID No. 519; SEQ ID No. 526; SEQ ID No. 532; SEQ ID No. 538; SEQ ID No. 539; SEQ ID No. 547; SEQ ID No. 550; SEQ ID No. 561; SEQ ID No. 568; SEQ ID No. 570; SEQ ID No. 574; SEQ ID No. 578; SEQ ID No. 579; SEQ ID No. 580; SEQ ID No. 582; SEQ ID No. 589; SEQ ID No. 593; SEQ ID No. 598; SEQ ID No. 601; SEQ ID No. 604; SEQ ID No. 610; SEQ ID No. 613; SEQ ID No. 617; SEQ ID No. 626; SEQ ID No. 632; SEQ ID No. 635; SEQ ID No. 638; SEQ ID No. 640; SEQ ID No. 641; SEQ ID No. 646; SEQ ID No. 649; SEQ ID No. 650; SEQ ID No. 651; SEQ ID No. 686; SEQ ID No. 711; SEQ ID No. 724; SEQ ID No. 732; SEQ ID No. 734; SEQ ID No. 744; SEQ ID No. 745; SEQ ID No. 749; SEQ ID No. 751; SEQ ID No. 769; SEQ ID No. 770; SEQ ID No. 771; SEQ ID No. 773; SEQ ID No. 776; SEQ ID No. 779; SEQ ID No. 780; SEQ ID No. 785; SEQ ID No. 787; SEQ ID No. 789; SEQ ID No. 801; SEQ ID No. 805; SEQ ID No. 812; SEQ ID No. 822; SEQ ID No. 825; SEQ ID No. 826; SEQ ID No. 839; SEQ ID No. 841; SEQ ID No. 843; SEQ ID No. 853; SEQ ID No. 861; SEQ ID No. 875; SEQ ID No. 876; SEQ ID No. 886; SEQ ID No. 893; SEQ ID No. 898; SEQ ID No. 906; SEQ ID No. 907; SEQ ID No. 908; SEQ ID No. 920; SEQ ID No. 922; SEQ ID No. 925; SEQ ID No. 933; SEQ ID No. 935; SEQ ID No. 936; SEQ ID No. 944; SEQ ID No. 946; SEQ ID No. 947; SEQ ID No. 954; SEQ ID No. 959; SEQ ID No. 961; SEQ ID No. 966; SEQ ID No. 967; SEQ ID No. 972; SEQ ID No. 978; SEQ ID No. 995; SEQ ID No. 996; SEQ ID No. 1000; SEQ ID No. 1003; SEQ ID No. 1010; SEQ ID No. 1011; SEQ ID No. 1012; SEQ ID No. 1017; SEQ ID No. 1020; SEQ ID No. 1030; SEQ ID No. 1036; SEQ ID No. 1038; SEQ ID No. 1043; SEQ ID No. 1046; SEQ ID No. 1048; SEQ ID No. 1050; SEQ ID No. 1058; SEQ ID No. 1071; SEQ ID No. 1073; SEQ ID No. 1084; SEQ ID No. 1085; SEQ ID No. 1086; SEQ ID No. 1087; SEQ ID No. 1091; SEQ ID No. 1092; SEQ ID No. 1094; SEQ ID No. 1096; SEQ ID No. 1100; SEQ ID No. 1104; SEQ ID No. 1111; SEQ ID No. 1112; SEQ ID No. 1114; SEQ ID No. 1117; SEQ ID No. 1122; SEQ ID No. 1125 and one of their representative fragments.

[0187] Preferably, the invention relates to a polypeptide according to the invention, characterized in that it is a Chlamydia pneumoniae transmembrane polypeptide or one of its representative fragments, having at least 7 transmembrane domains, and in that it is chosen from the polypeptides having the following sequences:

[0188] SEQ ID No. 17; SEQ ID No. 52; SEQ ID No. 68; SEQ ID No. 83; SEQ ID No. 87; SEQ ID No. 109; SEQ ID No. 112; SEQ ID No. 113; SEQ ID No. 120; SEQ ID No. 121; SEQ ID No. 127; SEQ ID No. 153; SEQ ID No. 204; SEQ ID No. 211; SEQ ID No. 218; SEQ ID No. 223; SEQ ID No. 275; SEQ ID No. 277; SEQ ID No. 295; SEQ ID No. 300; SEQ ID No. 302; SEQ ID No. 306; SEQ ID No. 327; SEQ ID No. 335; SEQ ID No. 342; SEQ ID No. 343; SEQ ID No. 347; SEQ ID No. 349; SEQ ID No. 361; SEQ ID No. 363; SEQ ID No. 369; SEQ ID No. 380; SEQ ID No. 388; SEQ ID No. 389; SEQ ID No. 397; SEQ ID No. 415; SEQ ID No. 432; SEQ ID No. 439; SEQ ID No. 446; SEQ ID No. 449; SEQ ID No. 472; SEQ ID No. 478; SEQ ID No. 500; SEQ ID No. 522; SEQ ID No. 524; SEQ ID No. 567; SEQ ID No. 575; SEQ ID No. 602; SEQ ID No. 606; SEQ ID No. 609; SEQ ID No. 636; SEQ ID No. 639; SEQ ID No. 643; SEQ ID No. 653; SEQ ID No. 668; SEQ ID No. 692; SEQ ID No. 702; SEQ ID No. 704; SEQ ID No. 713; SEQ ID No. 720; SEQ ID No. 778; SEQ ID No. 784; SEQ ID No. 800; SEQ ID No. 836; SEQ ID No. 838; SEQ ID No. 842; SEQ ID No. 864; SEQ ID No. 867; SEQ ID No. 883; SEQ ID No. 901; SEQ ID No. 916; SEQ ID No. 932; SEQ ID No. 934; SEQ ID No. 940; SEQ ID No. 942; SEQ ID No. 950; SEQ ID No. 956; SEQ ID No. 971; SEQ ID No. 973; SEQ ID No. 976; SEQ ID No. 988; SEQ ID No. 994; SEQ ID No. 1018; SEQ ID No. 1028; SEQ ID No. 1035; SEQ ID No. 1037; SEQ ID No. 1044; SEQ ID No. 1055; SEQ ID No. 1057; SEQ ID No. 1068; SEQ ID No. 1069; SEQ ID No. 1070; SEQ ID No. 1072; SEQ ID No. 1082; SEQ ID No. 1088; SEQ ID No. 1105; SEQ ID No. 1132; SEQ ID No. 1135 and one of their representative fragments.

[0189] Preferably, the invention relates to a polypeptide according to the invention, in that it is a Chlamydia pneumoniae surface exposed polypeptide or one of its representative fragments, and in that it is chosen from the polypeptides having the following sequences:

[0190] SEQ ID No. 15, SEQ ID No. 25, SEQ ID No. 26, SEQ ID No. 27, SEQ ID No. 28, SEQ ID No. 29, SEQ ID No. 30, SEQ ID No. 31, SEQ ID No. 32, SEQ ID No. 33, SEQ ID No. 35, SEQ ID No. 36, SEQ ID No. 1257, SEQ ID No. 280, SEQ ID No. 291, SEQ ID No. 314, SEQ ID No. 354, SEQ ID No. 380, SEQ ID No. 1266, SEQ ID No. 466, SEQ ID No. 467, SEQ ID No. 468, SEQ ID No. 469, SEQ ID No. 470, SEQ ID No. 472, SEQ ID No. 474, SEQ ID No. 476, SEQ ID No. 477, SEQ ID No. 478, SEQ ID No. 479, SEQ ID No. 480, SEQ ID No. 482, SEQ ID No. 483, SEQ ID No. 485, SEQ ID No. 486, SEQ ID No. 500, SEQ ID No. 501, SEQ ID No. 503, SEQ ID No. 504, SEQ ID No. 505, SEQ ID No. 506, SEQ ID No. 507, SEQ ID No. 1268, SEQ ID No. 1269, SEQ ID No. 543, SEQ ID No. 544, SEQ ID No. 578, SEQ ID No. 579, SEQ ID No. 580, SEQ ID No. 581, SEQ ID No. 595, SEQ ID No. 596, SEQ ID No. 597, SEQ ID No. 1271, SEQ ID No. 633, SEQ ID No. 637, SEQ ID No. 699, SEQ ID No. 706, SEQ ID No. 737, SEQ ID No. 744, SEQ ID No. 1273, SEQ ID No. 751, SEQ ID No. 775, SEQ ID No. 776, SEQ ID No. 777, SEQ ID No. 793, SEQ ID No. 815, SEQ ID No. 830, SEQ ID No. 1221, SEQ ID No. 849, SEQ ID No. 851, SEQ ID No. 852, SEQ ID No. 874, SEQ ID No. 891, SEQ ID No. 922, SEQ ID No. 940, SEQ ID No. 1231, SEQ ID No. 1281, SEQ ID No. 1035, SEQ ID No. 1079, SEQ ID No. 1087, SEQ ID No. 1108, and one of their representative fragments.

[0191] Preferably, the invention relates to a polypeptide according to the invention, characterized in that it is a Chlamydia pneumoniae lipoprotein or one of its representative fragments, and in that it is chosen from the polypeptides having the following sequences:

[0192] SEQ ID No. 3, SEQ ID No. 10, SEQ ID No. 11, SEQ ID No. 16, SEQ ID No. 1254, SEQ ID No. 1255, SEQ ID No. 38, SEQ ID No. 1256, SEQ ID No. 62, SEQ ID No. 85, SEQ ID No. 1258, SEQ ID No. 115, SEQ ID No. 1151, SEQ ID No. 151, SEQ ID No. 1259, SEQ ID No. 173, SEQ ID No. 1261, SEQ ID No. 186, SEQ ID No. 194, SEQ ID No. 205, SEQ ID No. 214, SEQ ID No. 216, SEQ ID No. 217, SEQ ID No. 238, SEQ ID No. 1177, SEQ ID No. 280, SEQ ID No. 291, SEQ ID No. 317, SEQ ID No. 327, SEQ ID No. 354, SEQ ID No. 364, SEQ ID No. 367, SEQ ID No. 414, SEQ ID No. 432, SEQ ID No. 1192, SEQ ID No. 460, SEQ ID No. 1267, SEQ ID No. 1268, SEQ ID No. 520, SEQ ID No. 536, SEQ ID No. 1270, SEQ ID No. 576, SEQ ID No. 597, SEQ ID No. 603, SEQ ID No. 609, SEQ ID No. 637, SEQ ID No. 1272, SEQ ID No. 652, SEQ ID No. 1213, SEQ ID No. 699, SEQ ID No. 705, SEQ ID No. 706, SEQ ID No. 708, SEQ ID No. 711, SEQ ID No. 727, SEQ ID No. 1274, SEQ ID No. 800, SEQ ID No. 814, SEQ ID No. 825, SEQ ID No. 829, SEQ ID No. 830, SEQ ID No. 831, SEQ ID No. 844, SEQ ID No. 849, SEQ ID No. 1275, SEQ ID No. 1276, SEQ ID No. 1277, SEQ ID No. 872, SEQ ID No. 878, SEQ ID No. 880, SEQ ID No. 891, SEQ ID No. 892, SEQ ID No. 1278, SEQ ID No. 1279, SEQ ID No. 1280, SEQ ID No. 941, SEQ ID No. 942, SEQ ID No. 1282, SEQ ID No. 1283, SEQ ID No. 952, SEQ ID No. 988, SEQ ID No. 998, SEQ ID No. 1009, SEQ ID No. 1285, SEQ ID No. 1235, SEQ ID No. 1028, SEQ ID No. 1056, SEQ ID No. 1070, SEQ ID No. 1287, SEQ ID No. 1087, SEQ ID No. 1288, SEQ ID No. 1289, SEQ ID No. 1098, SEQ ID No. 1246, SEQ ID No. 1291, SEQ ID No. 1108, SEQ ID No. 1109, SEQ ID No. 1112, SEQ ID No. 1133, and one of their representative fragments.

[0193] Preferably, the invention relates to a polypeptide according to the invention, in that it is a Chlamydia pneumoniae polypeptide involved in lipopolysaccharide (LPS) biosynthesis, and in that it is chosen from the polypeptides having the following sequences:

[0194] SEQ ID No. 316, SEQ ID No. 564, SEQ ID No. 610, SEQ ID No. 647, SEQ ID No. 1211, SEQ ID No. 688, SEQ ID No. 924, and one of their representative fragments.

[0195] Preferably, the invention relates to additional LPS-related polypeptides according to the invention, in that it is:

[0196] (a) a Chlamydia pneumoniae KDO (3-deoxy-D-manno-octylosonic acid)-related polypeptide or one of its representative fragments, and in that it is chosen from the polypeptides having the following sequences: SEQ ID No. 177, SEQ ID No. 1156, SEQ ID No. 245, SEQ ID No. 767, and one of their representative fragments;

[0197] (b) a Chlamydia pneumoniae phosphomannomutase-related polypeptide or one of its representative fragments, and in that it is chosen from the polypeptides having the following sequences: SEQ ID No. 74, and its representative fragment;

[0198] (c) a Chlamydia pneumoniae phosphoglucomutase-related polypeptide or one of its representative fragments, and in that it is chosen from the polypeptides having the following sequences: SEQ ID No. 1286, SEQ ID No. 1039, and its representative fragment; and

[0199] (d) a Chlamydia pneumoniae lipid A component-related polypeptide or one of its representative fragments, and in that it is chosen from the polypeptides having the following sequences: SEQ ID No. 689, SEQ ID No. 690, SEQ ID No. 691, SEQ ID No. 1037, and one of their representative fragments.

[0200] Preferably, the invention relates to a polypeptide according to the invention, in that it is a Chlamydia pneumoniae polypeptide or one of its representative fragments that contains an RGD sequence and is also an outer membrane protein, and in that it is chosen from the polypeptides having the following sequences: SEQ ID No. 468 and its representative fragments.

[0201] Preferably, the invention relates to a polypeptide according to the invention, in that it is a Chlamydia pneumoniae polypeptide or one of its representative fragments that contains an RGD sequence that shows homology to cds1, cds2, and copN type III virulence loci in Chlamydia Psitacci, and in that it is chosen from the polypeptides having the following sequences:

[0202] SEQ ID No. 350 and its representative fragments.

[0203] Preferably, the invention relates to a polypeptide according to the invention, in that it is a Chlamydia pneumoniae polypeptide or one of its representative fragments that is cysteine-rich and contains RGD sequence, and in that it is chosen from the polypeptides having the following sequences: SEQ ID No. 1290, SEQ ID No. 6846, SEQ ID No. 6848, and one of their representative fragments.

[0204] Preferably, the invention relates to a polypeptide according to the invention, in that it is a Chlamydia pneumoniae outer membrane polypeptide that contains cysteines in their first 30 amino acids and also contain an RGD sequence, and in that it is chosen from the polypeptides having the following sequences:

[0205] SEQ ID No. 105, SEQ ID No. 106, SEQ ID No. 114, SEQ ID No. 170, SEQ ID No. 171, SEQ ID No. 1264, SEQ ID No. 268, SEQ ID No. 1265, SEQ ID No. 350, SEQ ID No. 393, SEQ ID No. 394, SEQ ID No. 451, SEQ ID No. 452, SEQ ID No. 453, SEQ ID No. 473, SEQ ID No. 499, SEQ ID No. 515, SEQ ID No. 519, SEQ ID No. 525, SEQ ID No. 526, SEQ ID No. 538, SEQ ID No. 611, SEQ ID No. 645, SEQ ID No. 686, SEQ ID No. 700, SEQ ID No. 746, SEQ ID No. 755, SEQ ID No. 756, SEQ ID No. 757, SEQ ID No. 789, SEQ ID No. 814, SEQ ID No. 855, SEQ ID No. 856, SEQ ID No. 878, SEQ ID No. 957, SEQ ID No. 958, SEQ ID No. 989, SEQ ID No. 1290, and one of their representative fragments.

[0206] Preferably, the invention relates to a polypeptide according to the invention, in that it is a Chlamydia pneumoniae polypeptide or one of its representative fragments that contains RGD sequences homologous to Chlamydia trachomatis polypeptides containing RGD sequences, and in that it is chosen from the polypeptides having the following sequences:

[0207] SEQ ID No. 114, SEQ ID No. 468, SEQ ID No. 755, SEQ ID No. 756, SEQ ID No. 757, SEQ ID No. 855, SEQ ID No. 856, SEQ ID No. 905, SEQ ID No. 913, SEQ ID No. 914, SEQ ID No. 915, and one of their representative fragments.

[0208] Preferably, the invention relates to a polypeptide according to the invention, in that it is a Chlamydia pneumoniae Type III and non-Type III secreted polypeptide or one of its representative fragments, and in that it is chosen from the polypeptides having the following sequences:

[0209] SEQ ID No. 25, SEQ ID No. 28, SEQ ID No. 29, SEQ ID No. 33, SEQ ID No. 308, SEQ ID No. 309, SEQ ID No. 343, SEQ ID No. 344, SEQ ID No. 345, SEQ ID No. 367, SEQ ID No. 414, SEQ ID No. 415, SEQ ID No. 480, SEQ ID No. 550, SEQ ID No. 579, SEQ ID No. 580, SEQ ID No. 581, SEQ ID No. 597, SEQ ID No. 699, SEQ ID No. 744, SEQ ID No. 751, SEQ ID No. 776, SEQ ID No. 866, SEQ ID No. 874, SEQ ID No. 883, SEQ ID No. 884, SEQ ID No. 888, SEQ ID No. 891, SEQ ID No. 6845, and one of their representative fragments.

[0210] Preferably, the invention relates to a polypeptide according to the invention, in that it is a Chlamydia pneumoniae cell wall anchored surface polypeptide or one of its representative fragments, and in that it is chosen from the polypeptides having the following sequences: SEQ ID No. 267, SEQ ID No. 271, SEQ ID No. 419, SEQ ID No. 590, SEQ ID No. 932, SEQ ID No. 6844, SEQ ID No. 6847, and one of their representative fragments.

[0211] Preferably, the invention relates to a polypeptide according to the invention, in that it is a Chlamydia pneumoniae polypeptide or one of its representative fragments not found in Chlamydia trachomatis (Blastp P>e−10), and in that it is chosen from the polypeptides having the following sequences:

[0212] SEQ ID No. 7, SEQ ID No. 8, SEQ ID No. 9, SEQ ID No. 16, SEQ ID No. 17, SEQ ID No. 18, SEQ ID No. 19, SEQ ID No. 20, SEQ ID No. 21, SEQ ID No. 22, SEQ ID No. 1254, SEQ ID No. 23, SEQ ID No. 1255, SEQ ID No. 24, SEQ ID No. 1139, SEQ ID No. 1140, SEQ ID No. 46, SEQ ID No. 47, SEQ ID No. 51, SEQ ID No. 60, SEQ ID No. 1256, SEQ ID No. 61, SEQ ID No. 62, SEQ ID No. 63, SEQ ID No. 64, SEQ ID No. 1257, SEQ ID No. 65, SEQ ID No. 66, SEQ ID No. 67, SEQ ID No. 68, SEQ ID No. 1143, SEQ ID No. 1145, SEQ ID No. 83, SEQ ID No. 84, SEQ ID No. 1146, SEQ ID No. 85, SEQ ID No. 86, SEQ ID No. 87, SEQ ID No. 1258, SEQ ID No. 116, SEQ ID No. 117, SEQ ID No. 125, SEQ ID No. 1148, SEQ ID No. 143, SEQ ID No. 1150, SEQ ID No. 1151, SEQ ID No. 144, SEQ ID No. 145, SEQ ID No. 147, SEQ ID No. 148, SEQ ID No. 149, SEQ ID No. 150, SEQ ID No. 152, SEQ ID No. 1259, SEQ ID No. 162, SEQ ID No. 166, SEQ ID No. 1154, SEQ ID No. 167, SEQ ID No. 1261, SEQ ID No. 1156, SEQ ID No. 1157, SEQ ID No. 178, SEQ ID No. 179, SEQ ID No. 1158, SEQ ID No. 182, SEQ ID No. 183, SEQ ID No. 184, SEQ ID No. 185, SEQ ID No. 1159, SEQ ID No. 186, SEQ ID No. 1160, SEQ ID No. 187, SEQ ID No. 188, SEQ ID No. 189, SEQ ID No. 190, SEQ ID No. 1161, SEQ ID No. 1162, SEQ ID No. 191, SEQ ID No. 192, SEQ ID No. 194, SEQ ID No. 195, SEQ ID No. 1163, SEQ ID No. 196, SEQ ID No. 201, SEQ ID No. 202, SEQ ID No. 209, SEQ ID No. 212, SEQ ID No. 221, SEQ ID No. 224, SEQ ID No. 1167, SEQ ID No. 226, SEQ ID No. 227, SEQ ID No. 228, SEQ ID No. 229, SEQ ID No. 230, SEQ ID No. 231, SEQ ID No. 232, SEQ ID No. 1169, SEQ ID No. 1170, SEQ ID No. 1171, SEQ ID No. 234, SEQ ID No. 235, SEQ ID No. 236, SEQ ID No. 1172, SEQ ID No. 243, SEQ ID No. 251, SEQ ID No. 252, SEQ ID No. 1176, SEQ ID No. 253, SEQ ID No. 255, SEQ ID No. 254, SEQ ID No. 256, SEQ ID No. 1177, SEQ ID No. 1178, SEQ ID No. 262, SEQ ID No. 263, SEQ ID No. 1264, SEQ ID No. 278, SEQ ID No. 279, SEQ ID No. 1180, SEQ ID No. 280, SEQ ID No. 290, SEQ ID No. 291, SEQ ID No. 292, SEQ ID No. 296, SEQ ID No. 1181, SEQ ID No. 297, SEQ ID No. 298, SEQ ID No. 300, SEQ ID No. 1265, SEQ ID No. 322, SEQ ID No. 324, SEQ ID No. 325, SEQ ID No. 370, SEQ ID No. 1186, SEQ ID No. 371, SEQ ID No. 372, SEQ ID No. 1187, SEQ ID No. 373, SEQ ID No. 378, SEQ ID No. 1266, SEQ ID No. 382, SEQ ID No. 383, SEQ ID No. 384, SEQ ID No. 385, SEQ ID No. 386, SEQ ID No. 1188, SEQ ID No. 1189, SEQ ID No. 391, SEQ ID No. 392, SEQ ID No. 398, SEQ ID No. 400, SEQ ID No. 403, SEQ ID No. 1191, SEQ ID No. 423, SEQ ID No. 435, SEQ ID No. 445, SEQ ID No. 450, SEQ ID No. 1193, SEQ ID No. 456, SEQ ID No. 460, SEQ ID No. 461, SEQ ID No. 465, SEQ ID No. 1196, SEQ ID No. 471, SEQ ID No. 473, SEQ ID No. 475, SEQ ID No. 481, SEQ ID No. 484, SEQ ID No. 487, SEQ ID No. 488, SEQ ID No. 489, SEQ ID No. 490, SEQ ID No. 491, SEQ ID No. 492, SEQ ID No. 493, SEQ ID No. 494, SEQ ID No. 495, SEQ ID No. 496, SEQ ID No. 497, SEQ ID No. 498, SEQ ID No. 499, SEQ ID No. 502, SEQ ID No. 1267, SEQ ID No. 1268, SEQ ID No. 508, SEQ ID No. 510, SEQ ID No. 509, SEQ ID No. 512, SEQ ID No. 515, SEQ ID No. 519, SEQ ID No. 1197, SEQ ID No. 521, SEQ ID No. 1198, SEQ ID No. 522, SEQ ID No. 524, SEQ ID No. 528, SEQ ID No. 534, SEQ ID No. 537, SEQ ID No. 1269, SEQ ID No. 1270, SEQ ID No. 548, SEQ ID No. 551, SEQ ID No. 557, SEQ ID No. 1201, SEQ ID No. 1203, SEQ ID No. 562, SEQ ID No. 566, SEQ ID No. 593, SEQ ID No. 595, SEQ ID No. 600, SEQ ID No. 1271, SEQ ID No. 604, SEQ ID No. 611, SEQ ID No. 612, SEQ ID No. 614, SEQ ID No. 616, SEQ ID No. 625, SEQ ID No. 627, SEQ ID No. 628, SEQ ID No. 629, SEQ ID No. 631, SEQ ID No. 641, SEQ ID No. 1272, SEQ ID No. 648, SEQ ID No. 1212, SEQ ID No. 663, SEQ ID No. 685, SEQ ID No. 707, SEQ ID No. 714, SEQ ID No. 715, SEQ ID No. 716, SEQ ID No. 717, SEQ ID No. 722, SEQ ID No. 746, SEQ ID No. 1273, SEQ ID No. 761, SEQ ID No. 764, SEQ ID No. 770, SEQ ID No. 1217, SEQ ID No. 783, SEQ ID No. 1274, SEQ ID No. 803, SEQ ID No. 815, SEQ ID No. 1220, SEQ ID No. 835, SEQ ID No. 1221, SEQ ID No. 844, SEQ ID No. 845, SEQ ID No. 846, SEQ ID No. 847, SEQ ID No. 848, SEQ ID No. 849, SEQ ID No. 850, SEQ ID No. 851, SEQ ID No. 1275, SEQ ID No. 852, SEQ ID No. 862, SEQ ID No. 1276, SEQ ID No. 1277, SEQ ID No. 873, SEQ ID No. 1223, SEQ ID No. 892, SEQ ID No. 919, SEQ ID No. 1225, SEQ ID No. 1278, SEQ ID No. 926, SEQ ID No. 1228, SEQ ID No. 1229, SEQ ID No. 1230, SEQ ID No. 1279, SEQ ID No. 1281, SEQ ID No. 1282, SEQ ID No. 1283, SEQ ID No. 948, SEQ ID No. 950, SEQ ID No. 949, SEQ ID No. 951, SEQ ID No. 980, SEQ ID No. 982, SEQ ID No. 1233, SEQ ID No. 999, SEQ ID No. 1000, SEQ ID No. 1001, SEQ ID No. 1002, SEQ ID No. 1008, SEQ ID No. 1285, SEQ ID No. 1235, SEQ ID No. 1016, SEQ ID No. 1019, SEQ ID No. 1027, SEQ ID No. 1036, SEQ ID No. 1241, SEQ ID No. 1048, SEQ ID No. 1049, SEQ ID No. 1050, SEQ ID No. 1053, SEQ ID No. 1054, SEQ ID No. 1064, SEQ ID No. 1076, SEQ ID No. 1091, SEQ ID No. 1288, SEQ ID No. 1093, SEQ ID No. 1289, SEQ ID No. 1101, SEQ ID No. 1103, SEQ ID No. 1245, SEQ ID No. 1246, SEQ ID No. 1247, SEQ ID No. 1290, SEQ ID No. 1291, SEQ ID No. 1115, SEQ ID No. 1116, SEQ ID No. 1118, SEQ ID No. 1120, SEQ ID No. 1249, SEQ ID No. 1121, SEQ ID No. 1250, SEQ ID No. 1126, SEQ ID No. 1251, SEQ ID No. 1127, SEQ ID No. 1128, SEQ ID No. 1130, SEQ ID No. 1129, SEQ ID No. 1131, SEQ ID No. 1136, SEQ ID No. 1253, SEQ ID No. 6844, SEQ ID No. 6846, SEQ ID No. 6847, SEQ ID No. 6848, and one of their representative fragments

[0213] Preferably, the invention relates to a polypeptide according to the invention, characterized in that it is a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the intermediate metabolism, in particular in the metabolism of sugars and/or of cofactors, and in that it is chosen from the polypeptides having the following sequences:

[0214] SEQ ID No. 2; SEQ ID No. 55; SEQ ID No. 56; SEQ ID No. 69; SEQ ID No. 75; SEQ ID No. 80; SEQ ID No. 100; SEQ ID No. 110; SEQ ID No. 114; SEQ ID No. 120; SEQ ID No. 121; SEQ ID No. 157; SEQ ID No. 160; SEQ ID No. 161; SEQ ID No. 172; SEQ ID No. 180; SEQ ID No. 181; SEQ ID No. 198; SEQ ID No. 200; SEQ ID No. 225; SEQ ID No. 248; SEQ ID No. 249; SEQ ID No. 276; SEQ ID No. 277; SEQ ID No. 318; SEQ ID No. 319; SEQ ID No. 320; SEQ ID No. 323; SEQ ID No. 331; SEQ ID No. 347; SEQ ID No. 375; SEQ ID No. 376; SEQ ID No. 381; SEQ ID No. 393; SEQ ID No. 394; SEQ ID No. 395; SEQ ID No. 396; SEQ ID No. 409; SEQ ID No. 446; SEQ ID No. 447; SEQ ID No. 448; SEQ ID No. 449; SEQ ID No. 513; SEQ ID No. 516; SEQ ID No. 571; SEQ ID No. 647; SEQ ID No. 662; SEQ ID No. 697; SEQ ID No. 718; SEQ ID No. 793; SEQ ID No. 794; SEQ ID No. 808; SEQ ID No. 809; SEQ ID No. 838; SEQ ID No. 839; SEQ ID No. 840; SEQ ID No. 853; SEQ ID No. 854; SEQ ID No. 918; SEQ ID No. 923; SEQ ID No. 929; SEQ ID No. 931; SEQ ID No. 938; SEQ ID No. 939; SEQ ID No. 958; SEQ ID No. 959; SEQ ID No. 960; SEQ ID No. 966; SEQ ID No. 995; SEQ ID No. 1021; SEQ ID No. 1040; SEQ ID No. 1041; SEQ ID No. 1042; SEQ ID No. 1085; SEQ ID No. 1100; SEQ ID No. 1102; SEQ ID No. 1117; SEQ ID No. 1118; SEQ ID No. 1119; SEQ ID No. 1120; SEQ ID No. 1135 and one of their representative fragments.

[0215] Preferably, the invention relates to a polypeptide according to the invention, characterized in that it is a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the intermediate metabolism of nucleotides or nucleic acids, and in that it is chosen from the polypeptides having the following sequences:

[0216] SEQ ID No. 77; SEQ ID No. 78; SEQ ID No. 138; SEQ ID No. 189; SEQ ID No. 190; SEQ ID No. 233; SEQ ID No. 246; SEQ ID No. 338; SEQ ID No. 412; SEQ ID No. 421; SEQ ID No. 438; SEQ ID No. 607; SEQ ID No. 648; SEQ ID No. 657; SEQ ID No. 740; SEQ ID No. 783; SEQ ID No. 967; SEQ ID No. 989; SEQ ID No. 990; SEQ ID No. 992; SEQ ID No. 1011; SEQ ID No. 1058; SEQ ID No. 1059; SEQ ID No. 1073; SEQ ID No. 1074 and one of their representative fragments.

[0217] Preferably, the invention relates to a polypeptide according to the invention, characterized in that it is a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the metabolism of nucleic acids, and in that it is chosen from the polypeptides having the following sequences:

[0218] SEQ ID No. 14; SEQ ID No. 59; SEQ ID No. 70; SEQ ID No. 71; SEQ ID No. 97; SEQ ID No. 113; SEQ ID No. 137; SEQ ID No. 141; SEQ ID No. 169; SEQ ID No. 285; SEQ ID No. 287; SEQ ID No. 288; SEQ ID No. 313; SEQ ID No. 326; SEQ ID No. 358; SEQ ID No. 411; SEQ ID No. 443; SEQ ID No. 548; SEQ ID No. 569; SEQ ID No. 601; SEQ ID No. 651; SEQ ID No. 654; SEQ ID No. 658; SEQ ID No. 659; SEQ ID No. 664; SEQ ID No. 665; SEQ ID No. 694; SEQ ID No. 698; SEQ ID No. 704; SEQ ID No. 760; SEQ ID No. 762; SEQ ID No. 763; SEQ ID No. 786; SEQ ID No. 787; SEQ ID No. 788; SEQ ID No. 801; SEQ ID No. 802; SEQ ID No. 812; SEQ ID No. 819; SEQ ID No. 822; SEQ ID No. 870; SEQ ID No. 897; SEQ ID No. 898; SEQ ID No. 902; SEQ ID No. 908; SEQ ID No. 916; SEQ ID No. 954; SEQ ID No. 955; SEQ ID No. 961; SEQ ID No. 983; SEQ ID No. 996; SEQ ID No. 1007; SEQ ID No. 1012; SEQ ID No. 1013; SEQ ID No. 1014; SEQ ID No. 1015; SEQ ID No. 1038; SEQ ID No. 1137 and one of their representative fragments.

[0219] Preferably, the invention relates to a polypeptide according to the invention, characterized in that it is a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the metabolism of amino acids or polypeptides, and in that it is chosen from the polypeptides having the following sequences:

[0220] SEQ ID No. 99; SEQ ID No. 111; SEQ ID No. 127; SEQ ID No. 134; SEQ ID No. 140; SEQ ID No. 174; SEQ ID No. 175; SEQ ID No. 176; SEQ ID No. 353; SEQ ID No. 377; SEQ ID No. 404; SEQ ID No. 523; SEQ ID No. 539; SEQ ID No. 559; SEQ ID No. 561; SEQ ID No. 586; SEQ ID No. 598; SEQ ID No. 609; SEQ ID No. 636; SEQ ID No. 687; SEQ ID No. 700; SEQ ID No. 701; SEQ ID No. 759; SEQ ID No. 790; SEQ ID No. 857; SEQ ID No. 861; SEQ ID No. 904; SEQ ID No. 936; SEQ ID No. 952; SEQ ID No. 962; SEQ ID No. 963; SEQ ID No. 964; SEQ ID No. 965; SEQ ID No. 991; SEQ ID No. 1003; SEQ ID No. 1004; SEQ ID No. 1005; SEQ ID No. 1018; SEQ ID No. 1067; SEQ ID No. 1110; SEQ ID No. 1111; SEQ ID No. 1112; SEQ ID No. 1114; SEQ ID No. 1121; SEQ ID No. 1122; SEQ ID No. 1123; SEQ ID No. 1124; SEQ ID No. 1125 and one of their representative fragments.

[0221] Preferably, the invention relates to a polypeptide according to the invention, characterized in that it is a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the metabolism of polypeptides, and in that it is chosen from the polypeptides having the following sequences:

[0222] SEQ ID No. 4; SEQ ID No. 44; SEQ ID No. 45; SEQ ID No. 48; SEQ ID No. 54; SEQ ID No. 112; SEQ ID No. 130; SEQ ID No. 155; SEQ ID No. 163; SEQ ID No. 212; SEQ ID No. 257; SEQ ID No. 307; SEQ ID No. 343; SEQ ID No. 405; SEQ ID No. 416; SEQ ID No. 458; SEQ ID No. 540; SEQ ID No. 541; SEQ ID No. 542; SEQ ID No. 543; SEQ ID No. 544; SEQ ID No. 560; SEQ ID No. 594; SEQ ID No. 652; SEQ ID No. 699; SEQ ID No. 723; SEQ ID No. 747; SEQ ID No. 817; SEQ ID No. 827; SEQ ID No. 871; SEQ ID No. 909; SEQ ID No. 910; SEQ ID No. 911; SEQ ID No. 912; SEQ ID No. 1023; SEQ ID No. 1051; SEQ ID No. 1052; SEQ ID No. 1081 and one of their representative fragments.

[0223] Preferably, the invention relates to a polypeptide according to the invention, characterized in that it is a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the metabolism of fatty acids, and in that it is chosen from the polypeptides having the following sequences:

[0224] SEQ ID No. 76; SEQ ID No. 284; SEQ ID No. 308; SEQ ID No. 309; SEQ ID No. 310; SEQ ID No. 311; SEQ ID No. 312; SEQ ID No. 425; SEQ ID No. 433; SEQ ID No. 565; SEQ ID No. 688; SEQ ID No. 690; SEQ ID No. 691; SEQ ID No. 767; SEQ ID No. 797; SEQ ID No. 894; SEQ ID No. 895; SEQ ID No. 994; SEQ ID No. 1020; SEQ ID No. 1030; SEQ ID No. 1033; SEQ ID No. 1034; SEQ ID No. 1046; SEQ ID No. 1047; SEQ ID No. 1057 and one of their representative fragments.

[0225] Preferably, the invention relates to a polypeptide according to the invention, characterized in that it is a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the synthesis of the wall, and in that it is chosen from the polypeptides having the following sequences:

[0226] SEQ ID No. 49; SEQ ID No. 50; SEQ ID No. 177; SEQ ID No. 178; SEQ ID No. 245; SEQ ID No. 610; SEQ ID No. 972; SEQ ID No. 974; SEQ ID No. 978; SEQ ID No. 1037 and one of their representative fragments.

[0227] Preferably, the invention relates to a polypeptide according to the invention, characterized in that it is a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the transcription, translation and/or maturation process, and in that it is chosen from the polypeptides having the following sequences:

[0228] SEQ ID No. 90; SEQ ID No. 92; SEQ ID No. 131; SEQ ID No. 151; SEQ ID No. 199; SEQ ID No. 333; SEQ ID No. 334; SEQ ID No. 336; SEQ ID No. 379; SEQ ID No. 589; SEQ ID No. 590; SEQ ID No. 619; SEQ ID No. 630; SEQ ID No. 649; SEQ ID No. 739; SEQ ID No. 741; SEQ ID No. 806; SEQ ID No. 821; SEQ ID No. 843; SEQ ID No. 968; SEQ ID No. 971; SEQ ID No. 1061 and one of their representative fragments.

[0229] Preferably, the invention relates to a polypeptide according to the invention, characterized in that it is a Chlamydia pneumoniae ribosomal polypeptide or one of its representative fragments, and in that it is chosen from the polypeptides having the following sequences:

[0230] SEQ ID No. 93; SEQ ID No. 94; SEQ ID No. 95; SEQ ID No. 136; SEQ ID No. 259; SEQ ID No. 332; SEQ ID No. 348; SEQ ID No. 583; SEQ ID No. 584; SEQ ID No. 588; SEQ ID No. 591; SEQ ID No. 592; SEQ ID No. 663; SEQ ID No. 666; SEQ ID No. 667; SEQ ID No. 669; SEQ ID No. 670; SEQ ID No. 671; SEQ ID No. 672; SEQ ID No. 673; SEQ ID No. 674; SEQ ID No. 675; SEQ ID No. 676; SEQ ID No. 677; SEQ ID No. 678; SEQ ID No. 679; SEQ ID No. 680; SEQ ID No. 681; SEQ ID No. 683; SEQ ID No. 684; SEQ ID No. 738; SEQ ID No. 781; SEQ ID No. 1008; SEQ ID No. 1024; SEQ ID No. 1025; SEQ ID No. 1066 and one of their representative fragments.

[0231] Preferably, the invention also relates to a polypeptide according to the invention, characterized in that it is a Chlamydia pneumoniae transport polypeptide or one of its representative fragments, and in that it is chosen from the polypeptides having the following sequences:

[0232] SEQ ID No. 40; SEQ ID No. 41; SEQ ID No. 52; SEQ ID No. 105; SEQ ID No. 106; SEQ ID No. 107; SEQ ID No. 109; SEQ ID No. 133; SEQ ID No. 210; SEQ ID No. 211; SEQ ID No. 214; SEQ ID No. 215; SEQ ID No. 216; SEQ ID No. 217; SEQ ID No. 218; SEQ ID No. 219; SEQ ID No. 220; SEQ ID No. 223; SEQ ID No. 242; SEQ ID No. 260; SEQ ID No. 293; SEQ ID No. 299; SEQ ID No. 366; SEQ ID No. 369; SEQ ID No. 575; SEQ ID No. 602; SEQ ID No. 638; SEQ ID No. 639; SEQ ID No. 640; SEQ ID No. 643; SEQ ID No. 653; SEQ ID No. 702; SEQ ID No. 703; SEQ ID No. 724; SEQ ID No. 732; SEQ ID No. 855; SEQ ID No. 856; SEQ ID No. 901; SEQ ID No. 906; SEQ ID No. 933; SEQ ID No. 942; SEQ ID No. 1043; SEQ ID No. 1086; SEQ ID No. 1105 and one of their representative fragments.

[0233] Preferably, the invention relates to a polypeptide according to the invention, characterized in that it is a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the virulence process, and in that it is chosen from the polypeptides having the following sequences:

[0234] SEQ ID No. 546; SEQ ID No. 550; SEQ ID No. 778; SEQ ID No. 779; SEQ ID No. 886 and one of their representative fragments.

[0235] Preferably, the invention relates to a polypeptide according to the invention, characterized in that it is a Chlamydia pneumoniae polypeptide or one of its representative fragments which is involved in the secretory system and/or which is secreted, and in that it is chosen from the polypeptides having the following sequences:

[0236] SEQ ID No. 751; SEQ ID No. 874; SEQ ID No. 875; SEQ ID No. 876; SEQ ID No. 883; SEQ ID No. 884; SEQ ID No. 885 and one of their representative fragments.

[0237] The secreted polypeptides, including the Type III and other, non-Type III secreted polypeptides, of the present invention, as well as the corresponding nucleotide sequences, may be detected by techniques known to persons skilled in the art, such as for example the techniques using cloning combined with vectors allowing the expression of the said polypeptides fused to export markers such as the luc gene for luciferase or the PhoA gene for alkaline phosphatase.

[0238] Preferably, the invention relates to a polypeptide according to the invention, characterized in that it is a polypeptide specific to Chlamydia pneumoniae or one of its representative fragments(with a Blast E value of >10−5), and in that it is chosen from the polypeptides having the following sequences:

[0239] SEQ ID No. 7; SEQ ID No. 8; SEQ ID No. 17; SEQ ID No. 18; SEQ ID No. 19; SEQ ID No. 20; SEQ ID No. 22; SEQ ID No. 23; SEQ ID No. 24; SEQ ID No. 51; SEQ ID No. 60; SEQ ID No. 63; SEQ ID No. 65; SEQ ID No. 66; SEQ ID No. 67; SEQ ID No. 83; SEQ ID No. 84; SEQ ID No. 86; SEQ ID No. 87; SEQ ID No. 125; SEQ ID No. 143; SEQ ID No. 144; SEQ ID No. 179; SEQ ID No. 182; SEQ ID No. 184; SEQ ID No. 185; SEQ ID No. 187; SEQ ID No. 221; SEQ ID No. 252; SEQ ID No. 254; SEQ ID No. 278; SEQ ID No. 279; SEQ ID No. 387; SEQ ID No. 388; SEQ ID No. 397; SEQ ID No. 1048; SEQ ID No. 1049; SEQ ID No. 1050; SEQ ID No. 1128; SEQ ID No. 1130; SEQ ID No. 1131 and one of their representative fragments.

[0240] In general, in the present invention, the functional group to which a polypeptide of the invention belongs, as well as its corresponding nucleotide sequence, may be determined either by comparative analogy with sequences already known, or by the use of standard techniques of biochemistry, of cytology combined with the techniques of genetic engineering such as immunoaffinity, localization by immunolabelling, differential extraction, measurement of enzymatic activity, study of the activity inducing or repressing expression or the study of expression in E. coli.

[0241] It is clearly understood, on the one hand, that, in the present invention, the nucleotide sequences (ORF) and the amino acid sequences (SEQ ID No. 2 to SEQ ID No. 1291 and SEQ ID No. 6844 to SEQ ID No. 6848) which are listed by functional group, are not exhaustive within the group considered. Moreover, it is also clearly understood that, in the present invention, a nucleotide sequence (ORF) or an amino acid sequence mentioned within a given functional group may also be part of another group taking into account, for example, the interrelationship between the groups listed. Accordingly, and as an example of this interrelationship, an exported and/or secreted polypeptide as well as its coding nucleotide sequence may also be involved in the Chlamydia pneumoniae virulence process by modifying the defense mechanism of the infected host cell, or a transmembrane polypeptide or its coding nucleotide sequence is also part of the polypeptides or coding nucleotide sequences of the cellular envelope.

[0242] The subject of the present invention is also the nucleotide and/or polypeptide sequences according to the invention, characterized in that the said sequences are recorded on a medium, called recording medium, whose type and nature facilitate the reading, the analysis and the exploitation of the said sequences. These media may of course also contain other information extracted from the present invention, such as in particular the analogies with already known sequences, such as those mentioned in Table 1 of the present description, and/or may contain, in addition, information relating to the nucleotide and/or polypeptide sequences of other microorganisms so as to facilitate the comparative analysis and the exploitation of the results obtained.

[0243] Among these recording media, computer-readable media, such as magnetic, optical, electrical and hybrid media such as, for example, floppy disks, CD-ROMs or recording cassettes, are preferred in particular.

[0244] The invention also relates to nucleotide sequences which can be used as primer or probe, characterized in that the said sequences are chosen from the nucleotide sequences according to the invention.

[0245] The invention relates, in addition, to the use of a nucleotide sequence according to the invention, as primer or probe, for the detection and/or amplification of nucleic acid sequences.

[0246] The nucleotide sequences according to the invention may thus be used to amplify nucleotide sequences, in particular by the PCR technique (polymerase chain reaction) (Erlich, 1989; Innis et al., 1990; Rolfs et al., 1991, and White et al., 1997).

[0247] These oligodeoxyribonucleotide or oligoribonucleotide primers correspond to representative nucleotide fragments, and are advantageously at least 8 nucleotides, preferably at least 12 nucleotides, 15 nucleotides and still more preferably at least 20 nucleotides long.

[0248] Other techniques for amplifying the target nucleic acid may be advantageously used as alternatives to PCR.

[0249] The nucleotide sequences of the invention, in particular the primers according to the invention, may also be used in other methods for amplifying a target nucleic acid, such as:

[0250] the TAS (Transcription-based Amplification System) technique described by Kwoh et al. in 1989;

[0251] the 3SR (Self-Sustained Sequence Replication) technique described by Guatelli et al. in 1990;

[0252] the NASBA (Nucleic Acid Sequence Based Amplification) technique described by Kievitis et al. in 1991;

[0253] the SDA (Strand Displacement Amplification) technique (Walker et al., 1992);

[0254] the TMA (Transcription Mediated Amplification) technique.

[0255] The polynucleotides of the invention may also be used in techniques for amplifying or for modifying the nucleic acid serving as probe, such as:

[0256] the LCR (Ligase Chain Reaction) technique described by Landegren et al. in 1988 and perfected by Barany et al. in 1991, which uses a thermostable ligase;

[0257] the RCR (Repair Chain Reaction) technique described by Segev in 1992;

[0258] the CPR (Cycling Probe Reaction) technique described by Duck et al. in 1990;

[0259] the Q-beta-replicase amplification technique described by Miele et al. in 1983 and perfected in particular by Chu et al. in 1986, Lizardi et al. in 1988, and then by Burg et al. as well as by Stone et al. in 1996.

[0260] The invention also relates to the nucleotide sequences of fragments which can be obtained by amplification with the aid of at least one primer according to the invention. The present invention encompasses both hybridization probes and primers. In general, the complementary probes should be of a length sufficient to form a stable hybrid complex with the target sequences. Primers, while complementary to the target sequences need not form stable hybridization complexes with the target sequences alone. Rather, primers form stable complexes with the target sequences in the presence of polymerase to permit extension of the primer.

[0261] In the case where the target polynucleotide to be detected is possibly an RNA, for example an mRNA, it will be possible to use, prior to the use of an amplification reaction with the aid of at least one primer according to the invention or to the use of a method of detection with the aid of at least one probe of the invention, a reverse transcriptase-type enzyme so as to obtain a cDNA from the RNA contained in the biological sample. The cDNA obtained will then serve as target for the primer(s) or the probe(s) used in the amplification or detection method according to the invention.

[0262] The detection probe will be chosen so that it hybridizes with the target sequence or the amplicon generated from the target sequence. Such a detection probe will advantageously have as sequence a sequence of at least 12 nucleotides, in particular of at least 20 nucleotides, and preferably at least 100 nucleotides.

[0263] The invention also comprises the nucleotide sequences which can be used as probe or primer according to the invention, characterized in that they are labelled with a radioactive compound or with a nonradioactive compound.

[0264] The nonlabelled nucleotide sequences may be used directly as probes or primers; however, the sequences are generally labelled with a radioactive element (32P, 35S, 3H, 125I) or with a nonradioactive molecule (biotin, acetylaminofluorene, digoxigenin, 5-bromo-deoxyuridine, fluorescein) so as to obtain probes which can be used in numerous applications.

[0265] Examples of nonradioactive labelling of nucleotide sequences are described, for example, in French patent No. 78,10975 or by Urdea et al. or by Sanchez-Pescador et al. in 1988.

[0266] In the latter case, one of the labelling methods described in patents FR-2 422 956 and FR-2 518 755 may also be used.

[0267] The invention also relates to the nucleotide sequences of fragments which can be obtained by hybridization with the aid of at least one probe according to the invention.

[0268] The hybridization technique may be performed in various ways (Matthews et al., 1988). The most common method consists in immobilizing the nucleic acid extracted from Chlamydia pneumoniae cells on a support (such as nitrocellulose, nylon, polystyrene) and in incubating, under well-defined conditions, the target nucleic acid immobilized with the probe. After hybridization, the excess probe is removed and the hybrid molecules formed are detected by the appropriate method (measurement of the radioactivity, of the fluorescence or of the enzymatic activity linked to the probe).

[0269] The invention also comprises the nucleotide sequences according to the invention, characterized in that they are covalently or noncovalently immobilized on a support.

[0270] According to another advantageous embodiment of the nucleic sequences according to the invention, the latter may be used immobilized on a support and may thus serve to capture, through specific hybridization, the target nucleic acid obtained from the biological sample to be tested. If necessary, the solid support is separated from the sample and the hybridization complex formed between the so-called capture probe and the target nucleic acid is then detected by means of a second probe, called detection probe, labelled with an easily detectable element.

[0271] The nucleotide sequences according to the invention may also be used in new analytical systems, DNA chips, which allow sequencing, the study of mutations and of the expression of genes, and which are currently of interest given their very small size and their high capacity in terms of number of analyses.

[0272] The principle of the operation of these chips is based on molecular probes, most often oligonucleotides, which are attached onto a miniaturized surface, generally of the order of a few square centimetres. During an analysis, a sample containing fragments of a target nucleic acid to be analysed, for example DNA or RNA labelled, for example, after amplification, is deposited onto the DNA chip in which the support has been coated beforehand with probes. Bringing the labelled target sequences into contact with the probes leads to the formation, through hybridization, of a duplex according to the rule of pairing defined by J. D. Watson and F. Crick. After a washing step, analysis of the surface of the chip allows the effective hybridizations to be located by means of the signals emitted by the labels tagging the target. A hybridization fingerprint results from this analysis which, by appropriate computer processing, will make it possible to determine information such as the presence of specific fragments in the sample, the determination of sequences and the presence of mutations.

[0273] The chip consists of a multitude of molecular probes, precisely organized or arrayed on a solid support whose surface is miniaturized. It is at the centre of a system where other elements (imaging system, microcomputer) allow the acquisition and interpretation of a hybridization fingerprint.

[0274] The hybridization supports are provided in the form of flat or porous surfaces (pierced with wells) composed of various materials. The choice of a support is determined by its physicochemical properties, or more precisely, by the relationship between the latter and the conditions under which the support will be placed during the synthesis or the attachment of the probes or during the use of the chip. It is therefore necessary, before considering the use of a particular support (R. S. Matson et al., 1994), to consider characteristics such as its stability to pH, its physical strength, its reactivity and its chemical stability as well as its capacity to nonspecifically bind nucleic acids. Materials such as glass, silicon and polymers are commonly used. Their surface is, in a first step, called “functionalization”, made reactive towards the groups which it is desired to attach thereon. After the functionalization, so-called spacer molecules are grafted onto the activated surface. Used as intermediates between the surface and the probe, these molecules of variable size render unimportant the surface properties of the supports, which often prove to be problematic for the synthesis or the attachment of the probes and for the hybridization.

[0275] Among the hybridization supports, there may be mentioned glass which is used, for example, in the method of in situ synthesis of oligonucleotides by photochemical addressing developed by the company Affymetrix (E. L. Sheldon, 1993), the glass surface being activated by silane. Genosensor Consortium (P. Mérel, 1994) also uses glass slides carrying wells 3 mm apart, this support being activated with epoxysilane.

[0276] Polymers or silicon may also be mentioned among these hybridization supports. For example, the Andrein Mirzabekov team has developed a chip consisting of polyacrylamide squares polymerized on a silanized glass surface (G. Yershov et al., 1996). Several teams use silicon, in particular the IFOS laboratory of Ecole Centrale of Lyon which uses a silicon semiconductor substrate which is p-doped by introducing it into its crystalline structure atoms whose valency is different from that of silicon. Various types of metals, in particular gold and platinum, may also be used as support (Genosensor Consortium (K. Beattie et al., 1993)).

[0277] The probes according to the invention may be synthesized directly in situ on the supports of the DNA chips. This in situ synthesis may be carried out by photochemical addressing (developed by the company Affymax (Amsterdam, Holland) and exploited industrially by its subsidiary Affymetrix (United States)) or based on the VLSIPS (very large scale immobilized polymer synthesis) technology (S. P. A. Fodor et al., 1991) which is based on a method of photochemically directed combinatory synthesis and the principle of which combines solid-phase chemistry, the use of photolabile protecting groups and photolithography.

[0278] The probes according to the invention may be attached to the DNA chips in various ways such as electrochemical addressing, automated addressing or the use of probe printers (T. Livache et al., 1994; G. Yershov et al., 1996; J. Derisi et al., 1996, and S. Borman, 1996).

[0279] The revealing of the hybridization between the probes of the invention, deposited or synthesized in situ on the supports of the DNA chips, and the sample to be analysed, may be determined, for example, by measurement of fluorescent signals, by radioactive counting or by electronic detection.

[0280] The use of fluorescent molecules such as fluorescein constitutes the most common method of labelling the samples. It allows direct or indirect revealing of the hybridization and allows the use of various fluorochromes.

[0281] Affymetrix currently provides an apparatus or a scanner designed to read its Gene Chip™ chips. It makes it possible to detect the hybridizations by scanning the surface of the chip in confocal microscopy (R. J. Lipshutz et al., 1995). Other methods of detecting fluorescent signals have been tested: coupling of an epifluorescence microscope and a CCD camera (G. Yershov et al., 1996), the use of an optical fibre collecting system (E. L. Sheldon, 1993). A conventional method consists in carrying out an end labelling, with phosphorus 32, of the target sequences, by means of an appropriate apparatus, the Phosphorimager (marketed by Molecular Dynamics). The electronic detection is based on the principle that the hybridization of two nucleic acid molecules is accompanied by physical phenomena which can be quantified under certain conditions (system developed by Ecole Centrale of Lyon and called GEN-FET (GEN field effect transistor)). Genosensor Consortium and the company Beckman Instruments who are developing an electronic chip or Permittivity Chips™ may also be mentioned (K. Beattie et al., 1993).

[0282] The nucleotide sequences according to the invention may thus be used in DNA chips to carry out the analysis of mutations. This analysis is based on the production of chips capable of analysing each base of a nucleotide sequence according to the invention.

[0283] The nucleotide sequences according to the invention may also be used in DNA chips to carry out the analysis of the expression of the Chlamydia pneumoniae genes. This analysis of the expression of Chlamydia pneumoniae genes is based on the use of chips where probes of the invention, chosen for their specificity to characterize a given gene, are present (D. J. Lockhart et al., 1996; D. D. Shoemaker et al., 1996). For the methods of analysis of gene expression using the DNA chips, reference may, for example, be made to the methods described by D. J. Lockhart et al. (1996) and Sosnowsky et al. (1997) for the synthesis of probes in situ or for the addressing and the attachment of previously synthesized probes. The target sequences to be analysed are labelled and in general fragmented into sequences of about 50 to 100 nucleotides before being hybridized onto the chip. After washing as described, for example, by D. J. Lockhart et al. (1996) and application of different electric fields (Sosnowsky et al., 1997), the labelled compounds are detected and quantified, the hybridizations being carried out at least in duplicate. Comparative analyses of the signal intensities obtained with respect to the same probe for different samples and/or for different probes with the same sample, determine the differential expression of RNA or of DNA derived from the sample.

[0284] The nucleotide sequences according to the invention may, in addition, be used in DNA chips where other nucleotide probes specific for other microorganisms are also present, and may allow the carrying out of a serial test allowing rapid identification of the presence of a microorganism in a sample.

[0285] Accordingly, the subject of the invention is also the nucleotide sequences according to the invention, characterized in that they are immobilized on a support of a DNA chip.

[0286] The DNA chips, characterized in that they contain at least one nucleotide sequence according to the invention, immobilized on the support of the said chip, also form part of the invention.

[0287] The said chips will preferably contain several probes or nucleotide sequences of the invention of different length and/or corresponding to different genes so as to identify, with greater certainty, the specificity of the target sequences or the desired mutation in the sample to be analysed.

[0288] Accordingly, the analyses carried out by means of primers and/or probes according to the invention, immobilized on supports such as DNA chips, will make it possible, for example, to identify, in samples, mutations linked to variations such as intraspecies variations. These variations may be correlated or associated with pathologies specific to the variant identified and will make it possible to select the appropriate treatment.

[0289] The invention thus comprises a DNA chip according to the invention, characterized in that it contains, in addition, at least one nucleotide sequence of a microorganism different from Chlamydia pneumoniae, immobilized on the support of the said chip; preferably, the different microorganism will be chosen from an associated microorganism, a bacterium of the Chlamydia family, and a variant of the species Chlamydia pneumoniae.

[0290] Another subject of the present invention is a vector for the cloning and/or the expression of a sequence, characterized in that it contains a nucleotide sequence according to the invention. Among the said vectors according to the invention, the vectors containing a nucleotide sequence encoding a polypeptide of the cellular, preferably outer, envelope of Chlamydia pneumoniae or one of its representative fragments, are preferred. In a specific embodiment, the vectors contain a nucleotide sequence encoding a Chlamydia pneumoniae secreted polypeptide or one of its representative fragments or encoding a transport polypeptide, a surface exposed polypeptide, a lipoprotein or one of its representative fragments, a polypeptide involved in lipopolysaccharide (LPS) biosynthesis, a Type III and non-Type III secreted polypeptide, a polypeptide containing RGD attachment sites, a cell wall anchored surface polypeptide, a polypeptide not found in Chlamydia trachomatis, a ribosomal polypeptide or a polypeptide involved in secretion, transcription, translation, maturation of proteins, a polypeptide involved in the synthesis of the wall, a polypeptide involved in the virulence, a polypeptide involved in the intermediate metabolism, in particular in the metabolism of sugars and/or of cofactors, a polypeptide involved in the metabolism of nucleotides, of amino acids, of nucleic acids or of fatty acids of Chlamydia pneumoniae or one of their representative fragments, or a polypeptide specific to Chlamydia pneumoniae.

[0291] According to the invention, the vectors comprise the elements necessary to allow the expression and/or the secretion of the said nucleotide sequences in a given host cell, and form part of the invention. The vector should, in this case, comprise a promoter, signals for initiation and for termination of translation, as well as appropriate regions for regulation of transcription. It should be capable of being stably maintained in the host cell and may optionally possess particular signals specifying the secretion of the translated protein. These different elements are chosen according to the host cell used. To this effect, the nucleotide sequences according to the invention may be inserted into autonomously-replicating vectors within the chosen host, or integrative vectors in the chosen host.

[0292] Any of the standard methods known to those skilled in the art for the insertion of DNA fragments into a vector may be used to construct expression vectors containing a chimeric gene consisting of appropriate transcriptional/translational control signals and the protein coding sequences. These methods may include in vitro recombinant DNA and synthetic techniques and in vivo recombinants (genetic recombination).

[0293] Expression of a polypeptide, peptide or derivative, or analogs thereof encoded by a polynucleotide sequence in SEQ ID No. 1 or ORFs contained within SEQ ID No. 1 may be regulated by a second nucleic acid sequence so that the protein or peptide is expressed in a host transformed with the recombinant DNA molecule. For example, expression of a protein or peptide may be controlled by any promoter/enhancer element known in the art. Promoters which may be used to control expression include, but are not limited to, the CMV promoter, the SV40 early promoter region (Bernoist and Chambon, 1981, Nature 290:304-310), the promoter contained in the 3′ long terminal repeat of Rous sarcoma virus (Yamamoto, et al., 1980, Cell 22:787-797), the herpes thymidine kinase promoter (Wagner et al., 1981, Proc. Natl. Acad. Sci. U.S.A. 78:1441-1445), the regulatory sequences of the metallothionein gene (Brinster et al., 1982, Nature 296:39-42); prokaryotic expression vectors such as the ∃-lactamase promoter (Villa-Kamaroff, et al., 1978, Proc. Natl. Acad. Sci. U.S.A. 75:3727-3731), or the tac promoter (DeBoer, et al., 1983, Proc. Natl. Acad. Sci. U.S.A. 80:21-25); see also “Useful proteins from recombinant bacteria” in Scientific American, 1980, 242:74-94; plant expression vectors comprising the nopaline synthetase promoter region (Herrera-Estrella et al., 1983, Nature 303:209-213) or the cauliflower mosaic virus 35S RNA promoter (Gardner, et al., 1981, Nucl. Acids Res. 9:2871), and the promoter of the photosynthetic enzyme ribulose biphosphate carboxylase (Herrera-Estrella et al., 1984, Nature 310:115-120); promoter elements from yeast or other fungi such as the Gal 4 promoter, the ADC (alcohol dehydrogenase) promoter, PGK (phosphoglycerol kinase) promoter, alkaline phosphatase promoter, and the following animal transcriptional control regions, which exhibit tissue specificity and have been utilized in transgenic animals: elastase I gene control region which is active in pancreatic acinar cells (Swift et al., 1984, Cell 38:639-646; Ornitz et al., 1986, Cold Spring Harbor Symp. Quant. Biol. 50:399-409; MacDonald, 1987, Hepatology 7:425-515); insulin gene control region which is active in pancreatic beta cells (Hanahan, 1985, Nature 315:115-122), immunoglobulin gene control region which is active in lymphoid cells (Grosschedl et al., 1984, Cell 38:647-658; Adames et al., 1985, Nature 318:533-538; Alexander et al., 1987, Mol. Cell. Biol. 7:1436-1444), mouse mammary tumor virus control region which is active in testicular, breast, lymphoid and mast cells (Leder et al., 1986, Cell 45:485-495), albumin gene control region which is active in liver (Pinkert et al., 1987, Genes and Devel. 1:268-276), alpha-fetoprotein gene control region which is active in liver (Krumlauf et al., 1985, Mol. Cell. Biol. 5:1639-1648; Hammer et al., 1987, Science 235:53-58; alpha 1-antitrypsin gene control region which is active in the liver (Kelsey et al., 1987, Genes and Devel. 1:161-171), beta-globin gene control region which is active in myeloid cells (Mogram et al., 1985, Nature 315:338-340; Kollias et al., 1986, Cell 46:89-94; myelin basic protein gene control region which is active in oligodendrocyte cells in the brain (Readhead et al., 1987, Cell 48:703-712); myosin light chain-2 gene control region which is active in skeletal muscle (Sani, 1985, Nature 314:283-286), and gonadotropic releasing hormone gene control region which is active in the hypothalamus (Mason et al., 1986, Science 234:1372-1378).

[0294] The vectors according to the invention are, for example, vectors of plasmid or viral origin. In a specific embodiment, a vector is used that comprises a promoter operably linked to a protein or peptide-encoding a nucleic acid sequence in SEQ ID No. 1, or ORFs contained within SEQ ID No. 1, one or more origins of replication, and, optionally, one or more selectable markers (e.g., an antibiotic resistance gene). Expression vectors comprise regulatory sequences that control gene expression, including gene expression in a desired host cell. Preferred vectors for the expression of the polypeptides of the invention include the pET-type plasmid vectors (Promega) or pBAD plasmid vectors (Invitrogen). Furthermore, the vectors according to the invention are useful for transforming host cells so as to clone or express the nucleotide sequences of the invention.

[0295] Expression can also be achieved using targeted homologous recombination to activate Chlamydia pneumoniae genes present in the cloned genomic DNA. A heterologous regulatory element may be inserted into a stable cell line or cloned microorganism, such that it is operatively linked with an endogenous Chlamydia pneumoniae gene present in the cloned genome, using techniques, such as targeted homologous recombination, which are well known to those of skill in the art (See, e.g., Chappel, U.S. Pat. No. 4,215,051 and Skoultchi, WO 91/06667 each of which is incorporated herein in its entirety).

[0296] Expression vector/host cell systems containing inserts of polynucleotide sequences in SEQ ID No. 1 or ORFs within SEQ ID No. 1, which encode polypeptides, peptides or derivatives, or analogs thereof, can be identified by three general approaches: (a) nucleic acid hybridization, (b) presence or absence of “marker” gene functions, and (c) expression of inserted sequences. In the first approach, the presence of a polynucleotide sequence inserted in an expression vector can be detected by nucleic acid hybridization using probes comprising sequences that are homologous to an inserted polynucleotide sequence. In the second approach, the recombinant vector/host system can be identified and selected based upon the presence or absence of certain “marker” gene functions (e.g., thymidine kinase activity, resistance to antibiotics, transformation phenotype, occlusion body formation in baculovirus, etc.) caused by the insertion of a polynucleotide sequence in the vector. For example, if the polynucleotide sequence in SEQ ID No. 1 or ORFs within SEQ ID No. 1 is, inserted within the marker gene sequence of the vector, recombinants containing the insert can be identified by the absence of the marker gene function. In the third approach, recombinant expression vectors can be identified by assaying the product of the polynucleotide sequence expressed by the recombinant. Such assays can be based, for example, on the physical or functional properties of the expressed polypeptide in in vitro assay systems, e.g., binding with antibody, promotion of cell proliferation.

[0297] Once a particular recombinant DNA molecule is identified and isolated, several methods known in the art may be used to propagate it. The clones identified may be introduced into an appropriate host cell by standard methods, such as for example lipofection, electroporation, and heat shock. Once a suitable host system and growth conditions are established, recombinant expression vectors can be propagated and prepared in quantity.

[0298] The invention also encompasses the host cells transformed by a vector according to the invention. These cells may be obtained by introducing into host cells a nucleotide sequence inserted into a vector as defined above, and then culturing the said cells under conditions allowing the replication and/or the expression of the transfected nucleotide sequence. The host cell may be chosen from eukaryotic or prokaryotic systems, such as for example bacterial cells (Olins and Lee, 1993), but also yeast cells (Buckholz, 1993), as well as animal cells, in particular cultures of mammalian cells (Edwards and Aruffo, 1993), and in particular Chinese hamster ovary (CHO) cells, but also insect cells in which methods using baculoviruses for example may be used (Luckow, 1993).

[0299] Furthermore, a host cell strain may be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Expression from certain promoters can be elevated in the presence of certain inducers; thus, expression of the genetically engineered polypeptide may be controlled. Furthermore, different host cells have characteristic and specific mechanisms for the translational and post-translational processing and modification (e.g., glycosylation, phosphorylation) of proteins. Appropriate cell lines or host systems can be chosen to ensure the desired modification and processing of the foreign protein expressed. For example, expression in a bacterial system can be used to produce an unglycosylated core protein product. Expression in yeast will produce a glycosylated product. Expression in mammalian cells can be used to ensure “native” glycosylation of a heterologous protein. Furthermore, different vector/host expression systems may effect processing reactions to different extents.

[0300] A preferred host cell for the expression of the proteins of the invention consists of prokaryotic cells, such as Gram− bacteria. A further preferred host cell according to the invention is a bacterium belonging to the Chlamydia family, more preferably belonging to the species Chlamydia pneumoniae or chosen from a microorganism associated with the species Chlamydia pneumoniae.

[0301] In other specific embodiments, the polypeptides, peptides or derivatives, or analogs thereof may be expressed as a fusion, or chimeric protein product (comprising the protein, fragment, analog, or derivative joined via a peptide bond to a heterologous protein sequence (of a different protein)). Such a chimeric product can be made by ligating the appropriate nucleic acid sequences encoding the desired amino acid sequences to each other by methods known in the art, in the proper coding frame, and expressing the chimeric product by methods commonly known in the art. Alternatively, such a chimeric product may be made by protein synthetic techniques, e.g., by use of a peptide synthesizer.

[0302] Genomic sequences can be cloned and expressed as translational gene products (i.e., peptides, polypeptides, and proteins) or transcriptional gene products (i.e., antisense and ribozymes).

[0303] The invention further relates to the intracellular production of an antisense nucleic acid sequence of SEQ ID No. 1 by transcription from an exogenous sequence. For example, a vector can be introduced in vivo such that it is taken up by a cell, within which cell the vector or a portion thereof is transcribed, producing an antisense nucleic acid (RNA) of the invention. Such a vector would contain a sequence encoding an antisense nucleic acid. Such a vector can remain episomal or become chromosomally integrated, as long as it can be transcribed to produce the desired antisense RNA. Such vectors can be constructed by recombinant DNA technology methods standard in the art. Vectors can be plasmid, viral, or others known in the art, used for replication and expression in mammalian cells. Expression of the sequence encoding the an antisense RNA can be by any promoter known in the art to act in mammalian, preferably human, cells. Such promoters can be inducible or constitutive. Such promoters include but are not limited to: the CMV promoter, the SV40 early promoter region (Bernoist and Chambon, 1981, Nature 290:304-310), the promoter contained in the 3N long terminal repeat of Rous sarcoma virus (Yamamoto et al., 1980, Cell 22:787-797), the herpes thymidine kinase promoter (Wagner et al., 1981, Proc. Natl. Acad. Sci. U.S.A. 78:1441-1445), the regulatory sequences of the metallothionein gene (Brinster et al., 1982, Nature 296:39-42), etc.

[0304] In a specific embodiment, the antisense oligonucleotide comprises catalytic RNA, or a ribozyme (see, e.g., PCT International Publication WO 90/11364, published Oct. 4, 1990; Sarver et al., 1990, Science 247:1222-1225). In another embodiment, the oligonucleotide is a 2N-0-methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res. 15:6131-6148), or a chimeric RNA-DNA analog (Inoue et al., 1987, FEBS Lett. 215:327-330).

[0305] In another embodiment, the antisense nucleic acids of the invention comprise a sequence complementary to at least a portion of an RNA transcript of a polynucleotide sequence in SEQ ID No. 1. However, absolute complementarity, although preferred, is not required. A sequence “complementary to at least a portion of an RNA,” as referred to herein, means a sequence having sufficient complementarity to be able to hybridize with the RNA, forming a stable duplex; in the case of double-stranded antisense nucleic acid sequence, a single strand of the duplex DNA may thus be tested, or triplex formation may be assayed. The ability to hybridize will depend on both the degree of complementarity and the length of the antisense nucleic acid. Generally, the longer the hybridizing nucleic acid, the more base mismatches with an RNA transcribed from SEQ ID No. 1 may contain and still form a stable duplex (or triplex, as the case may be). One skilled in the art can ascertain a tolerable degree of mismatch by use of standard procedures to determine the melting point of the hybridized complex.

[0306] The invention also relates to the animals, except humans, comprising one of the above-described transformed cells according to the invention.

[0307] The production of transgenic animals according to the invention overexpressing one or more of the Chlamydia pneumoniae genes will be preferably carried out on rats, mice or rabbits according to methods well known to persons skilled in the art such as viral or nonviral transfections. The transgenic animals overexpressing one or more of the said genes may be obtained by transfection of multiple copies of the said genes under the control of a powerful promoter of a ubiquitous nature, or which is selective for one type of tissue. The transgenic animals may also be obtained by homologous recombination on embryonic stem cells, transfer of these stem cells to embryos, selection of the chimeras affected at the level of the reproductive lines, and growth of the said chimeras.

[0308] The transformed cells as well as the transgenic animals according to the invention can be used in methods of preparing the recombinant polypeptide.

[0309] It is now possible to produce recombinant polypeptides in a relatively large quantity by genetic engineering using the cells transformed with expression vectors according to the invention or using transgenic animals according to the invention.

[0310] The methods of preparing a polypeptide of the invention in recombinant form, characterized in that they use a vector and/or a cell, transformed with a vector according to the invention and/or a transgenic animal comprising one of the said transformed cells according to the invention, are themselves included in the present invention.

[0311] Among the said methods of preparing a polypeptide of the invention in recombinant form, the methods of preparation using a vector, and/or a cell transformed with the said vector and/or a transgenic animal comprising one of the said transformed cells, containing a nucleotide sequence encoding a polypeptide of the cellular envelope of Chlamydia pneumoniae or one of its representative fragments, more preferably encoding a polypeptide of the outer cellular envelope of Chlamydia pneumoniae or one of its fragment, are preferred.

[0312] Among the said methods of preparing a polypeptide of the invention in recombinant form, the methods of preparation using a vector, and/or a cell transformed with the said vector and/or a transgenic animal comprising one of the said transformed cells, containing a nucleotide sequence encoding a Chlamydia pneumoniae secreted polypeptide or one of its representative fragments or encoding a transport polypeptide, a surface exposed polypeptide, a lipoprotein or one of its representative fragments, a polypeptide involved in lipopolysaccharide biosynthesis, a Type III or other secreted polypeptide, a polypeptide containing RGD attachment sites, a cell wall anchored surface polypeptide, a polypeptide not found in Chlamydia trachomatis, a ribosomal polypeptide or a polypeptide involved in secretion, transcription, translation, maturation of proteins, a polypeptide involved in the synthesis of the wall, a polypeptide involved in the virulence, a polypeptide involved in the intermediate metabolism, in particular in the metabolism of sugars and/or of cofactors, a polypeptide involved in the metabolism of nucleotides, of amino acids, of nucleic acids or of fatty acids of Chlamydia pneumoniae or one of their representative fragments, or a polypeptide specific to Chlamydia pneumoniae, are also preferred.

[0313] The recombinant polypeptides obtained as indicated above may be provided either in glycosylated or non-glycosylated form and may or may not have the natural tertiary structure.

[0314] A preferred variant consists in producing a recombinant polypeptide fused to a “carrier” protein (chimeric protein). The advantage of this system is that it allows a stabilization and a reduction in proteolysis of the recombinant product, an increase in solubility during renaturation in vitro and/or a simplification of purification when the fusion partner has affinity for a specific ligand.

[0315] More particularly, the invention relates to a method of preparing a polypeptide of the invention comprising the following steps:

[0316] a) culture of the transformed cells under conditions allowing the expression of a recombinant polypeptide having a nucleic acid sequence according to the invention;

[0317] b) where appropriate, recovery of the said recombinant polypeptide.

[0318] When the method of preparing a polypeptide of the invention uses a transgenic animal according to the invention, the recombinant polypeptide is then extracted from the said animal.

[0319] The subject of the invention is also a polypeptide capable of being obtained by a method of the invention as described above.

[0320] The invention also comprises a method of preparing a synthetic polypeptide, characterized in that it uses an amino acid sequence of polypeptides according to the invention.

[0321] The invention also relates to a synthetic polypeptide obtained by a method according to the invention.

[0322] Polypeptides according to the invention may also be prepared by conventional techniques in the field of peptide synthesis under conditions suitable to produce the polypeptides encoded by the polynucleotide of the invention. This synthesis may be carried out in and recovered from a homogeneous solution or on a solid phase.

[0323] For example, the synthesis technique in a homogeneous solution described by Houbenweyl in 1974 may be used.

[0324] This method of synthesis consists in successively condensing, in pairs, the successive amino acids in the required order, or in condensing amino acids and fragments previously formed and already containing several amino acids in the appropriate order, or alternatively several fragments thus previously prepared, it being understood that care will have been taken to protect beforehand all the reactive functional groups carried by these amino acids or fragments, with the exception of the amine functional groups of one and the carboxyl functional groups of the other or vice versa, which should normally take part in the formation of the peptide bonds, in particular after activation of the carboxyl functional group, according to methods well known in peptide synthesis.

[0325] According to another preferred technique of the invention, the one described by Merrifield is used.

[0326] To manufacture a peptide chain according to the Merrifield method, a highly porous polymer resin is used, onto which the first C-terminal amino acid of the chain is attached. This amino acid is attached onto a resin via its carboxyl group and its amine functional group is protected. The amino acids which will constitute the peptide chain are thus attached, one after another, onto the amine group, each time deprotected beforehand, of the portion of the peptide chain already formed, and which is attached to the resin. When the entire peptide chain desired is formed, the protecting groups are removed from the various amino acids constituting the peptide chain and the peptide is detached from the resin with the aid of an acid.

[0327] The invention relates, in addition, to hybrid (fusion) polypeptides having at least one polypeptide or one of its representative fragments according to the invention, and a sequence of a polypeptide capable of eliciting an immune response in humans or animals.

[0328] Advantageously, the antigenic determinant is such that it is capable of eliciting a humoral and/or cellular response. An antigenic determinant may be identified by screening expression libraries of the Chlamydia pneumoniae genome with antibodies contained in the serum of patients infected with a bacterium belonging to the species Chlamydia pneumoniae. An antigenic determinant may comprise a polypeptide or one of its representative fragments according to the invention, in glycosylated form, used in order to obtain immunogenic compositions capable of inducing the synthesis of antibodies directed against multiple epitopes. The said polypeptides or their glycosylated fragments also form part of the invention.

[0329] These hybrid molecules may consist, in part, of a carrier molecule for polypeptides or for their representative fragments according to the invention, combined with a portion which may be immunogenic, in particular an epitope of the diphtheria toxin, the tetanus toxin, a hepatitis B virus surface antigen (patent FR 79 21811), the poliomyelitis virus VP1 antigen or any other viral or bacterial toxin or antigen.

[0330] The methods of synthesizing the hybrid molecules include the methods used in genetic engineering to construct hybrid nucleotide sequences encoding the desired polypeptide sequences. Reference may be advantageously made, for example, to the technique for producing genes encoding fusion proteins described by Minton in 1984.

[0331] The said hybrid nucleotide sequences encoding a hybrid polypeptide as well as the hybrid polypeptides according to the invention, characterized in that they are recombinant polypeptides obtained by the expression of the said hybrid nucleotide sequences, also form part of the invention.

[0332] The invention also comprises the vectors characterized in that they contain one of the said hybrid nucleotide sequences. The host cells transformed by the said vectors, the transgenic animals comprising one of the said transformed cells as well as the methods of preparing recombinant polypeptides using the said vectors, the said transformed cells and/or the said transgenic animals of course also form part of the invention.

[0333] The polypeptides according to the invention, the antibodies according to the invention described below and the nucleotide sequences according to the invention may advantageously be used in in vitro and/or in vivo methods for the detection and/or the identification of bacteria belonging to the species Chlamydia pneumoniae, in a biological sample (biological tissue or fluid) which is likely to contain them. These methods, depending on the specificity of the polypeptides, of the antibodies and of the nucleotide sequences according to the invention which will be used, may in particular detect and/or identify the bacterial variants belonging to the species Chlamydia pneumoniae as well as the associated microorganisms capable of being detected by the polypeptides, the antibodies and the nucleotide sequences according to the invention which will be chosen. It may, for example, be advantageous to choose a polypeptide, an antibody or a nucleotide sequence according to the invention, which is capable of detecting any bacterium of the Chlamydia family by choosing a polypeptide, an antibody and/or a nucleotide sequence according to the invention which is specific to the family or, on the contrary, it will be most particularly advantageous to target a variant of the species Chlamydia pneumoniae, which is responsible, for example, for the induction or the worsening of pathologies specific to the targeted variant, by choosing a polypeptide, an antibody and/or a nucleotide sequence according to the invention which is specific to the said variant.

[0334] The polypeptides according to the invention may advantageously be used in a method for the detection and/or the identification of bacteria belonging to the species Chlamydia pneumoniae or to an associated microorganism, in a biological sample (biological tissue or fluid) which is likely to contain them, characterized in that it comprises the following steps:

[0335] a) bringing this biological sample into contact with a polypeptide or one of its representative fragments according to the invention (under conditions allowing an immunological reaction between the said polypeptide and the antibodies which may be present in the biological sample);

[0336] b) detecting the antigen-antibody complexes which may be formed.

[0337] Preferably, the biological sample consists of a fluid, for example a human or animal serum, blood or biopsies.

[0338] Any conventional procedure may be used to carry out such a detection of the antigen-antibody complexes which may be formed.

[0339] By way of example, a preferred method uses immunoenzymatic procedures based on the ELISA technique, immunofluorescence procedures or radioimmunological procedures (RIA), and the like.

[0340] Accordingly, the invention also relates to the polypeptides according to the invention, labelled with the aid of a suitable label such as a label of the enzymatic, fluorescent or radioactive type.

[0341] Such methods comprise, for example, the following steps:

[0342] deposition of defined quantities of a polypeptide composition according to the invention into the wells of a microtitre plate,

[0343] introduction, into the said wells, of increasing dilutions of serum, or of a different biological sample as defined above, which has to be analysed,

[0344] incubation of the microplate,

[0345] introduction, into the wells of the microtitre plate, of labelled antibodies directed against human or animal immunoglobulins, these antibodies having been labelled with the aid of an enzyme selected from those which are capable of hydrolyzing a substrate, thereby modifying the absorption of the radiation of the latter, at least at a defined wavelength, for example at 550 nm,

[0346] detection, by comparison with a control, of the quantity of substrate hydrolyzed.

[0347] The invention also relates to a kit or set for the detection and/or the identification of bacteria belonging to the species Chlamydia pneumoniae or to an associated microorganism, characterized in that it comprises the following components:

[0348] a polypeptide according to the invention,

[0349] where appropriate, the reagents for constituting the medium appropriate for the immunological or specific reaction,

[0350] the reagents allowing the detection of the antigen-antibody complexes produced by the immunological reaction between the polypeptide(s) of the invention and the antibodies which may be present in the biological sample, it being possible for these reagents also to carry a label, or to be capable of being recognized in turn by a labelled reagent, more particularly in the case where the polypeptide according to the invention is not labelled,

[0351] where appropriate, a reference biological sample (negative control) free of antibodies recognized by a polypeptide according to the invention,

[0352] where appropriate, a reference biological sample (positive control) containing a predetermined quantity of antibodies recognized by a polypeptide according to the invention.

[0353] According to the invention, the polypeptides, peptides, fusion proteins or other derivatives, or analogs thereof encoded by a polynucleotide sequence in SEQ ID No. 1, may be used as an immunogen to generate antibodies which immunospecifically bind such an immunogen. Such antibodies may include, but are not limited to, polyclonal and monoclonal antibodies, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab′)2 fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above. In a specific embodiment, the antibody to a polypeptide, peptide or other derivative, or analog thereof encoded by a polynucleotide sequence in SEQ ID No. 1 is a bispecific antibody (see generally, e.g. Fanger and Drakeman, 1995, Drug News and Perspectives 8: 133-137). Such a bispecific antibody is genetically engineered to recognize both (1) an epitope and (2) one of a variety of “trigger” molecules, e.g. Fc receptors on myeloid cells, and CD3 and CD2 on T cells, that have been identified as being able to cause a cytotoxic T-cell to destroy a particular target. Such bispecific antibodies can be prepared either by chemical conjugation, hybridoma, or recombinant molecular biology techniques known to the skilled artisan.

[0354] Various procedures known in the art may be used for the production of polyclonal antibodies to a polypeptide, peptide or other derivative, or analog thereof encoded by a polynucleotide sequence in SEQ ID No. 1. For the production of antibody, various host animals can be immunized by injection with a polypeptide, or peptide or other derivative, or analog thereof, including but not limited to rabbits, mice, rats, etc. Various adjuvants, depending on the host species, may be used to increase the immunological response, including but not limited to Stimulon™ QS-21 (Aquila Biopharmaceuticals, Inc., Framingham, Mass.), MPLTM (3-O-deacylated monophosphoryl lipid A; RIBI ImmunoChem Research, Inc., Hamilton, Mont.), aluminum phosphate, IL-12 (Genetics Institute, Cambridge, Mass.), Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, BCG (bacille Calmette-Guerin), and corynebacterium parvum. Alternatively, polyclonal antibodies may be prepared by purifying, on an affinity column onto which a polypeptide according to the invention has been previously attached, the antibodies contained in the serum of patients infected with a bacterium belonging to the species Chlamydia pneumoniae.

[0355] For preparation of monoclonal antibodies directed toward a polypeptide, peptide or other derivative, or analog, any technique which provides for the production of antibody molecules by continuous cell lines in culture may be used. For example, the hybridoma technique originally developed by Kohler and Milstein (1975, Nature 256:495-497), as well as the trioma technique, the human B-cell hybridoma technique (Kozbor et al., 1983, Immunology Today 4:72), and the EBV-hybridoma technique to produce human monoclonal antibodies (Cole et al., 1985, in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96). In an additional embodiment of the invention, monoclonal antibodies can be produced in germ-free animals utilizing technology described in PCT/US90/02545. In another embodiment of the invention, transgenic non-human animals can be used for the production of human antibodies utilizing technology described in WO 98/24893 and WO 96/33735. According to the invention, human antibodies may be used and can be obtained by using human hybridomas (Cote et al., 1983, Proc. Natl. Acad. Sci. U.S.A. 80:2026-2030) or by transforming human B cells with EBV virus in vitro (Cole et al., 1985, in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, pp. 77-96). In fact, according to the invention, techniques developed for the production of “chimeric antibodies” (Morrison et al., 1984, PROC. NATL. ACAD. SCI. U.S.A. 81:6851-6855; Neuberger et al., 1984, Nature 312:604-608; Takeda et al., 1985, Nature 314:452-454) by splicing the genes from a mouse antibody molecule specific for a polypeptide, peptide or other derivative, or analog together with genes from a human antibody molecule of appropriate biological activity can be used; such antibodies are within the scope of this invention.

[0356] According to the invention, techniques described for the production of single chain antibodies (U.S. Pat. No. 4,946,778) can be adapted to produce polypeptide or peptide-specific single chain antibodies. An additional embodiment of the invention utilizes the techniques described for the construction of Fab expression libraries (Huse et al., 1989, Science 246:1275-1281) to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity for polypeptides, derivatives, or analogs.

[0357] Antibody fragments which contain the idiotype of the molecule can be generated by known techniques. For example, such fragments include but are not limited to: the F(ab′)2 fragment which can be produced by pepsin digestion of the antibody molecule; the Fab′ fragments which can be generated by reducing the disulfide bridges of the F(ab′)2 fragment, the Fab fragments which can be generated by treating the antibody molecule with papain and a reducing agent, and Fv fragments.

[0358] In addition, techniques have been developed for the production of chimerized (See, e.g., Boss, M. et al., U.S. Pat. No. 4,816,397; and Cabilly, S. et al., U.S. Pat. No. 5,585,089 each of which is incorporated herein by reference in its entirety) humanized antibodies (See, e.g., Queen, U.S. Pat. No. 5,585,089, which is incorporated herein by reference in its entirety.) An immunoglobulin light or heavy chain variable region consists of a “framework” region interrupted by three hypervariable regions, referred to as complementarily determining regions (CDRs). The extent of the framework region and CDRs have been precisely defined (See, “Sequences of Proteins of Immunological Interest”, Kabat, E. et al., U.S. Department of Health and Human Services (1983). Briefly, humanized antibodies are antibody molecules from non-human species having one or more CDRs from the non-human species and a framework from a human immunoglobulin molecule.

[0359] The antibodies of the invention may also be labelled in the same manner as described above for the nucleic probes of the invention such as an enzymatic, fluorescent or radioactive type labelling.

[0360] The invention relates, in addition, to a method for the detection and/or the identification of bacteria belonging to the species Chlamydia pneumoniae or to an associated microorganism in a biological sample, characterized in that it comprises the following steps:

[0361] a) bringing the biological sample (biological tissue or fluid) into contact with a mono- or polyclonal antibody according to the invention (under conditions allowing an immunological reaction between the said antibodies and the polypeptides of the bacterium belonging to the species Chlamydia pneumoniae or to an associated microorganism which may be present in the biological sample, that is, under conditions suitable for the formation of immune complexes);

[0362] b) detecting the antigen-antibody complex which may be formed.

[0363] Also falling within the scope of the invention is a kit or set for the detection and/or the identification of bacteria belonging to the species Chlamydia pneumoniae or to an associated microorganism, characterized in that it comprises the following components:

[0364] a polyclonal or monoclonal antibody according to the invention, labeled where appropriate;

[0365] where appropriate, a reagent for constituting the medium appropriate for carrying out the immunological reaction;

[0366] a reagent allowing the detection of the antigen-antibody complexes produced by the immunological reaction, it being possible for this reagent also to carry a label, or to be capable of being recognized in turn by a labelled reagent, more particularly in the case where the said monoclonal or polyclonal antibody is not labelled;

[0367] where appropriate, reagents for carrying out the lysis of the cells in the sample tested.

[0368] The principle of the DNA chip which was explained above may also be used to produce protein “chips” on which the support has been coated with a polypeptide or an antibody according to the invention, or arrays thereof, in place of the DNA. These protein “chips” make it possible, for example, to analyze the biomolecular interactions (BIA) induced by the affinity capture of target analytes onto a support coated, for example, with proteins, by surface plasma resonance (SPR). Reference may be made, for example, to the techniques for coupling proteins onto a solid support which are described in EP 524 800 or to the methods describing the use of biosensor-type protein chips such as the BIAcore-type technique (Pharmacia) (Arlinghaus et al., 1997, Krone et al., 1997, Chatelier et al., 1995). These polypeptides or antibodies according to the invention, capable of specifically binding antibodies or polypeptides derived from the sample to be analysed, may thus be used in protein chips for the detection and/or the identification of proteins in samples. The said protein chips may in particular be used for infectious diagnosis and may preferably contain, per chip, several polypeptides and/or antibodies of the invention of different specificity, and/or polypeptides and/or antibodies capable of recognizing microorganisms different from Chlamydia pneumoniae.

[0369] Accordingly, the subject of the present invention is also the polypeptides and the antibodies according to the invention, characterized in that they are immobilized on a support, in particular of a protein chip.

[0370] The protein chips, characterized in that they contain at least one polypeptide or one antibody according to the invention immobilized on the support of the said chip, also form part of the invention.

[0371] The invention comprises, in addition, a protein chip according to the invention, characterized in that it contains, in addition, at least one polypeptide of a microorganism different from Chlamydia pneumoniae or at least one antibody directed against a compound of a microorganism different from Chlamydia pneumoniae, immobilized on the support of the said chip.

[0372] The invention also relates to a kit or set for the detection and/or the identification of bacteria belonging to the species Chlamydia pneumoniae or to an associated microorganism, or for the detection and/or the identification of a microorganism characterized in that it comprises a protein chip according to the invention.

[0373] The subject of the present invention is also a method for the detection and/or the identification of bacteria belonging to the species Chlamydia pneumoniae or to an associated microorganism in a biological sample, characterized in that it uses a nucleotide sequence according to the invention.

[0374] More particularly, the invention relates to a method for the detection and/or the identification of bacteria belonging to the species Chlamydia pneumoniae or to an associated microorganism in a biological sample, characterized in that it comprises the following steps:

[0375] a) where appropriate, isolation of the DNA from the biological sample to be analysed, or optionally production of a cDNA from the RNA in the biological sample;

[0376] b) specific amplification of the DNA of bacteria belonging to the species Chlamydia pneumoniae or to an associated microorganism with the aid of at least one primer according to the invention;

[0377] c) detection of the amplification products.

[0378] These may be detected, for example, by the molecular hybridization technique using a nucleic probe according to the invention. This probe will be advantageously labelled with a nonradioactive (cold probe) or radioactive element.

[0379] For the purposes of the present invention, “DNA in the biological sample” or “DNA contained in the biological sample” will be understood to mean either the DNA present in the biological sample considered, or optionally the cDNA obtained after the action of a reverse transcriptase-type enzyme on the RNA present in the said biological sample.

[0380] Another aim of the present invention consists in a method according to the invention, characterized in that it comprises the following steps:

[0381] a) bringing a nucleotide probe according to the invention into contact with a biological sample, the DNA contained in the biological sample having, where appropriate, been previously made accessible to hybridization, under conditions allowing the hybridization of the probe to complementary base pairs of the DNA of a bacterium belonging to the species Chlamydia pneumoniae or to an associated microorganism;

[0382] b) detecting the hybridization complex formed between the nucleotide probe and the DNA in the biological sample.

[0383] The present invention also relates to a method according to the invention, characterized in that it comprises the following steps:

[0384] a) bringing a nucleotide probe immobilized on a support according to the invention into contact with a biological sample, the DNA in the sample having, where appropriate, been previously made accessible to hybridization, under conditions allowing the hybridization of the probe to the DNA of a bacterium belonging to the species Chlamydia pneumoniae or to an associated microorganism;

[0385] b) bringing the hybrid formed between the nucleotide probe immobilized on a support and the DNA contained in the biological sample, where appropriate after removal of the DNA in the biological sample which has not hybridized with the probe, into contact with a labelled nucleotide probe according to the invention;

[0386] c) detecting the new hybrid formed in step b).

[0387] According to an advantageous embodiment of the method for the detection and/or the identification defined above, it is characterized in that, prior to step a), the DNA in the biological sample is primer-extended and/or amplified beforehand with the aid of at least one primer according to the invention.

[0388] The invention relates, in addition, to a kit or set for the detection and/or the identification of bacteria belonging to the species Chlamydia pneumoniae or to an associated microorganism, characterized in that it comprises the following components:

[0389] a) a nucleotide probe according to the invention;

[0390] b) where appropriate, the reagents necessary for carrying out a hybridization reaction;

[0391] c) where appropriate, at least one primer according to the invention as well as the reagents (e.g., polymerase and/or deoxynucleotide triphosphates) necessary for a DNA amplification reaction.

[0392] The invention also relates to a kit or set for the detection and/or the identification of bacteria belonging to the species Chlamydia pneumoniae or to an associated microorganism, characterized in that it comprises the following components:

[0393] a) a nucleotide probe, called capture probe, according to the invention;

[0394] b) an oligonucleotide probe, called detection probe, according to the invention;

[0395] c) where appropriate, at least one primer according to the invention as well as the reagents (e.g., polymerase and/or deoxynucleotide triphosphates) necessary for a DNA amplification reaction.

[0396] The invention also relates to a kit or set for the detection and/or the identification of bacteria belonging to the species Chlamydia pneumoniae or to an associated microorganism, characterized in that it comprises the following components:

[0397] a) at least one primer according to the invention;

[0398] b) where appropriate, the reagents necessary for carrying out a DNA amplification reaction;

[0399] c) where appropriate, a component which makes it possible to check the sequence of the amplified fragment, more particularly an oligonucleotide probe according to the invention.

[0400] The invention relates, in addition, to a kit or set for the detection and/or the identification of bacteria belonging to the species Chlamydia pneumoniae or to an associated microorganism, or for the detection and/or the identification of a microorganism characterized in that it comprises a DNA chip according to the invention.

[0401] The invention also relates to a method or to a kit or set according to the invention for the detection and/or the identification of bacteria belonging to the species Chlamydia pneumoniae, characterized in that the said primer and/or the said probe according to the invention are chosen from the nucleotide sequences specific to the species Chlamydia pneumoniae, in that the said polypeptides according to the invention are chosen from the polypeptides specific to the species Chlamydia pneumoniae and in that the said antibodies according to the invention are chosen from the antibodies directed against the polypeptides according to the invention chosen from the polypeptides specific to the species Chlamydia pneumoniae.

[0402] Preferably, the said method or the said kit or set above according to the invention, for the detection and/or the identification of bacteria belonging to the species Chlamydia pneumoniae is characterized in that the said primer and/or the said probe or the said polypeptides are chosen from the nucleotide sequences or polypeptides according to the invention which have been identified as being specific to the species Chlamydia pneumoniae and in that the said antibodies according to the invention are chosen from the antibodies directed against the polypeptides according to the invention chosen from the polypeptides identified as being specific to the species Chlamydia pneumoniae.

[0403] The invention relates, in addition, to a method or a kit or set according to the invention for the diagnosis of predispositions to, or of a condition caused by, cardiovascular diseases, preferably linked to the presence of atheroma, which are induced or worsened by a Chlamydia pneumoniae infection.

[0404] The invention also relates to a method or a kit or set according to the invention for the diagnosis of predispositions to, or of conditions caused by, respiratory diseases induced or worsened by a Chlamydia pneumoniae infection; preferably, the said respiratory disease is asthma.

[0405] According to another aspect, the subject of the invention is the use of polypeptides according to the invention, of cells transformed with a vector according to the invention and/or of transformed animals according to the invention, for the biosynthesis or the biodegradation of organic or inorganic compounds.

[0406] As has been mentioned above, the nucleotide sequences of the invention were identified by homology with sequences known to encode, for example, polypeptides or fragments of enzymatic polypeptides involved in the biosynthesis or the biodegradation of organic or inorganic molecules.

[0407] It is thus possible to use the said polypeptides of the invention in a similar manner for the biosynthesis or the biodegradation of organic or inorganic compounds of industrial or therapeutic interest (called compounds of interest).

[0408] Among these polypeptides, there may be mentioned in particular the enzymes involved in metabolism, such as the proteolytic enzymes, amino transferases, glucose metabolism, or the enzymes which may be used in the biosynthesis of sugars, amino acids, fatty acids, polypeptides, nucleotides, nucleic acids or any other organic or inorganic compound or in the biodegradation of organic or inorganic compounds.

[0409] Among these polypeptides, there may be mentioned, in addition, the mutated or modified enzymes corresponding to mutated or modified polypeptides according to the invention which may also be used for the biosynthesis or the biodegradation of organic or inorganic compounds at the industrial level, such as, for example, the production of compounds of interest, the reprocessing of manufacturing residues applied to the food industries, to the papermaking industry or to the chemical and pharmaceutical industries.

[0410] The methods of biosynthesis or biodegradation of organic or inorganic compounds, characterized in that they use a polypeptide or one of its representative fragments according to the invention, transformed cells according to the invention and/or a transformed animal according to the invention, also form part of the invention.

[0411] The invention relates, in addition, to the use of a nucleotide sequence according to the invention, of a polypeptide according to the invention, of an antibody according to the invention, of a cell according to the invention, and/or of a transformed animal according to the invention, for the selection of an organic or inorganic compound capable of modulating, regulating, inducing or inhibiting the expression of genes, and/or of modifying the cellular replication of eukaryotic or prokaryotic cells or capable of inducing, inhibiting or worsening the pathologies linked to an infection by Chlamydia pneumoniae or one of its associated microorganisms.

[0412] The invention also comprises screening assays that comprise methods of selecting compounds capable of binding to a polypeptide, fusion polypeptide or one of its representative fragments according to the invention, capable of binding to a nucleotide sequence according to the invention, or capable of recognizing an antibody according to the invention, and/or capable of modulating, regulating, inducing or inhibiting the expression of genes, and/or of modifying the growth or the cellular replication of eukaryotic or prokaryotic cells, or capable of inducing, inhibiting or worsening, in an animal or human organism, the pathologies linked to an infection by Chlamydia pneumoniae or one of its associated microorganisms, characterized in that it comprises the following steps:

[0413] a) bringing the said compound into contact with the said polypeptide, the said nucleotide sequence, with a transformed cell according to the invention and/or administering the said compound to a transformed animal according to the invention;

[0414] b) determining the capacity of the said compound to bind with the said polypeptide or the said nucleotide sequence, or to modulate, regulate, induce or inhibit the expression of genes, or to modulate growth or cellular replication, or to induce, inhibit or worsen in the said transformed animal, the pathologies linked to an infection by Chlamydia pneumoniae or one of its associated microorganisms.

[0415] The transformed cells and/or animals according to the invention may advantageously serve as a model and may be used in methods for studying, identifying and/or selecting compounds capable of being responsible for pathologies induced or worsened by Chlamydia pneumoniae, or capable of preventing and/or of treating these pathologies such as, for example, cardiovascular or respiratory diseases. In particular, the transformed host cells, in particular bacteria of the Chlamydia family whose transformation with a vector according to the invention may, for example, increase or inhibit its infectivity, or modulate the pathologies usually induced or worsened by the infection, may be used to infect animals in which the onset of pathologies will be monitored. These nontransformed animals, infected for example with transformed Chlamydia bacteria, may serve as a study model. In the same manner, the transformed animals according to the invention may, for example, exhibit predispositions to cardiovascular and/or respiratory diseases and thus be used in methods for selecting compounds capable of preventing and/or of treating the said diseases. The said methods using the said transformed cells and/or transformed animals form part of the invention.

[0416] The compounds capable of being selected may be organic compounds such as polypeptides or carbohydrates or any other organic or inorganic compounds already known, or new organic compounds produced using molecular modeling techniques and obtained by chemical or biochemical synthesis, these techniques being known to persons skilled in the art.

[0417] The said selected compounds may be used to modulate the growth and/or the cellular replication of Chlamydia pneumoniae or any other associated microorganism and thus to control infection by these microorganisms. The said compounds according to the invention may also be used to modulate the growth and/or the cellular replication of all eukaryotic or prokaryotic cells, in particular tumour cells and infectious microorganisms, for which the said compounds will prove active, the methods which make it possible to determine the said modulations being well known to persons skilled in the art.

[0418] Compound capable of modulating the growth of a microorganism is understood to designate any compound which makes it possible to act, to modify, to limit and/or to reduce the development, the growth, the rate of proliferation and/or the viability of the said microorganism.

[0419] This modulation may be achieved, for example, by an agent capable of binding to a protein and thus of inhibiting or of potentiating its biological activity, or capable of binding to a membrane protein of the outer surface of a microorganism and of blocking the penetration of the said microorganism into the host cell or of promoting the action of the immune system of the infected organism directed against the said microorganism. This modulation may also be achieved by an agent capable of binding to a nucleotide sequence of a DNA or RNA of a microorganism and of blocking, for example, the expression of a polypeptide whose biological or structural activity is necessary for the growth or for the reproduction of the said microorganism.

[0420] Associated microorganism is understood to designate in the present invention any microorganism whose gene expression may be modulated, regulated, induced or inhibited, or whose growth or cellular replication may also be modulated by a compound of the invention. Associated microorganism is also understood to designate in the present invention any microorganism containing nucleotide sequences or polypeptides according to the invention. These microorganisms may, in some cases, contain polypeptides or nucleotide sequences identical or homologous to those of the invention may also be detected and/or identified by the detection and/or identification methods or kit according to the invention and may also serve as a target for the compounds of the invention.

[0421] The invention relates to the compounds capable of being selected by a method of selection according to the invention.

[0422] The invention also relates to a pharmaceutical composition comprising a compound chosen from the following compounds:

[0423] a nucleotide sequence according to the invention;

[0424] a polypeptide according to the invention;

[0425] a vector according to the invention;

[0426] an antibody according to the invention; and

[0427] a compound capable of being selected by a method of selection according to the invention, optionally in combination with a pharmaceutically acceptable vehicle.

[0428] An effective quantity is understood to designate a sufficient quantity of the said compound or antibody, or of a polypeptide of the invention, which makes it possible to modulate the growth of Chlamydia pneumoniae or of an associated microorganism.

[0429] The invention also relates to a pharmaceutical composition comprising one or more polypeptides according to the invention and/or one or more fusion polypeptides according to the invention. Such compositions further comprise a pharmaceutically acceptable carrier or vehicle. Pharmaceutical compositions include compositions that comprise a polypeptide or fusion polypeptide that immunoreacts with seropositive serum of an individual infected with Chlamydia pneumoniae. In one embodiment, a pharmaceutical composition according to the invention can be utilized for the prevention or the treatment of an infection by a bacterium belonging to the species Chlamydia pneumoniae or by an associated microorganism.

[0430] The invention relates, in addition, to an immunogenic composition or a vaccine composition, characterized in that it comprises one or more polypeptides according to the invention and/or one or more hybrid (fusion) polypeptides according to the invention. Such compositions further comprise a pharmaceutically acceptable carrier or vehicle. Immunogenic compositions or fusion polypeptide include compositions that comprise a polypeptide that immunoreacts with seropositive serum of an individual infected with Chlamydia pneumoniae.

[0431] Immunogenic or vaccine compositions can also comprise DNA immunogenic or vaccine compositions comprising polynucleotide sequences of the invention operatively associated with a regulatory sequence that controls gene expression. Such compositions can include compositions that direct expression of a neutralizing epitope of Chlamydia pneumoniae.

[0432] The invention also comprises the use of a transformed cell according to the invention, for the preparation of a vaccine composition.

[0433] The invention also relates to a vaccine composition, characterized in that it contains a nucleotide sequence according to the invention, a vector according to the invention and/or a transformed cell according to the invention.

[0434] The invention also relates to the vaccine compositions according to the invention, for the prevention or the treatment of an infection by a bacterium belonging to the species Chlamydia pneumoniae or by an associated microorganism.

[0435] The invention also relates to the use of DNA encoding polypeptides of Chlamydia pneumoniae, in particular antigenic determinants, to be formulated as vaccine compositions. In accordance with this aspect of the invention, the DNA of interest is engineered into an expression vector under the control of regulatory elements, which will promote expression of the DNA, i.e., promoter or enhancer elements. In one preferred embodiment, the promoter element may be cell-specific and permit substantial transcription of the DNA only in predetermined cells. The DNA may be introduced directly into the host either as naked DNA (U.S. Pat. No. 5,679,647 incorporated herein by reference in their entirety) or formulated in compositions with other agents which may facilitate uptake of the DNA including viral vectors, i.e., adenovirus vectors, or agents which facilitate immunization, such as bupivicaine and other local anesthetics (U.S. Pat. No. 5,593,972 incorporated herein by reference in their entirety), saponins (U.S. Pat. No. 5,739,118 incorporated herein by reference in their entirety) and cationic polyamines (published international application WO 96/10038 incorporated herein by reference in their entirety).

[0436] The DNA sequence encoding the antigenic polypeptide and regulatory element may be inserted into a stable cell line or cloned microorganism, using techniques, such as targeted homologous recombination, which are well known to those of skill in the art, and described e.g., in Chappel, U.S. Pat. No. 4,215,051; Skoultchi, WO 91/06667 each of which is incorporated herein by reference in its entirety.

[0437] Such cell lines and microorganisms may be formulated for vaccine purposes. In yet another embodiment, the DNA sequence encoding the antigenic polypeptide and regulatory element may be delivered to a mammalian host and introduced into the host genome via homologous recombination (See, Chappel, U.S. Pat. No. 4,215,051; Skoultchi, WO 91/06667 each of which is incorporated herein by reference in its entirety.

[0438] Preferably, the immunogenic and/or vaccine compositions according to the invention intended for the prevention and/or the treatment of an infection by Chlamydia pneumoniae or by an associated microorganism will be chosen from the immunogenic and/or vaccine compositions comprising a polypeptide or one of its representative fragments corresponding to a protein, or one of its representative fragments, of the cellular envelope of Chlamydia pneumoniae. The vaccine compositions comprising nucleotide sequences will also preferably comprise nucleotide sequences encoding a polypeptide or one of its representative fragments corresponding to a protein, or one of its representative fragments, of the cellular envelope of Chlamydia pneumoniae.

[0439] Among these preferred immunogenic and/or vaccine compositions, the most preferred are those comprising a polypeptide or one of its representative fragments, or a nucleotide sequence or one of its representative fragments whose sequences are chosen from the nucleotide or amino acid sequences identified in this functional group and listed above.

[0440] The polypeptides of the invention or their representative fragments entering into the immunogenic compositions according to the invention may be selected by techniques known to persons skilled in the art, such as for example on the capacity of the said polypeptides to stimulate T cells, which results, for example, in their proliferation or the secretion of interleukins, and which leads to the production of antibodies directed against the said polypeptides.

[0441] In mice, in which a weight dose of the vaccine composition comparable to the dose used in humans is administered, the antibody reaction is tested by collecting serum followed by a study of the formation of a complex between the antibodies present in the serum and the antigen of the vaccine composition, according to the customary techniques.

[0442] According to the invention, the said vaccine compositions will be preferably in combination with a pharmaceutically acceptable vehicle and, where appropriate, with one or more appropriate immunity adjuvants.

[0443] Various types of vaccines are currently available for protecting humans against infectious diseases: attenuated live microorganisms (M. bovis—BCG for tuberculosis), inactivated microorganisms (influenza virus), acellular extracts (Bordetella pertussis for whooping cough), recombinant proteins (hepatitis B virus surface antigen), polysaccharides (pneumococci). Experiments are underway on vaccines prepared from synthetic peptides or from genetically modified microorganisms expressing heterologous antigens. Even more recently, recombinant plasmid DNAs carrying genes encoding protective antigens were proposed as an alternative vaccine strategy. This type of vaccination is carried out with a particular plasmid derived from an E. coli plasmid which does not replicate in vivo and which encodes only the vaccinal protein. Animals were immunized by simply injecting the naked plasmid DNA into the muscle. This technique leads to the expression of the vaccine protein in situ and to a cell-type (CTL) and a humoral type (antibody) immune response. This double induction of the immune response is one of the main advantages of the technique of vaccination with naked DNA.

[0444] The vaccine compositions of the present invention can be evaluated in in vitro and in vivo animal models prior to host, e.g., human, administration. For example, in vitro neutralization assays such as those described by Peterson et al. (1988) can be utilized. The assay described by Peterson et al. (1988) is suitable for testing vaccine compositions directed toward either Chlamydia pneumoniae or Chlamydia trachomatis.

[0445] Briefly, hyper-immune antisera is diluted in PBS containing 5% guinea pig serum, as a complement source. Chlamydiae (104 IFU; infectious units) are added to the antisera dilutions. The antigen-antibody mixtures are incubated at 37EC for 45 minutes and inoculated into duplicate confluent Hep-2 or HeLa cell monolayers contained in glass vials (e.g., 15 by 45 mm), which have been washed twice with PBS prior to inoculation. The monolayer cells are infected by centrifugation at 1000× g for 1 hour followed by stationary incubation at 37E for 1 hour. Infected monolayers are incubated for 48 or 72 hours, fixed and stained with a Chlamydiae specific antibody, such as anti-MOMP for C. trachomatis, etc. IFUs are counted in ten fields at a magnification of 200×. Neutralization titer is assigned based on the dilution that gives 50% inhibition as compared to control monolayers/IFU.

[0446] The efficacy of vaccine compositions can be determined in vivo by challenging animal models of Chlamydia pneumoniae infection, eg., mice or rabbits, with the vaccine compositions. For example, in vivo vaccine composition challenge studies can be performed in the murine model of Chlamydia pneumonia infection described by Moazed et al. (1997). Briefly, male homozygous apoe deficient and/or C57 BL/6J mice are immunized with vaccine compositions. Post-vaccination, the mice are mildly sedated by subcutaneous injection of a mixture of ketamine and xylazine, and inoculated intranasally with a total volume of 0.03-0.05 ml of organisms suspended in SPG medium or with SPG alone. The inoculations of Chlamydia pneumoniae are approximately 3×107 IFU/mouse. The mice are inoculated with Chlamydia pneumoniae at 8, 10, and 12 weeks of age. Tissues are then collected from the lung, spleen, heart, etc. at 1-20 weeks after the first inoculation. The presence of organisms is scored using PCR, histology and immunocytochemistry, or by quantitative culture/IFU after tissue homogenization.

[0447] Alternatively, in vivo vaccine composition challenge studies can be performed in the rabbit model of Chlamydia pneumoniae described by Laitinen et al. (1997). Briefly, New Zealand white rabbits (5 months old) are immunized with the vaccine compositions. Post-vaccination, the rabbits are sedated with Hypnorm, 0.3 ml/Kg of body weight, intramuscularly, and inoculated intranasally with a total of 0.5 ml of Chlamydia pneumoniae suspended in SPG medium or with SPG alone. The inoculations of Chlamydia pneumoniae are approximately 3×107 IFU/rabbit. The rabbits are reinfected in the same manner and with the same dose 3 weeks after the primary inoculation. Tissues are then collected 2 weeks after the primary infection and 1, 2, and 4 weeks after the reinfection. The presence of Chlamydia pneumoniae is scored using PCR, histology and immunocytochemistry, or by quantitative culture/IFU after tissue homogenization.

[0448] The vaccine compositions comprising nucleotide sequences or vectors into which the said sequences are inserted are in particular described in International Application No. WO 90/11092 and also in International Application No. WO 95/11307.

[0449] The nucleotide sequence constituting the vaccine composition according to the invention may be injected into the host after having been coupled to compounds which promote the penetration of this polynucleotide inside the cell or its transport up to the cell nucleus. The resulting conjugates may be encapsulated into polymeric microparticles, as described in International Application No. WO 94/27238 (Medisorb Technologies International).

[0450] According to another embodiment of the vaccine composition according to the invention, the nucleotide sequence, preferably a DNA, is complexed with the DEAE-dextran (Pagano et al., 1967) or with nuclear proteins (Kaneda et al., 1989), with lipids (Felgner et al., 1987) or encapsulated into liposomes (Fraley et al., 1980) or alternatively introduced in the form of a gel facilitating its transfection into the cells (Midoux et al., 1993, Pastore et al., 1994). The polynucleotide or the vector according to the invention may also be in suspension in a buffer solution or may be combined with liposomes.

[0451] Advantageously, such a vaccine will be prepared in accordance with the technique described by Tacson et al. or Huygen et al. in 1996 or alternatively in accordance with the technique described by Davis et al. in International Application No. WO 95/11307.

[0452] Such a vaccine may also be prepared in the form of a composition containing a vector according to the invention, placed under the control of regulatory elements allowing its expression in humans or animals. It is possible, for example, to use, as vector for the in vivo expression of the polypeptide antigen of interest, the plasmid pcDNA3 or the plasmid pcDNA1/neo, both marketed by Invitrogen ® & D Systems, Abingdon, United Kingdom). It is also possible to use the plasmid V1Jns.tPA, described by Shiver et al. in 1995. Such a vaccine will advantageously comprise, in addition to the recombinant vector, a saline solution, for example a sodium chloride solution.

[0453] The immunogenic compositions of the invention can also be utilized as part of methods for immunization, wherein such methods comprise administering to a host, e.g., a human host, an immunizing amount of the immunogenic compositions of the invention. In a preferred embodiment, the method of immunizing is a method of immunizing against Chlamydia pneumoniae.

[0454] A pharmaceutically acceptable vehicle is understood to designate a compound or a combination of compounds entering into a pharmaceutical or vaccine composition which does not cause side effects and which makes it possible, for example, to facilitate the administration of the active compound, to increase its life and/or its efficacy in the body, to increase its solubility in solution or alternatively to enhance its preservation. These pharmaceutically acceptable vehicles are well known and will be adapted by persons skilled in the art according to the nature and the mode of administration of the active compound chosen.

[0455] As regards the vaccine formulations, these may comprise appropriate immunity adjuvants which are known to persons skilled in the art, such as, for example, aluminum hydroxide, a representative of the family of muramyl peptides such as one of the peptide derivatives of N-acetyl-muramyl, a bacterial lysate, or alternatively incomplete Freund's adjuvant, Stimulon™ QS-21 (Aquila Biopharmaceuticals, Inc., Framingham, Mass.), MPLTM (3-O-deacylated monophosphoryl lipid A; RIBI ImmunoChem Research, Inc., Hamilton, Mont.), aluminum phosphate, IL-12 (Genetics Institute, Cambridge, Mass.).

[0456] Preferably, these compounds will be administered by the systemic route, in particular by the intravenous route, by the intranasal, intramuscular, intradermal or subcutaneous route, or by the oral route. More preferably, the vaccine composition comprising polypeptides according to the invention will be administered several times, spread out over time, by the intradermal or subcutaneous route.

[0457] Their optimum modes of administration, dosages and galenic forms may be determined according to criteria which are generally taken into account in establishing a treatment adapted to a patient, such as for example the patient's age or body weight, the seriousness of his general condition, tolerance of the treatment and the side effects observed.

[0458] The invention comprises the use of a composition according to the invention for the treatment or the prevention of cardiovascular diseases, preferably linked to the presence of atheroma, which are induced or worsened by Chlamydia pneumoniae.

[0459] Finally, the invention comprises the use of a composition according to the invention for the treatment or the prevention of respiratory diseases which are induced or worsened by the presence of Chlamydia pneumoniae, preferably asthma.

[0460] Other characteristics and advantages of the invention appear in the following examples and figures:

[0461] Legend to the Figures:

[0462]
FIG. 1: Line for the production of Chlamydia pneumoniae sequences

[0463]
FIG. 2: Analysis of the sequences and assembling

[0464]
FIG. 3: Finishing techniques

[0465]

FIG. 3

a
): Assembly map

[0466]

FIG. 3

b
): Determination and use of the orphan ends of the contigs

EXAMPLES

[0467] Experimental Procedures

[0468] Cells

[0469] The Chlamydia pneumoniae strain (CM1) used by the inventors is obtained from ATCC (American Culture Type Collection) where it has the reference number ATCC 1360-VR.

[0470] It is cultured on HeLa 229 cells, obtained from the American Type Culture Collection, under the reference ATCC CCL-2.1.

[0471] Culture of the cells

[0472] The HeLa ATCC CCL-2.1 cells are cultured in 75-ml cell culture flasks (Coming). The culture medium is Dulbecco's modified cell culture medium (Gibco BRL No. 04101965) supplemented with MEM amino acids (Gibco BRL-No. 04301140) L (5 ml per 500 ml of medium) and 5% fetal calf serum (Gibco BRL No. 10270 batch 40G8260K) without antibiotics or antifungals.

[0473] The cell culture stock is maintained in the following manner. The cell cultures are examined under an inverted microscope. 24 hours after confluence, each cellular lawn is washed with PBS (Gibco BRL No. 04114190), rinsed and then placed for 5 min in an oven in the presence of 3 ml of trypsine (Gibco BRL No. 25200056). The cellular lawn is then detached and then resuspended in 120 ml of culture medium, the whole is stirred in order to make the cellular suspension homogeneous. 30 ml of this suspension are then distributed per cell culture flask. The flasks are kept in a CO2 oven (5%) for 48 hours at a temperature of 37° C. The cell stock is maintained so as to have available daily 16 flasks of subconfluent cells. It is these subconfluent cells which will be used so as to be infected with Chlamydia. 25-ml cell culture flasks are also used, these flasks are prepared in a similar manner but the volumes used for maintaining the cells are the following: 1 ml of trypsine, 28 ml of culture medium to resuspend the cells, 7 ml of culture medium are used per 25-ml flask.

[0474] Infection of the Cells with Chlamydia

[0475] Initially, the Chlamydiae are obtained frozen from ATCC (−70° C.), in suspension in a volume of 1 ml. This preparation is slowly thawed, 500 l are collected and brought into contact with subconfluent cells, which are obtained as indicated above, in a 25-ml cell culture flask, containing 1 ml of medium, so as to cover the cells. The flask is then centrifuged at 2000 rpm in a “swing” rotor for microtitre plates, the centrifuge being maintained at a temperature of 35° C. After centrifugation, the two flasks are placed in an oven at 35° C. for three hours. 6 ml of culture medium containing cycloheximide (1 μg/ml) are then added and the flask is stored at 35° C. After 72 hours, the level of infection is evaluated by direct immunofluorescence and by the cytopathogenic effect caused to the cells.

[0476] Direct Immunofluorescence

[0477] Starting with infected cells, which were obtained as indicated above, a cellular smear is deposited with a Pasteur pipette on a microscope slide. The cellular smear is fixed with acetone for 10 minutes; after draining the acetone, the smear is covered with 30 μl of murine monoclonal antibodies directed against MOMP (major outer membrane protein) of Chlamydia (Syva, Biomérieux) labelled with fluorescein isothiocyanate. The whole is then incubated in a humid chamber at a temperature of 37° C. The slides are then rinsed with water, slightly dried, and then after depositing a drop of mounting medium, a coverslip is mounted before reading. The reading is carried out with the aid of a fluorescence microscope equipped with the required filters (excitation at 490 nm, emission at 520 nm).

[0478] Harvesting of the Chlamydia Pneumoniae

[0479] After checking the infection by direct immunofluorescence, carried out as indicated above, the culture flasks are opened under a sterile cabinet, sterile glass beads with a diameter of the order of a millimeter are placed in the flask. The flask is closed and then vigorously stirred while being maintained horizontally, the cellular lawn at the bottom, so that the glass beads can have a mechanical action on the cellular lawn. Most of the cells are thus detached or broken; the effect of the stirring is observed under an optical microscope so as to ensure proper release of Chlamydiae.

[0480] Large-Scale Infection of the Cell Cultures

[0481] The product of the Chlamydiae harvest (culture medium and cellular debris) is collected with a pipette, and distributed into three cell culture flasks containing subconfluent HeLa ATCC CCL-2.1 cells, obtained as indicated above. The cells thus inoculated are placed under gentle stirring (swing) in an oven at 35° C. After one hour, the flasks are kept horizontally in an oven so that the culture medium covers the cells for 3 hours. 30 ml of culture medium containing actydione (1 μg/ml) are then added to each of the flasks. The culture flasks are then stored at 35° C. for 72 hours. The cells thus infected are examined under an optical microscope after 24 hours, the cytopathogenic effect is evaluated by the appearance of cytoplasmic inclusions which are visible under an inverted optical microscope. After 72 hours, the vacuoles containing the Chlamydiae occupy the cytoplasm of the cell and push the cell nucleus sideways. At this stage, numerous cells are spontaneously destroyed and have left free elementary bodies in the culture medium. The Chlamydiae are harvested as described above and are either frozen at −80° C. or used for another propagation.

[0482] Purification of the Chlamydiae

[0483] The product of the Chlamydia harvests is stored at −80° C. and thawed on a water bath at room temperature. After thawing, each tube is vigorously stirred for one minute and immersed for one minute in an ultrasound tank (BRANSON 1200); the tubes are then stirred by inverting before being centrifuged for 5 min at 2000 rpm. The supernatant is carefully removed and kept at cold temperature (ice). The supernatant is vigorously stirred and then filtered on nylon filters having pores of 5 microns in diameter on a support (Nalgene) allowing a delicate vacuum to be established under the nylon filter. For each filtration, three nylon filters are superposed; these filters are replaced after every 40 ml of filtrate. Two hundred milliliters of filtration product are kept at cold temperature, and then after stirring by inverting, are centrifuged at 10,000 rpm for 90 min, the supernatant is removed and the pellet is taken up in 10 ml of 10 mM Tris, vigorously vortexed and then centrifuged at 10,000 rpm for 90 min. The supernatant is removed and the pellet is taken up in a buffer (20 mM Tris pH 8.0, 50 mM KCl, 5 mM MgCl2) to which 800 units of DNAse I (Boehringer) are added. The whole is kept at 37° C. for one hour. One ml of 0.5 M EDTA is then added, the whole is vortexed and frozen at −20° C.

[0484] Preparation of the DNA

[0485] The Chlamydiae purified above are thawed and subjected to a proteinase K (Boehringer) digestion in a final volume of 10 ml. The digestion conditions are the following: 0.1 mg/ml proteinase K, 0.1×SDS at 55EC, stirring every 10 min. The product of digestion is then subjected to a double extraction with phenol-chloroform, two volumes of ethanol are added and the DNA is directly recovered with a Pasteur pipette having one end in the form of a hook. The DNA is dried on the edge of the tube and then resuspended in 500 μl of 2 mM Tris pH 7.5. The DNA is stored at 4° C. for at least 24 hours before being used for the cloning.

[0486] Cloning of the DNA

[0487] After precipitation, the DNA is quantified by measuring the optical density at 260 nm. Thirty μg of Chlamydia DNA are distributed into 10 tubes of 1.5 ml and diluted in 300 μl of water. Each of the tubes is subjected to 10 applications of ultrasound lasting for 0.5 sec in a sonicator (unisonix XL2020). The contents of the 10 tubes are then grouped and concentrated by successive extractions with butanol (Sigma B1888) in the following manner: two volumes of butanol are added to the dilute DNA mixture. After stirring, the whole is centrifuged for five minutes at 2500 rpm and the butanol is removed. This operation is repeated until the volume of the aqueous phase is less than 1 ml. The DNA is then precipitated in the presence of ethanol and of 0.5 M sodium acetate pH 5.4, and then centrifuged for thirty minutes at 15,000 rpm at cold temperature (4° C.). The pellet is washed with 75% ethanol, centrifuged for five minutes at 15,000 rpm and dried at room temperature. A tenth of the preparation is analysed on a 0.8% agarose gel. Typically, the size of the DNA fragments thus prepared is between 200 and 8000 base pairs.

[0488] To allow the cloning of the DNA obtained, the ends are repaired. The DNA is distributed in an amount of 10 μg/tube, in the following reaction medium: 100 μl final volume, 1×buffer (Biolabs 201L), 0.5 μl BSA 0.05 mg/ml, 0.1 mM dATP, 0.1 mM each of dGTP, dCTP or dTTP, 60,000 IU T4 DNA polymerase. The reaction is incubated for thirty minutes at 16° C. The contents of each of the tubes are then grouped before carrying out an extraction with phenol-chloroform and then precipitating the aqueous phase as described above. After this step, the DNA thus prepared is phosphorylated. For that, the DNA is distributed into tubes in an amount of 10 μg per tube, and then in a final volume of 50 μl, the reaction is prepared in the following manner: 1 mM ATP, 1×kinase buffer, 10 IU T4 polynucleotide kinase (Biolabs 201L). The preparation is incubated for thirty minutes at 37° C. The contents of the tubes are combined and a phenol-chloroform extraction and then a precipitation are carried out in order to precipitate the DNA. The latter is then suspended in 1 μl of water and then the DNA fragments are separated according to their size on a 0.8% agarose gel (1×TAE). The DNA is subjected to an electric field of 5 V/cm and then visualized on a UV table. The fragments whose size varies between 1200 and 2000 base pairs are selected by cutting out the gel. The gel fragment thus isolated is placed in a tube and then the DNA is purified with the Qiaex kit (20021 Qiagen), according to the procedure provided by the manufacturer.

[0489] Preparation of the Vector

[0490] 14 μg of the cloning vector pGEM-5Zf (Proméga P2241) are diluted in a final volume of 150 μl and are subjected to digestion with the restriction enzyme EcoRV 300 IU (Biolabs 195S) according to the protocol and with the reagents provided by the manufacturer. The whole is placed at 37° C. for 150 min and then distributed in the wells of a 0.8% agarose gel subjected to an electric field of 5 V/cm. The linearized vector is visualized on a UV table, isolated by cuffing out the gel and then purified by the Qiaex kit (Qiagen 20021) according to the manufacturer's recommendations. The purification products are grouped in a tube, the volume is measured and then half the volume of phenol is added and the whole is vigorously stirred for 1 min. Half the volume of chloroform-isoamyl alcohol 24:1 is added and vigorously stirred for 1 min. The whole is centrifuged at 15,000 rpm for 5 min at 4° C., the aqueous phase is recovered and transferred into a tube. The DNA is precipitated in the presence of 0.3 M sodium acetate, pH 5.4 and 3 volumes of ethanol and placed at −20° C. for 1 hour. The DNA is then centrifuged at 15,000 rpm for 30 min at 4° C., the supernatant is removed while preserving the pellet, washed twice with 70% ethanol. After drying at room temperature, the DNA is suspended in 25 μl of water.

[0491] Phosphorylation of the Vector

[0492] 25 μl of the vector prepared in the preceding step are diluted in a final volume of 500 μl of the following reaction mixture:

[0493] After repair, the DNA is subjected to a phenol-chloroform extraction and a precipitation, the pellet is then taken up in 10 μl of water, the DNA is quantified by measuring the optical density at 260 nm. The quantified DNA is ligated into the vector PGEm-5Zf(+) prepared by the restriction enzyme EcoRV and dephosphorylated (see preparation of the vector). The ligation is carried out under three conditions which vary in the ratio between the number of vector molecules and the number of insert molecules. Typically, an equimolar ratio, a ratio of 1:3 and a ratio of 3:1 are used for the ligations which are, moreover, carried out under the following conditions: vector PGEm-5Zf(+) 25 ng, cut DNA, ligation buffer in a final volume of 20 μl with T4 DNA ligase (Amersham E70042X); the whole is then placed in a refrigerator overnight and then a phenol-chloroform extraction and a precipitation are carried out in a conventional manner. The pellet is taken up in 5 μl of water.

[0494] Transformation of the Bacteria

[0495] Plating of the Bacteria

[0496] Petri dishes containing LB Agar medium containing ampicillin (50 μg/ml), Xgal (280 μg/ml) [5-bromo-4-chloro-indolyl-beta-D-galactopyranoside (Sigma B-4252)], IPTG (140 μg/ml) [isopropyl-beta-D-thiogalactoside (Sigma I-6758)] are used, 50 and 100 μl of bacteria are plated for each of the ligations. The Petri dishes are placed upside down at 37° C. for 15 to 16 hours in an oven. The number of “recombinant” positive clones is evaluated by counting the white colonies and the blue colonies which are thought to contain the vector alone.

[0497] Evaluation of the “Recombinant” Positive Clones

[0498] Ninety-four white colonies and two blue colonies are collected with the aid of sterile cones and are deposited at the bottom of the wells of plates designed for carrying out the amplification techniques. 30 μl of the following reaction mixture are added to each well: 1.7 mM MgCl2, 0.2 mM each of dATP, dCTP, dGTP and dTTP, two synthetic oligonucleotides corresponding to sequences flanking the cloning site on either side and orienting the synthesis of the DNA in a convergent manner (0.5 μM RP and PU primers, 1 U TAQ polymerase (GibcoBRL 18038-026)).

[0499] The colonies thus prepared are subjected to a temperature of 94° C. for 5 min and then to 30 thermal cycles composed of the following steps: 94° C. for 40 s, 50° C. for 30 s, 72° C. for 180 s. The reaction is then kept for 7 min at 72° C. and then kept at 4° C.

[0500] The amplification products are deposited on an agarose gel (0.8%), stained with ethidium bromide, subjected to electrophoresis, and then analysed on an ultraviolet table. The presence of an amplification fragment having a size greater than 500 base pairs indicates the presence of an insert. The bacterial clones are then prepared so as to study the sequence of their insert.

[0501] Sequencing

[0502] To sequence the inserts of the clones obtained as above, these were amplified by PCR on bacteria cultures carried out overnight using the primers for the vectors flanking the inserts. The sequence of the ends of these inserts (on average 500 bases on each side) was determined by automated fluorescent sequencing on an ABI 377 sequencer, equipped with the ABI Prism DNA Sequencing Analysis software (version 2.1.2).

[0503] Analysis of the Sequences

[0504] The sequences obtained by sequencing in a high-yield line (FIG. 1) are stored in a database; this part of the production is independent of any treatment of the sequences. The sequences are extracted from the database, avoiding all the regions of inadequate quality, that is to say the regions for which uncertainties are observed on the sequence at more than 95%. After extraction, the sequences are introduced into a processing line, the diagram of which is described in FIG. 2. In a first path of this processing line, the sequences are assembled by the Gap4 software from R. Staden (Bonfield et al., 1995) (OS UNIX/SUN Solaris); the results obtained by this software are kept in the form of two files which will be used for a subsequent processing. The first of these files provides information on the sequence of each of the contigs obtained. The second file represents all the clones participating in the composition of all the contigs as well as their positions on the respective contigs.

[0505] The second processing path uses a sequence assembler (TIGR-Asmg assembler UNIX/SUN Solaris); the results of this second processing path are kept in the form of a file in the TIGR-Asmg format which provides information on the relationship existing between the sequences selected for the assembly. This assembler is sometimes incapable of linking contigs whose ends overlap over several hundreds of base pairs.

[0506] The results obtained from these two assemblers are compared with the aid of the BLAST program, each of the contigs derived from one assembly path being compared with the contigs derived from the other path.

[0507] For the two processing paths, the strict assembly parameters are fixed (95% homology, 30 superposition nucleotides). These parameters avoid 3 to 5% of the clones derived from eukaryotic cells being confused with sequences obtained from the clones derived from Chlamydia pneumoniae. The eukaryotic sequences are however preserved during the course of this project; the strategy introduced, which is described below, will be designed, inter alia, not to be impeded by these sequences derived from contaminating clones.

[0508] The results of these two assemblers are processed in a software developed for this project. This software operates on a Windows NT platform and receives, as data, the results derived from the STADEN software and/or the results derived from the TIGR-Asmg assembler, the software, results, after processing of the data, in the determination of an assembly map which gives the proximity relationship and the orientation of the contigs in relation to one another (FIG. 3a). Using this assembly map, the software determines all the primers necessary for finishing the project. This treatment, which will be detailed below, has the advantage of distinguishing the isolated sequences derived from the contaminations, by the DNA eukaryotic cells, of the small-sized sequences clearly integrated into the project by the relationships which they establish with contigs. In order to allow, without any risk of error, the arrangement and the orientation of the contigs in relation to one another, a statistical evaluation of the accuracy of the names (naming) “naming” of sequence is made from the results of “contigation”. This evaluation makes it possible to give each of the clone plates, as well as each of the subsets of plates, a weight which is inversely proportional to probable error rate existing in the “naming” of the sequences obtained from this plate or from a subset of this plate. In spite of a low error rate, errors may occur throughout the steps of production of the clones and of the sequences. These steps are numerous, repetitive and although most of them are automated, others, like the deposition in the sequencers, are manual; it is then possible for the operator to make mistakes such as the inversion of two sequences. This type of error has a repercussion on the subsequent processing of the data, by resulting in relationships (between the contigs) which do not exist in reality, then in attempts at directed sequencing between the contigs which will end in failure. It is because of this that the evaluation of the naming errors is of particular importance since it allows the establishment of a probabilistic assembly map from which it becomes possible to determine all the clones which will serve as template to obtain sequences separating two adjacent contigs. Table 2 of parent U.S. application serial No. 60/107,078 filed Nov. 4, 1998 and French application 97-14673 filed Nov. 21, 1997, each of which is incorporated by reference herein in its entirety, gives the clones and the sequences of the primers initially used during the initial operations.

[0509] To avoid the step which consists in ordering and then preparing the clones by conventional microbiological means, outer and inner primers oriented towards the regions not yet sequenced are defined by the software. The primers thus determined make it possible to prepare, by PCR, a template covering the nonsequenced region. It is the so-called outer primers (the ones most distant from the region to be sequenced) which are used to prepare this template. The template is then purified and a sequence is obtained on each of the two strands during 2 sequencing reactions which each use one of the 2 inner primers. In order to facilitate the use of this approach, the two outer primers and the two inner primers are prepared and then stored on the same position of 4 different 96-well plates. The two plates containing the outer primers are used to perform the PCRs which will serve to prepare the templates. These templates will be purified on purification columns preserving the topography of the plates. Each of the sequences will be obtained using primers situated on one and then on the other of the plates containing the inner primers. This distribution allows a very extensive automation of the process and results in a method which is simple to use for finishing the regions not yet sequenced. Table 3 of parent U.S. application serial No. 60/107,078 filed Nov. 4, 1998 and French application 97-14673 filed Nov. 21, 1997, each of which is incorporated by reference herein in its entirety, gives the names and the sequences of the primers used for finishing Chlamydia pneumoniae.

[0510] Finally, a number of contigs exist in a configuration where one of their ends is not linked to any other contig end (FIG. 3b) by a connecting clone relationship (a connecting clone is defined as a clone having one sequence end on a contig and the other end of its sequence on another contig; furthermore, this clone must be derived from a plate or a subset of plates with adequate naming quality). For the Chlamydia pneumoniae project, this particular case occurred 24 times. Two adjacent PCR primers orienting the synthesis of the DNA towards the end of the consensus sequence are defined for each of the orphan ends of the consensus sequence. The primer which is closest to the end of the sequence is called the inner primer whereas the primer which is more distant from the end of the sequence is called the outer primer. The outer primers are used to explore the mutual relationship between the orphan ends of the different contigs. The presence of a single PCR product and the possibility of amplifying this product unambiguously using the inner primers evokes the probable relationship between the contigs on which the primers which allowed the amplification are situated. This relationship will be confirmed by sequencing and will allow the connection between the orphan ends of the consensus sequences. This strategy has made it possible to obtain a complete map of the Chlamydia pneumoniae chromosome and then to finish the project.

[0511] Quality Control

[0512] All the bases not determined with certainty in the chromosomal sequence were noted and the density of uncertainties was measured on the entire chromosome. The regions with a high density of uncertainties were noted and the PCR primers spanning these regions were drawn and are represented in Table 4 of parent U.S. application serial No. 60/107,078 filed Nov. 4, 1998 and French application 97-14673 filed Nov. 21, 1997 each-of which is incorporated by reference herein in its entirety.

[0513] The sequence of each of the PCR products was obtained with two operational primers different from the amplification primers. The sequences were obtained in both directions for all the PCRs (100% success).

[0514] Data Banks

[0515] Local reorganizations of major public banks were used. The protein bank used consists of the nonredundant fusion of the Genpept bank (automated translation of GenBank, NCBI; Benson et al., 1996).

[0516] The entire BLAST software (public domain, Altschul et al., 1990) for searching for homologies between a sequence and protein or nucleic data banks was used. The significance levels used depend on the length and the complexity of the region tested as well as the size of the reference bank. They were adjusted and adapted to each analysis.

[0517] The results of the search for homologies between a sequence according to the invention and protein or nucleic data banks are presented and summarized in Table 1 below.

[0518] Table 1: List of coding chromosome regions and homologies between these regions and the sequence banks.

[0519] Legend to Table 1: Open reading frames are identified with the GenMark software version 2.3A (GenePro), the template used is Chlamydia pneumoniae of order 4 on a length of 196 nucleotides with a window of 12 nucleotides and a minimum signal of 0.5. The reading frames ORF2 to ORF 1137 are numbered in order of appearance on the chromosome, starting with ORF2 (ORF column). The positions of the beginning and of the end are then given in column 2 (position). When the position of the beginning is greater than the position of the end, this means that the region is encoded by the strand complementary to the sequence which was given in the sequence SEQ ID No. 1.

[0520] All the putative products were subjected to a search for homology on GENPEPT (release 102 for SEQ ID No. 2 to SEQ ID No. 1137, and release 108 for SEQ ID No. 1138 to SEQ ID No. 1291 and SEQ ID No. 6844 to SEQ ID No. 6849) with the BLASTP software (Altschul et al. 1990). With, as parameters, the default parameters with the exception of the expected value E set at 105 (for SEQ ID No. 2 to SEQ ID No. 1137) and P value set at e−10 (for SEQ ID No. 1138 to SEQ ID No. 1291 and SEQ ID No. 6844 to SEQ ID No. 6849). Subsequently, only the identities greater than 30% (1% column) were taken into account. The description of the most homologous sequence is given in the Homology column; the identifier for the latter sequence is given in the ID column and the animal species to which this sequence belongs is given in the Species column. The Homology score is evaluated by the sum of the blast scores for each region of homology and reported in the Score column.

[0521] Materials and Methods for Transmembrane Domains:

[0522] The DAS software was used as recommended by the authors (Cserzo et al., 1997).

[0523] This method uses, to predict the transmembrane domains, templates derived from a sampling of selected proteins. All the regions for which a “Cutoff” greater than 1.5 was found by the program were taken into account.

[0524] Additional ORF Finder Programs

[0525] For this analysis, two additional ORF finder programs were used to predict potential open reading frames of a minimum length of 74 amino acids; Glimmer (Salzberg, S. L., Delcher, A., Kasif, S., and W. White. 1998. Microbial gene identification using interpolated Markov models. Nucleic Acids Res. 26:544-548.), and an in-house written program. The in-house program used a very simple search algorithm. The analysis required the that the genomic DNA sequence text be in the 5′ to 3′ direction, the genome is circular, and that TAA, TAG, and TGA are stop codons. The search parameters were as follows:

[0526] (1) A search for an ORF that started with a GTG codon was performed. If no GTG codons were found, then a search for an ATG codon was performed. However, if a GTG codon was found, then a search downstream for a ATG codon was performed. All start and stop nucleotide positions were recorded.

[0527] (2) A search for an ORF that started with a TTG codon was performed. If no TTG codons were found, then a search for a ATG codon was performed. However, if a TTG codon was found, then a search downstream for a ATG codon was performed. All start and stop nucleotide positions were recorded.

[0528] (3) The analysis described in steps 1 and 2 were repeated for the opposite strand of DNA sequence.

[0529] (4) A search for ORFs that determined all ORF lengths using start and stop positions in the same reading frames was performed.

[0530] (5) All ORFs whose DNA length was less than 225 nucleotides were eliminated from the search.

[0531] Surface Exposed Protein Search Criteria

[0532] Potential cell surface vaccine targets are outer membrane proteins such as porins, lipoproteins, adhesions and other non-integral proteins. In Chlamydia psittaci, the major immunogens is a group of putative outer membrane proteins (POMPs) and no homologs have been found in Chlamydia pneumoniae and Chlamydia trachomatis by traditional analysis (Longbottom, D., Russell, M., Dunbar, S. M., Jones, G. E., and A. J. Herring. 1998. Molecular Cloning and Characterization of the Genes Coding for the Highly Immunogenic Cluster of 90-Kilodalton Envelope Proteins from Chlamydia psittaci Subtype That Causes Abortion in Sheep. Infect Immun 66:1317-1324.) Several putative outer membrane proteins have been identified in Chlamydia pneumoniae, all of which may represent vaccine candidates. The major outer membrane protein (MOMP) gene (omp1) has been found in various isolates of Chlamydia pneumoniae (Jantos, C A., Heck, S., Roggendorf, R., Sen-Gupta, M., and Hegemann, J H. 1997. Antigenic and molecular analyses of different Chlamydia pneumoniae strains. J. Clin Microbiology 35(3):620-623.) Various criteria, as listed below, were used to identify putative surface exposed ORFs from the genomic DNA sequence of Chlamydia pneumoniae (French application 97-14673 filed Nov. 21, 1997). Any ORF which met any one or more of the individual criteria were listed in this category.

[0533] Protein homology searches were done using the Blastp 2.0 tool (Altschul, S. F., Madden, T. L., Schaffer, A. A., Zhang, J., Zhang, Z., Miller, W., and D. J. Lipman. 1997. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25:3389-3402.) An ORF product was labeled surface exposed if there was homology to a known, or hypothetical, or putative surface exposed protein with a P score better than e−10.

[0534] Most, if not all, proteins that are localized to the membrane of bacteria, via a secretory pathway, contain a signal peptide. A software program, SignalP, analyzes the amino acid sequence of an ORF for such a signal peptide (Nielsen, H., Engelbrecht. J., Brunak, S., and G. von Heijne. 1997. Identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites. Protein Engineering 10:1-6.) The first 60 N-terminal amino acids of each ORF were analyzed by SignalP using the Gram-Negative software database. The output generates four separate values, maximum C, maximum Y, maximum S, and mean S. The S-score, or signal region, is the probability of the position belonging to the signal peptide. The C-score, or cleavage site, is the probability of the position being the first in the mature protein. The Y-score is the geometric average of the C-score and a smoothed derivative of the S-score. A conclusion of either a Yes or No is given next to each score. If all four conclusions are Yes and the C-terminal amino acid is either a phenylalanine (F) or a tyrosine (Y), the ORF product was labelled outer membrane (Struyve, M., Moons, M., and J. Tommassen. 1991. Carboxy-terminal Phenylalanine is Essential for the Correct Assembly of a Bacterial Outer Membrane Protein. J. Mol. Biol. 218:141-148.)

[0535] The program called Psort, determines the localization of a protein based on its signal sequence, recognition of transmembrane segments, and analysis of its amino acid composition (Nakai, K., and M. Kanehisa. 1991. Expert system for predicting protein localization sites in gram-negative bacteria. Proteins 11:95-110.) An ORF product is considered to be an outer membrane protein if the output data predicts the protein as outer membrane with a certainty value of 0.5 or better and whose value is at least twice as large as the next predicted localized certainty value.

[0536] Finally, ORF products that were not predicted to be outer membrane or surface exposed, based on the above criteria, were further analyzed. The blastp output data for these ORFs were searched using various general and specific keywords, suggestive of known cell surface exposed proteins. An ORF was labeled surface exposed if the keywords matched had a Blastp hit, had a P score better than e−10, and that there was no better data indicating otherwise. The following is a list of the searched keywords:

1AdhesionAdhesinInvasinInvasionExtensinOmpOuter SurfacePorinOuterMembraneCell SurfaceCell WallPilusPilinFlagellarBtuBsheathCirChuACopBExeDFadLFecAFepAFhuAFmdCFomAFrpBGspDHemRHgbAHgpHmbRHmuRHMWHrcCHrpInvGLamBLbpALcrQLmplMxiDMOMPPilEHpaANolWNspAOpcPOpnPOprOspAPhoEPldAPorPscCPulDPupAQuiXRafYScrYSepCShuASomASpiATbplYopYscCmipTol

[0537] Those ORFs that did not meet the minimum requirement for being an outer membrane protein based on the above search criteria but which were homologous to identified outer membrane ORFs in Chlamydia trachomatis were included. The Chlamydia trachomatis genome (French patent applications FR97-15041, filed Nov. 28, 1997 and 97-16034 filed Dec. 17, 1997) was analyzed using the above search criteria and a number of outer membrane ORFs were identified. These Chlamydia trachomatis ORFs were then tested against the Chlamydia pneumoniae genome using Blastp. Any Chlamydia pneumoniae ORF with a Blastp P value better than e−10 against a Chlamydia trachomatis outer membrane was included in this section, if there was no better data indicating otherwise. A list of ORFs in the Chlamydia pneumoniae genome encoding putative surface exposed proteins is set forth above in the specification.

[0538] Identification of Putative Lipoproteins in the Genome of Chlamydia Pneumoniae

[0539] Lipoproteins are the most abundant post-translationally modified bacterial secretory proteins (Pugsley, A. P. 1993. The complete general secretory pathway in Gram-negative bacteria. Microbiol. Rev. 57:50-108). The characteristic features of lipoproteins are a thiol-linked diacylglyceride and an amine-linked monoacyl group on the cysteine that becomes the amino-terminal residue after signal peptide cleavage by Signal Peptidase II. (Pugsley, A. P. 1993. The complete general secretory pathway in Gram-negative bacteria. Microbiol. Rev. 57:50-108). The identification of putative lipoproteins from the genomic sequencing of Chlamydia pneumoniae was done by examining the deduced amino acid sequence of identified ORFs for the presence of a signal peptide with a Signal Peptidase II cleavage site analogous to the consensus sequence for prolipoprotein modification and processing reactions (Hayashi, S., and H. C. Wu. 1992. Identification and characterization of lipid-modified proteins in bacteria, p. 261-285. In N. M. Hooper and A. J. Turner (ed.) Lipid modification of proteins: A practical approach. Oxford University Press, New York; Sutcliffe, I. C. and R. R. B. Russell. 1995. Lipoproteins of Gram-positive bacteria. J. Bacteriol. 177:1123-1128.).

[0540]

Chlamydia pneumoniae
ORFs were initially screened for the most basic of lipoprotein characteristics, a cysteine in the first 30 amino acids of the deduced protein. ORFs with a standard start codon (ATG, GTG, or TTG) and having one or more of the following characteristics were selected for direct analysis of their first 30 amino acids:

[0541] (a) Significant Signal P value (at least two out of the four values are Yes)

[0542] (b) PSORT value indicating membrane passage (IM-inner membrane, Peri-periplasm, or OM-outer membrane)

[0543] (c) Identification of the word lipoprotein among the ORF blastp data set.

[0544] (d) A Blastp value of <e−10 with a putative lipoprotein from Chlamydia trachomatis

[0545] (French applications 97-15041 filed Nov. 28, 1997 and 97-16034 filed Dec. 17, 1997).

[0546] The first 30 amino acids of each ORF in this set were analyzed for the characteristics commonly found in lipoprotein signal peptides (Pugsley, A. P. 1993. The complete general secretory pathway in Gram-negative bacteria. Microbiol. Rev. 57:50-108; Hayashi, S., and H. C. Wu. 1992. Identification and characterization of lipid-modified proteins in bacteria, p. 261-285. In N. M. Hooper and A. J. Turner (ed.) Lipid modification of proteins: A practical approach. Oxford University Press, New York; Sutcliffe, T. C. and R. R. B. Russell. 1995. Lipoproteins of Gram-positive bacteria. J. Bacteriol. 177:1123-1128.) Putative lipoprotein signal peptides were required to have a cysteine between amino acid 10 and 30 and reach a minimum score of three based on the following criteria for lipoprotein signal peptides:

[0547] (a) Identification of specific amino acids in specific positions around the cysteine which are part of the consensus Signal Peptidase II cleavage site (Hayashi, S., and H. C. Wu. 1992. Identification and characterization of lipid-modified proteins in bacteria, p. 261-285. In N. M. Hooper and A. J. Turner (ed.) Lipid modification of proteins: A practical approach. Oxford University Press, New York); Sutcliffe, I. C. and R. R. B. Russell. 1995. Lipoproteins of Gram-positive bacteria. J. Bacteriol. 177:1123-1128). Since the identification of the cleavage site is the most important factor in identifying putative lipoproteins, each correctly-positioned amino acid contributed toward reaching the minimum score of three. (b) A hydrophobic region rich in alanine and leucine prior to the cleavage site (Pugsley, A. P. 1993. The complete general secretory pathway in Gram-negative bacteria. Microbiol. Rev. 57:50-108) contributed toward reaching the minimum score of three.

[0548] (c) A short stretch of hydrophilic amino acids greater than or equal to 1 usually lysine or arginine following the N-terminal methionine (Pugsley, A. P. 1993. The complete general secretory pathway in Gram-negative bacteria. Microbiol. Rev. 57:50-108) contributed toward reaching the minimum score of three.

[0549] A list of ORFs in the Chlamydia pneumoniae genome encoding putative lipoproteins is set forth above in the specification.

[0550] LPS-Related ORFs of Chlamydia Pneumoniae

[0551] Lipopolysaccharide (LPS) is an important major surface antigen of Chlamydia cells. Monoclonal antibodies (Mab) directed against LPS of Chlamydia pneumoniae have been identified that can neutralize the infectivity of Chlamydia pneumoniae both in vitro and in vivo (Peterson, E. M., de la Maza, L. M., Brade, L., Brade, H. 1998. Characterization of a Neutralizing Monoclonal Antibody Directed at the Lipopolysaccharide of Chlamydia pneumonia. Infect. Immun. Aug. 66(8):3848-3855.) Chlamydial LPS is composed of lipid A and a core oligosaccharide portion and is phenotypically of the rough type (R-LPS) (Lukacova, M., Baumann, M., Brade, L., Mamat, U., Brade, H. 1994. Lipopolysaccharide Smooth-Rough Phase Variation in Bacteria of the Genus Chlamydia. Infect. Immun. June 62(6):2270-2276.) The lipid A component is composed of fatty acids which serve to anchor LPS in the outer membrane. The core component contains sugars and sugar derivatives such as a trisaccharide of 3-deoxy-D-manno-octulosonic acid (KDO) (Reeves, P. R., Hobbs, M., Valvano, M. A., Skumik, M., Whitfield, C., Coplin, D., Kido, N., Klena, J., Maskell, D., Raetz, C. R. H., Rick, P. D. 1996. Bacterial Polysaccharide Synthesis and Gene Nomenclature pp. 10071-10078, Elsevier Science Ltd.). The KDO gene product is a multifunctional glycosyltransferase and represents a shared epitope among the Chlamydia. For a review of LPS biosynthesis see, e.g., Schnaitman, C. A., Klena, J. D. 1993. Genetics of Lipopolysaccharide Biosynthesis in Enteric Bacteria. Microbiol. Rev. 57:655-682.

[0552] A text search of the ORF blastp results identified several genes that are involved in Chlamydial LPS production with a P score better than e−10. The following key-terms were used in the text search: KDO, CPS (Capsular Polysaccharide Biosynthesis), capsule, LPS, rfa, rfb, rfc, rfe, rha, rhl, core, epimerase, isomerase, transferase, pyrophosphorylase, phosphatase, aldolase, heptose, manno, glucose, lpxB, fibronectin, fibrinogen, fucosyltransferase, lic, Igt, pgm, toIC, rol, ChoP, phosphorylcholine, waaF, PGL-Th1. A list of ORFs in the Chlamydia pneumoniae genome encoding putative polypeptides involved: in LPS-biosynthesis is set forth above in the specification.

[0553] Type III And Other Secreted Products

[0554] Type III secretion enables gram-negative bacteria to secrete and inject pathogenicity proteins into the cytosol of eukaryotic host cells (Hueck, C. J., 1998. Type III Protein Secretion Systems in Bacterial Pathogens of Animals and Plants. In Microbiology and Molecular Biology Reviews. 62:379-433.) These secreted factors often resemble eukaryotic signal transduction factors, thus enabling the bacterium to redirect host cell functions (Lee, C. A., 1997. Type III secretion systems: machines to deliver bacterial proteins into eukaryotic cells? Trends Microbiol. 5:148-156.) In an attempt to corrupt normal cellular functions, Chlamydial pathogenicity factors injected into the host cytosol will nonetheless, as cytoplasmic constituents be processed and presented in the context of the Major Histocompatibility Complex (MHC class I). As such, these pathogenicity proteins represent MHC class I antigens and will play an important role in cellular immunity. Also included in this set are secreted non-type III products that may play a role as vaccine components.

[0555] A text search of the ORF blastp results identified genes that are involved in Chlamydia pneumoniae protein secretion with a P score better than e−10. The following key-terms were used in the text search in an effort to identify surface localized or secreted products: Yop, Lcr, Ypk, Exo, Pcr, Pop, Ipa, Vir, Ssp, Spt, Esp, Tir, Hrp, Mxi, hemolysin, toxin, IgA protease, cytolysin, tox, hap, secreted and Mip.

[0556]

Chlamydia pneumoniae
ORFs that did not meet the above keyword search criteria, but have homologs in Chlamydia trachomatis that do meet the search criteria are included herein. The Chlamydia trachomatis genome (French patent applications FR97-15041, filed Nov. 28, 1997 and 97-16034 filed Dec. 17, 1997) was analyzed using the above search criteria and a number of ORFs were identified. These Chlamydia trachomatis ORFs were tested against the Chlamydia pneumoniae genome using Blastp. Any Chlamydia pneumoniae ORF with a Blastp P value <e−10 against a Chlamydia trachomatis homolog, identified using the above search criteria, was included. A list of ORFs in the Chlamydia pneumoniae genome encoding putative secreted proteins is in the specification.

[0557]

Chlamydia Pneumoniae
: RGD Recognition Sequence

[0558] Proteins that contain Arg-Gly-Asp (RGD) attachment site, together with integrins that serve as their receptor constitute a major recognition system for cell adhesion. The RGD sequence is the cell attachment site of a large number of adhesive extracellular matrix, blood, and cell surface proteins and nearly half of the known integrins recognize this sequence in their adhesion protein ligands. There are many RGD containing microbial proteins such as the penton protein of adenovirus, the coxsackie virus, the foot and mouth virus and pertactin, a 69 kDa (kilodalton) surface protein of Bordetella pertussis, that serve as ligands through which these microbes bind to integrins on the cell surfaces and gain entry into the cell. The following provides evidence supporting the importance of RGD in microbial adhesion:

[0559] a) The adenovirus penton base protein has a cell rounding activity and when penton base was expressed in E. coli, it caused cell rounding and cells adhered to polystyrene wells coated with the protein. Mutant analysis showed that both these properties required an RGD sequence. Virus mutants with amino acid substitutions in the RGD sequence, showed much less adherence to HeLa S3 cells, and also were delayed in virus reproduction (Bai, M., Harfe, B., and Freimuth, P. 1993. Mutations That Alter an RGD Sequence in the Adenovirus Type 2 Penton Base Protein Abolish Its Cell-Rounding Activity and Delay Virus Reproduction in Flat Cells. J. Virol. 67:5198-5205).

[0560] b) It has been shown that attachment and entry of coxsackie virus A9 to GMK cells were dependent on an RGD motif in the capsid protein VP1. VP1 has also been shown to bind αvβ3 integrin, which is a vitronectin receptor (Roivainen, M., Piirainen, L., Hovi, T., Virtanen, I., Riikonen, T., Heino, J., and Hyypia, T. 1994. Entry of Coxsackievirus A9 into Host Cells: Specific Interactions with αvβ3 Integrin, the Vitronectin Receptor Virology, 203:357-65).

[0561] c) During the course of whooping cough, Bordetella pertussis interacts with alveolar macrophages and other leukocytes on the respiratory epithelium. Whole bacteria adheres by means of two proteins, filamentous hemagglutinin (FHA) and pertussis toxin. FHA interacts with two classes of molecules on macrophages, galactose containing glycoconjugates and the integrin CR3. The interaction between CR3 and-FHA involves recognition of RGD sequence at the positions 1097-1099 in FHA (Relman, D., Tuomanen, E., Falkow, S., Golenbock, D. T., Saukkonen, K., and Wright, S. D. “Recognitition of a Bacterial Adhesin by an Integrin: Macrophage CR3 Binds Filamentous Hemagglutinin of Bordetella Pertussis.” Cell, 61:1375-1382 (1990)).

[0562] d) Pertactin, a 69 kDa outer membrane protein of Bordetella pertussis, has been shown to promote attachment of Chinese hamster ovary cells (CHO). This attachment is mediated by recognition of RGD sequence in pertactin by integrins on CHO cells and can be inhibited by synthetic RGD containing peptide homologous to the one present in pertactin (Leininger, E., Roberts, M., Kenimer, J. G., Charles, I. G., Fairweather, N., Novotny, P., and Brennan, M. J. 1991. Pertactin, an Arg-Gly-Asp containing Bordetella pertussis surface protein that promotes adherence of mammalian cells Proc. Natl. Acad. Sci. USA, 88:345-349).

[0563] e) The RGD sequence is highly conserved in the VP1 protein of foot and mouth disease virus (FMDV). Attachment of FMDV to baby hamster kidney cells (BHK) has been shown to be mediated by VP1 protein via the RGD sequence. Antibodies against the RGD sequence of VP1 blocked attachment of virus to BHK cells (Fox, G., Parry, N. R., Barnett, P. V., McGinn, B., Rowland, D. J., and Brown, F. 1989. The Cell Attachment Site on Foot-and-Mouth Disease Virus Includes the Amino Acid Sequence RGD (Arginine-Glycine-Aspartic Acid) J. Gen. Virol., 70:625-637).

[0564] It has been demonstrated that bacterial adherence can be based on interaction of a bacterial adhesin RGD sequence with an integrin and that bacterial adhesins can have multiple binding site characteristic of eukaryotic extracellular matrix proteins. RGD recognition is one of the important mechanisms used by microbes to gain entry into eukaryotic cells.

[0565] The complete deduced protein sequence of the Chlamydia pneumoniae genome was searched for the presence of RGD sequence. There were a total of 54 ORFs that had one or more RGD sequences. Not all RGD containing proteins mediate cell attachment. It has been shown that RGD containing peptides that have proline immediately following the RGD sequence are inactive in cell attachment assays (Pierschbacher & Ruoslahti. 1987. Influence of stereochemistry of the sequence Arg-Gly-Asp-Xaa on binding specificity in cell adhesion. J. Biol. Chem. 262:17294-98). ORFs that had RGD, with proline as the amino acid following the RGD sequence were excluded from the list. Also, RGD sequence may not be available at the surface of the protein or may be present in a context that is not compatible with integrin binding. Since not all RGD-containing proteins are involved in cell attachment, several other criteria were used to refine the list of RGD-containing proteins. A list of ORFs in the Chlamydia pneumoniae genome encoding polypeptides with RGD recognition sequence(s) is in the specification.

[0566] Non-Chlamydia Trachomatis ORFs

[0567]

Chlamydia pneumoniae
ORFs were compared to the ORFs in the Chlamydia trachomatis genome (French patent applications FR97-15041, filed Nov. 28, 1997 and 97-16034 filed Dec. 17, 1997) using Blastp. Any Chlamydia pneumoniae ORF with a Blastp P value worse than e−10 (i.e. >e−10) against Chlamydia trachomatis ORFs are included in this section. A list of ORFs in the Chlamydia pneumoniae genome which are not found in Chlamydia trachomatis is set forth above in the specification.

[0568] Cell Wall Anchor Surface ORFs

[0569] Many surface proteins are anchored to the cell wall of Gram-positive bacteria via the conserved LPXTG motif (Schneewind, O., Fowler, A., and Faull, K. F. 1995. Structure of the Cell Wall Anchor of Surface Proteins in Staphylococcus aureus. Science 268:103-106). A search of the Chlamydia pneumoniae ORFs was done using the motif LPXTG. A list of ORFs in the Chlamydia pneumoniae genome encoding polypeptides anchored to the cell wall is in the specification.

[0570] ATCC Deposits

[0571] Samples of Chlamydia pneumoniae were deposited with the American Type Culture Collection (ATCC), Rockville, Md., on Nov. 19, 1998 and assigned the accession number VR-2634. Cells can be grown, harvested and purified, and DNA can be prepared as discussed above. In order to enable recovery of specific fragments of the chromosome, one can run targeted PCR reactions, whose amplification products can then be sequenced and/or cloned into any suitable vector, according to standard procedures known to those skilled in the art.

[0572] In addition, a sample of three pools of clones covering chromosomal regions of interest were deposited with the American Type Culture Collection (ATCC), Rockville, Md., on Nov. 19, 1998 and assigned the indicated accession number:207000; 207001; and 207002. Each pool of clones contains a series of clones. When taken together, the three pools in the sample cover a portion of the chromosome, with a redundancy of slightly more than two. The total number of clones in the sample is 196.

[0573] The clones cover the following three regions of interest:

[0574] (i) position 30,000 to 40,000 of SEQ ID No. 1, referred to as region A;

[0575] (ii) position 501,500 to 557,000 of SEQ ID No. 1, referred to as region B; and

[0576] (iii) position 815,000 to 830,000 of SEQ ID No. 1, referred to as region C.

[0577] Table 4 lists groups of oligonucleotides to be used to amplify each of ORFs 2-1291 according to standard procedures known to those skilled in the art. Such oligonucleotides are listed as SEQ ID Nos. 1292 to 6451. For each ORF, the following is listed: one forward primer positioned 2,000 bp upstream of the beginning of the ORF; one forward primer positioned 200 bp upstream of the beginning of the ORF; one reverse primer positioned 2,000 bp downstream at the end of ORF, which is 2,000 bp upstream of the end site of the ORF on the complementary strand; and one reverse primer 200 bp downstream at the end of ORF, which is 200 bp upstream of the end site of the ORF on the complementary strand. The corresponding SEQ ID Nos. for the primers are listed in Table 4, where Fp is the proximal forward primer; Fd is the distal forward primer; Bp is the proximal reverse primer; and Bd is the distal reverse primer. The positions of the 5′ ends of each of these primers on the nucleotide sequence of SEQ ID No. 1 are shown in Table 5.

[0578] Table 6 lists oligonucleotides (SEQ ID Nos. 6452-6843) to be used to amplify the inserts of each of the 196 clones present in the pooled sample according to standard procedures well known to those of skill in the art. These primers can also be utilized to amplify the chromosomal region corresponding to the region A, B or C within which the particular insert lies. Their positions are indicated in Table 7.

[0579] The present invention is not to be limited in scope by the specific embodiments described herein, which are intended as single illustrations of individual aspects of the invention, and functionally equivalent methods and components are within the scope of the invention. Indeed, various modifications of the invention, in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

[0580] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Incorporation of Related Applications

[0581] This application hereby incorporates each of the provisional applications, non-provisional applications, and applications to which foreign priority is claimed, as listed on the Application Data Sheet that is associated with the subject application, by reference and in their entireties, including any figures, tables, nucleic acid sequences, amino acid sequences, and/or drawings.

2TABLE 1ORFBeginEndHomologyIDSpeciesScoreI %ORF242794triosephosphate isomeraseL27492Thermotoga maritima56754ORF312581614putativeORF418072418polypeptide deformylaseD90906Synechocystis sp.31640ORF533932491hypothetical proteinZ75208Bacillus subtilis33842ORF636394067unknownU87792Bacillus subtilis11738ORF756494270putativeORF874636012putativeORF980518962putativeORF1091299959putativeORF111068710361putativeORF121092711232putativeORF131124612727amidaseU49269Moraxella catarrhalis110842ORF141269114190PET112D90913Synechocystis sp.104446ORF151448417249POMP91AU65942Chlamydia psittaci107443ORF161603915770putativeORF171784520853putativeORF182113722042putativeORF192204623476putativeORF202368126110putativeORF212610925861putativeORF222624126978putativeORF232696027754putativeORF242774728577putativeORF252888729492POMP91AU65942Chlamydia psittaci18039ORF262943230028POMP91AU65942Chlamydia psittaci36151ORF273002431472POMP91AU65942Chlamydia psittaci87954ORF283175832288putative 98 kDa outer membrane proteinU72499Chlamydia psittaci14443ORF293220133991putative 98 kDa outer membrane proteinU72499Chlamydia psittaci112648ORF303385234541putative 98 kDa outer membrane proteinU72499Chlamydia psittaci58962ORF313478336063POMP91B precursorU65943Chlamydia psittaci46946ORF323600937529putative 98 kDa outer membrane proteinU72499Chlamydia psittaci133851ORF333788139362putative 98 kDa outer membrane proteinU72499Chlamydia psittaci67140ORF343941839161putativeORF353936640715POMP90A precursorU65942Chlamydia psittaci90447ORF364307641094putativeORF374380043066putativeORF384482843785putativeORF394534044753homologous to unidentified E. coli proteinM96343Bacillus subtilis13644ORF404575245372o530; This 530 aa orf is 33 pct identical (14 gaps) toAE000184Escherichia coli26943525 residues of an approx. 640 aa proteinYHES_HAEIN SW: P44808ORF414699645701ABC transporter, ATP-binding proteinAE000596Helicobacter pylori87839(yheS)ORF424796147569putativeORF434896048040hypothetical proteinD64001Synechocystis sp.40437ORF445145250133Lon protease-like proteinX74215Homo sapiens123254ORF455260651335unknownZ54285Schizosaccharomyces pombe78147ORF465368453319putativeORF475419553746putativeORF485527856453heat-shock proteinU15010Legionella pneumophila97545ORF495649357266branched chain alpha-keto acidM97391Bacillus subtilis32936dehydrogenase E1-alphaORF505729758526branched chain alpha-keto acidM97391Bacillus subtilis70750dehydrogenase E1-betaORF515985158565putativeORF526149559924ComED90903Synechocystis sp.13455ORF536132462151putativeORF546213262470Hpr proteinX12832Bacillus subtilis13636ORF556247463733enzyme I (ptsI)U32844Haemophilus influenzae38135ORF566388164186f831; This 831 aa orf is 46 pct identical (11AE000326Escherichia coli12334gaps) to 709 residues of an approx. 712 aaprotein PT1A_ECOLI SW: P32670ORF576461164318ORF107X17014Bacillus subtilis12833ORF586548564673putativeORF596599965301dnaZX-like ORF put. DNA polymerase IIIX06803Bacillus subtilis59652ORF606624467281putativeORF616726567699putativeORF626770368539putativeORF636880570736putativeORF646917268831putativeORF657064271142putativeORF667132572029putativeORF677206073637putativeORF687406176175YqfFD84432Bacillus subtilis54244ORF697835177680porphobilinogen deaminaseD28503Clostridium josui26242ORF707935678355sms proteinD90914Synechocystis sp.73652ORF717998379693ribonuclease III (rnc)AE000579Helicobacter pylori9833ORF728044179938ORF3D64116Bacillus subtilis26844ORF738047580969putativeORF748129683080hypothetical proteinY14079Bacillus subtilis89338ORF758329183932manganese superoxide dismutaseX77021Caenorhabditis elegans62258ORF768400584769acetyl-CoA carboxylase beta subunit (accD)AE000604Helicobacter pylori60250ORF778497585244deoxyuridinetriphosphatase (dut)U32776Haemophilus influenzae11041ORF788512385425deoxyuridine 5′-triphosphateAE000596Helicobacter pylori26568nucleotidohydrolase (dut)ORF798539785903ORF2L26916Pseudomonas aeruginosa17334ORF808590986583enzyme IIANtrU18997Escherichia coli17042ORF818662688065putativeORF828925791026putativeORF839129193030putativeORF849329594086putativeORF859528594707putativeORF869566796557putativeORF879631797456putativeORF889843597968putativeORF899946098426putativeORF90100144101325elongation factor TuL22216Chlamydia trachomatis191795ORF91101457101720putativeORF92101704102273transcription factorL10348Thermus aquaticus thermophilus37649ORF93102356102805ribosomal protein L11D13303Bacillus subtilis45863ORF94102835103530ribosomal protein L1Z11839Thermotoga maritima64251ORF95103549104058ribosomal protein L10M89911Streptomyces antibioticus8231ORF96104096104491rp112 (AA 1-128)X53178Synechocystis PCC680332547ORF97104601108386DNA-directed RNA polymerase beta chainX64172Staphylococcus aureus274052ORF98108401112054rpoCV00339Escherichia coli294754ORF99112033112590acetylornithine deacetylase (EC 5.1.1.16)M22622Leptospira biflexa51462ORF100112672113682transaldolaseL19437Homo sapiens75549ORF101113726114121putativeORF102114711114136putativeORF103115267115755putativeORF104115911116543putativeORF105116736118055ATPase alpha-subunitX63855Thermus aquaticus thermophilus93450ORF106117968118522adenosine triphosphatase A subunitD50528Acetabularia acetabulum14732ORF107118530119843V-ATPase B subunitU96487Desulfurococcus sp. SY75148ORF108119816120457putativeORF109120451122430v-type Na-ATPaseX76913Enterococcus hirae26435ORF110122504122950ATP synthase, subunit KU67478Methanococcus jannaschii18431ORF111123528126347valyl-tRNA synthetaseX05891Escherichia coli167949ORF112126332129166protein kinase-like proteinU19250Streptomyces coelicolor42737ORF113134690129213UvrAD49911Thermus thermophilus310741ORF114134925136382pyruvate kinaseU83196Chlamydia trachomatis174871ORF115137870136482HtrB proteinX61000Escherichia coli14738ORF116137899138240putativeORF117138239137928putativeORF118139558138257putativeORF119140352139516YbbPAB002150Bacillus subtilis23146ORF120140498141841cyanide insensitive terminal oxidaseY10528Pseudomonas aeruginosa53850ORF121141855142658cyanide insensitive terminal oxidaseY10528Pseudomonas aeruginosa31040ORF122144258143050putativeORF123145258144494putativeORF124145454146749product similar to E. coli PhoH proteinZ97025Bacillus subtilis83647ORF125147318146767putativeORF126148261147677putativeORF127149029152157isoleucyl-tRNA synthetaseU04953Homo sapiens236152ORF128154108152201leader peptidase ID90904Synechocystis sp.22547ORF129155135154308putativeORF130155141155467YtiAAF008220Bacillus subtilis20143ORF131155703156779orf 361; ranslated orf similarity to SW:X78969Coxiella burnetii86359RF1_SALTY peptide chain release factor 1of Salmonella typhimuriumORF132156748157635product similar to E.coli PRFA2 proteinZ49782Bacillus subtilis14437ORF133157653158996FfhU82109Thermus aquaticus79745ORF134159363159986tRNA (guanine-N1)-methyltransferaseU32705Haemophilus influenzae54549(trmD)ORF135159880160446putativeORF136160477160839ribosomal protein L19X72627Synechocystis sp.31950ORF137160898161539putative protein highly homologous to E.D32253Magnetospirillum sp.42749coli RNase HII.ORF1381615271621535′guanylate kinase (gmk)U32848Haemophilus influenzae38543ORF139162144162443putativeORF140162437164098methionyl-tRNA synthetaseAB004537Schizosaccharomyces pombe86154ORF141165451164228exodeoxyribonuclease V (recD)U32811Haemophilus influenzae43232ORF142166349165411putativeORF143166949168442putativeORF144169416171029putativeORF145170857171459putativeORF146172652173428putative biotin-protein ligaseZ97992Schizosaccharomyces pombe29244ORF147174626173439putativeORF148174816175613putativeORF149175598175954putativeORF150175958176935putativeORF151177708176938orf 3′of chaperonin homolog hypBS40172Chlamydia psittaci37674[Chlamydia psittaci, pigeon strain P-1041,Peptide Partial, 98 aa]ORF152177128177376putativeORF153179472177841putativeM69217Chlamydia pneumoniae2678100ORF154179822179517putativeM69217Chlamydia pneumoniae49899ORF155181793179943Pz-peptidaseD88209Bacillus licheniformis108838ORF156182628181876o247; This 247 aa orf is 51 pct identical (0AE000174Escherichia coli40142gaps) to 117 residues of an approx. 160 aaprotein YPH7_CHRVI SW: P45371ORF157184420183074glutamate-1-semialdehyde 2,1-aminomutaseX53696Escherichia coli82341ORF158184988184467ORF_o211U28377Escherichia coli8754ORF159185483185112hypothetical proteinD90906Synechocystis sp.9133ORF160185902185483ribose 5-phosphate isomeraseU28377Escherichia coli11141ORF161186174185839ribose 5-phosphate isomerase AU32729Haemophilus influenzae19046(SP: P27252)ORF162187720186587hypotheticalD83026Bacillus subtilis53642ORF163188318190933ATP-dependent protease binding subunitM29364Escherichia coli201053ORF164191090191635putativeORF165191547192743putativeORF166192969193469putativeORF167194044193610putativeORF168194196195809unknownZ84395Mycobacterium tuberculosis24252ORF169196088198073DNA ligase (EC 6.5.1.2)M24278Escherichia coli131746ORF170198132199454putativeORF171199351202818putativeORF172204552202999PcpBU60175Sphingomonas chlorophenolica8041ORF173205648204692putativeORF174205807207327leucine tRNA synthetaseAF008220Bacillus subtilis159557ORF175207182207775leucyl-tRNA synthetaseX06331Escherichia coli36351ORF176207779208267transfer RNA-Leu synthetaseM88581Bacillus subtilis28543ORF177208267209577KDO transferaseZ31593Chlamydia pneumoniae2262100ORF178211807211271KDO-transferaseX80061Chlamydia psittaci10538ORF179212188211844putativeORF180214079212448pyrophosphate-dependentZ32850Ricinus communis100345phosphofructokinase beta subunitORF181214907214083CinIU44893Butyrivibrio fibrisolvens11141ORF182216154215429putativeORF183216115216678putativeORF184216728217282putativeORF185217267217866putativeORF186218593218261putativeORF187219821218994putativeORF188221382220309putativeORF189222719221433GMP synthetaseM10101Escherichia coli115148ORF190223521222724IMP dehydrogenaseX66859Acinetobacter calcoaceticus77858ORF191224499225008putativeORF192225140225559putativeORF193225555226802putativeORF194227800226892putativeORF195228335228072putativeORF196229251228643putativeORF197230983229622YqhXD84432Bacillus subtilis138656ORF198231483230983acetyl-CoA carboxylase biotin carboxylU38804Porphyra purpurea19952carrier proteinORF199232063231509elongation factor PD64001Synechocystis sp.28232ORF200232739232053pentose-5-phosphate-3-epimeraseD90911Synechocystis sp.46343ORF201233166234356putativeORF202233518233165putativeORF203234536235186ORF2L35036Chlamydia psittaci57060ORF204235379236689putativeORF205236680237618putativeORF206237521238345putativeORF207238281238973putativeORF208238871240115putativeORF209240191241564putativeORF210242281241604YqiZD84432Bacillus subtilis37939ORF211242933242274f222; This 222 aa orf is 48 pct identical (0AE000284Escherichia coli38245gaps) to 208 residues of an approx. 232 aaprotein YCKA_BACSU SW: P42399ORF212243416242976arginine repressor protein (argR)U32800Haemophilus influenzae22946ORF213243500244531sialoglycoproteaseU15958Pasteurella haemolytica56553ORF214244480246021oligopeptide permease homolog AIIAF000366Borrelia burgdorferi45734ORF215246330247811OppAIVAF000948Borrelia burgdorferi45335ORF216247831249174OppA gene productX56347Bacillus subtilis25537ORF217249437251038dciAEX56678Bacillus subtilis46937ORF218251325252212OppB gene productX56347Bacillus subtilis65242ORF219253156254007oligopeptidepermeaseX89237Streptococcus pyogenes57448ORF220253974254852ATP binding proteinL18760Lactococcus lactis43340ORF221255258256094KDO-transferaseX80061Chlamydia psittaci10646ORF222256640257455putativeORF2232575022582392-OXOGLUTARATA47930Spinacia oleracea63652ORF224257869257501putativeORF225259248260897pyrophosphate-fructose 6-phosphate 1-M55191Solanum tuberosum105544phosphotransferase beta-subunitORF226262753261788putativeORF227263059262757putativeORF228264375263182putativeORF229265985264747putativeORF230266637266059putativeORF231267338266538putativeORF232267922267473putativeORF233269647270771tRNA guanine transglycosylaseL33777Zymomonas mobilis62844ORF234272777273145ORF 4D00624Bacteriophage chp110041ORF235273253273636putativeORF236273705273977putativeORF237276016275717putativeORF238276439276020putativeORF239276792277253putativeORF240277318277599putativeORF241278578277877putativeORF242279258278554FbpCU33937Neisseria gonorrhoeae31239ORF243280435279533putativeORF244281547280849putativeORF245281696282325CMP-2-keto-3-deoxyoctulosonic acidU15192Chlamydia trachomatis63763synthetaseORF246282459284069CTP synthetaseU15192Chlamydia trachomatis200068ORF247284056284517ORF3U15192Chlamydia trachomatis45365ORF248284606285775glucose 6-phosphate dehydrogenaseU83195Chlamydia trachomatis126377ORF249285592285987glucose 6-phosphate dehydrogenaseU83195Chlamydia trachomatis51979ORF250286179286976glucose-6-phosphate dehydrogenaseD88189Actinobacillus21640isozymeactinomycetemcomitansORF251287583287002putativeORF252287951287451putativeORF253288499288816putativeORF254289674288505putativeORF255288839289213putativeORF256289970290254putativeORF257291931292803gamma-D-glutamyl-L-diamino acidX64809Bacillus sphaericus9539endopeptidase IIORF258293258292755ScoS9U43429Streptomyces coelicolor23345ORF259293718293272ribosomal protein L13 (rpL13)U32823Haemophilus influenzae36447ORF260294630293953glutamine transport ATP-binding protein QU67524Methanococcus jannaschii38746ORF261296153294636putativeORF262294817295068putativeORF263296354297862conserved hypothetical proteinAE000586Helicobacter pylori64146ORF264298415297879putativeORF265298777298253putativeORF266299572298781putativeORF267300487299633putativeORF268301586300702putativeORF269302440301571putativeORF270302838302437putativeORF271303335302745putativeORF272304394303852putativeORF273304606305223f311; This 311 aa orf is 22 pct identical (13AE000232Escherichia coli25038gaps) to 186 residues of an approx. 488 aaprotein YACA_BACSU SW: P37563; pyu1of D21139ORF274305394306236survival protein surEU81296Sinorhizobium meliloti15642ORF275306501307439YqfUD84432Bacillus subtilis54742ORF2763080333074583-octaprenyl-4-hydroxybenzoate carboxylyaseU61168Bacillus firmus40342ORF2773089243080374-hydroxybenzoate octaprenyltransferaseU61168Bacillus firmus15240ORF278309485310180putativeORF279310426311214putativeORF280311597311253putativeORF281312772311780putativeORF282313425312772putativeORF283313646313377putativeORF284313937314665lysophospholipase homologAF006678Schistosoma mansoni14144ORF285315576314755dnaZXX17014Bacillus subtilis15439ORF286316157315531unknownD26185Bacillus subtilis28431ORF287318657316156DNA gyraseL47978Aeromonas salmonicida178548ORF288321042318676DNA gyrase subunit BU35453Clostridium acetobutylicum183859ORF289321445321098putativeORF290322309321710putativeORF291323190322366outer membrane proteinAE000654Helicobacter pylori37643ORF292323843323181hypotheticalU70214Escherichia coli35637ORF293324878323856ATP-binding protein (abc)U32744Haemophilus influenzae54544ORF294325340326410f374; This 374 aa orf is 30 pct identical (9AE000299Escherichia coli119462gaps) to 102 residues of an approx. 512 aaprotein FLIC_SALMU SW: P06177ORF295326433327836Xas AAE000246Escherichia coli47933ORF296328465327839putativeORF297329360328857putativeORF298330907329357putativeORF299332455330956MgtEU18744Bacillus firmus20336ORF300334536332395putativeORF301336091334877putativeORF302336103337302putativeORF303338129338830putativeORF304338965339501putativeORF305339508340143putativeORF306340247342967putativeORF307343385343810cAMP-dependent protein kinase type IU75932Rattus norvegicus10237regulatory subunitORF308344171343935acyl carrier protein (acpP)AE000570Helicobacter pylori19855ORF3093450823443303-ketoacyl-ACP reductaseU39441Vibrio harveyi59848ORF310346005345082malonyl-CoA: Acyl carrier proteinU59433Bacillus subtilis53845transacylaseORF311346784346437beta-ketoacyl-acyl carrier protein synthaseAE000540Helicobacter pylori27350III (fabH)ORF312347029346715beta-ketoacyl-acyl carrier protein synthaseM77744Escherichia coli26563IIIORF313347034347723recombination proteinD90916Synechocystis sp.36342ORF314348075350459putativeORF315350598351071putativeORF316351075352175rifampicin resistance proteinL22690Rickettsia rickettsii49546ORF317353291352230putativeORF318353442354467pyruvate dehydrogenase E1 component,D90915Synechocystis sp.57144alpha subunitORF319354451354933pyruvate dehydrogenase E1 beta subunitU09137Arabidopsis thaliana49559ORF320355000355449pyruvate dehydrogenase E1 component, betaU38804Porphyra purpurea33647subunitORF321355448356743F23B12.5Z77659Caenorhabditis elegans75946ORF322355953355642putativeORF323359310356827glycogen phosphorylase BU47025Homo sapiens219357ORF324359120359377putativeORF325359525359908putativeORF326361290359947DnaAD89066Staphylococcus aureus37546ORF327363785361362hypotheticalU32781Haemophilus influenzae39444ORF328364496363888putativeORF329364832365290putativeORF330365304365669dpjM76470Escherichia coli16045ORF331366599365667NADPH thioredoxin reductaseAC002329Arabidopsis thaliana97560ORF332367291369030ribosomal protein S1 (rpS1)U32801Haemophilus influenzae120941ORF333369134369808NusAU74759Chlamydia trachomatis99587ORF334369917370438NusAU74759Chlamydia trachomatis76087ORF335370365372647U74759Chlamydia trachomatis217361ORF336372557373066initiation factor IF2-beta (infB; gtg startX00513Escherichia coli33339codon)ORF337373020373442ORF6 gene productZ18631Bacillus subtilis19234ORF338373467374195tRNA pseudouridine 55 synthaseD90917Synechocystis sp.35847ORF339374176375099hypothetical 34.6 kD protein in rpsT-ileSAE000113Escherichia coli39539intergenic regionORF340375676375083hypothetical GTP-binding protein in pth 3′AE000219Escherichia coli50753regionORF341376173375634hypotheticalU32723Haemophilus influenzae48059ORF342376564377643YscUU08019Yersinia enterocolitica53837ORF343377956379773lcrD gene productX67771Yersinia enterocolitica130247ORF344379781380425putativeORF345380281381000putativeORF346381008381460putativeORF3473814603830374-alpha-glucanotransferaseL37874Clostridium butyricum30238ORF348383257383523ribosomal protein L28 (rpL28)U32776Haemophilus influenzae17555ORF349383553385304hypothetical proteinD90901Synechocystis sp.56538ORF350385397386458comE ORF1D64002Synechocystis sp.18710ORF351387242386514putativeORF352388764387013putativeORF353390120390932methylenetetrahydrofolate dehydrogenaseD64000Synechocystis sp.58853ORF354390919391818f351; Residues 1-121 are 100 pct identical toAE000310Escherichia coli18639YOJL_ECOLI SW: P33944 (122 aa) and aa152-351 are 100 pct identical toYOJK_ECOLI SW: P33943ORF355392379391885small proteinD90914Synechocystis sp.38746ORF356392582392986putativeORF357392776393684putativeORF358394151394804RecF proteinD90907Synechocystis sp.23234ORF359394928395308putativeORF360395259395990putativeORF361397815395953hypotheticalU32773Haemophilus influenzae39136ORF362398850397831H. influenzae predicted coding regionU32763Haemophilus influenzae58039HI0807ORF363400085399099putativeORF364401245400073YtgCAF008220Bacillus subtilis24430ORF365401474401136putativeORF366402199401423unknownU52850Erysipelothrix rhusiopathiae53446ORF367403193402186putativeORF368403650404165putativeORF369404343405914adenine nucleotide translocaseZ49227Arabidopsis thaliana128055ORF370405984407327putativeORF371407712408806putativeORF372410439409075putativeORF373411826410954putativeORF374412482414302lepA gene productX91655Bacillus subtilis182759ORF3754154024144076-phosphogluconate dehydrogenase,U32737Haemophilus influenzae68751decarboxylating (gnd)ORF3764158484152376-phosphogluconate dehydrogenase, 6PGDS67873Ceratitis capitata69564[Ceratitis capitata = medflies, Peptide, 481aa]ORF377417131415866tyrosyl-tRNA synthetase (tyrS)J01719Escherichia coli82145ORF378417258417566putativeORF379418326417454whiG-Stv gene productX68709Streptoverticillium griseocarneum46441ORF380420057418426FLHA gene productX63698Bacillus subtilis45549ORF381420448420720ferredoxin IVM59855Rhodobacter capsulatus17463ORF382420980421552putativeORF383421556422029putativeORF384422461422925putativeORF385423562424320putativeORF386424250424591putativeORF387424830426047putativeORF388426240427397putativeORF389428841430703GcpED90908Synechocystis sp.87747ORF390430694431446YfiHU50134Escherichia coli13635ORF391431597432100putativeORF392432165432779putativeORF393433272432832dihydrolipoamide succinyltransferase (sucB)U32839Haemophilus influenzae47564ORF394433925433227dihydrolipoamide succinyltransferase (sucB)U32839Haemophilus influenzae33245ORF395436678433934alpha-ketoglutarate dehydrogenaseU41762Rhodobacter capsulatus153044ORF396437176438357oxygen-independent coproporphyrinogen IIIAE000628Helicobacter pylori44242oxidase (hemN)ORF397440317438518putativeORF398440001440345putativeORF399441233440517ORF_f286U18997Escherichia coli16845ORF400440719441012putativeORF401442192441230putativeORF402442888442343putativeORF403442371442961putativeORF404443578443003[karp] gene productsM86605Chlamydia trachomatis50578ORF405444500443526aminopeptidaseD17450Mycoplasma salivarium27339ORF406444842444528putativeORF407445009444743putativeL39923Mycobacterium leprae13333ORF408445718445182putativeORF409445807447804SulpU18908Zea mays130752ORF410448738447803putativeORF411449628448618RuvB proteinU38840Thermotoga maritima84553ORF412450298450867deoxycytidine triphosphate deaminase (dcd)AE000554Helicobacter pylori57358ORF413450713451207putativeORF414451211452452hemolysinD90914Synechocystis sp.22739ORF415452448453659similar to [SwissProt Accession NumberD90888Escherichia coli9633P37908]ORF416454843453725NifS gene productL34879Anabaena azollae53338ORF417455608454865hypothetical proteinD90908Synechocystis sp.37136ORF418456243457007putativeORF419457016457708putativeORF420458368457979unknownD26185Bacillus subtilis15236ORF421459496458372mutY homologU63329Homo sapiens46646ORF422459493460194hypothetical proteinD90914Synechocystis sp.9838ORF423461446460355putativeORF424462298461450putativeORF425462444463349enoyl-ACP reductaseY13861Nicotiana tabacum100869ORF426464241463342putativeORF427464574465065putativeORF428465129465611putativeORF429465571466317putativeORF430466317467093H. pylori predicted coding region HP0152AE000536Helicobacter pylori24636ORF431466999467502putativeORF432469691467715unidentified transporter-ATP bindingZ82044Bacillus subtilis49645ORF433470691469660acetyl-CoA carboxylase subunitAF008220Bacillus subtilis78152ORF434472010470709putativeORF435471545471799putativeORF436472359472045putativeORF437473523472732orf1X75413Escherichia coli31342ORF438474889473441murE gene productZ15056Bacillus subtilis67937ORF439477323475365penicillin-binding protein 2X59630Neisseria meningitidis45142ORF440478496477597hypothetical proteinD90906Synechocystis sp.53452ORF441478722479273putativeORF442479277479705putativeORF443480050481450chromosomal replication initiator proteinD90909Synechocystis sp.79340DnaAORF444481469482053OrfHU35673Borrelia burgdorferi15737ORF445482600482025putativeORF446482654484204NADH: ubiquinone oxidoreductase subunit BZ37111Vibrio alginolyticus80149ORF447484211485170NADH: ubiquinone oxidoreductaseU32702Haemophilus influenzae25848(GP: Z37111_4)ORF448485170485838NADH: uniquinone oxidoreductaseZ37111Vibrio alginolyticus54355ORF449485813486580unidentified protein of Na+-translocatingD49364Vibrio alginolyticus48848NADH-quinone reductaseORF450486976486638putativeORF451489071487764putativeORF452489341489090putativeORF453489958489152putativeORF454490549489962putativeORF455491163490522putativeORF456491396491112putativeORF457492121491390putativeORF458492304494838ClpC adenosine triphosphataseU02604Bacillus subtilis237046ORF459495943494822hypothetical protein in purB 5′ regionAE000213Escherichia coli92753ORF460496011496565putativeORF461496569497228putativeORF462497358497834putativeORF463497770498327putativeORF464499209499589putativeORF465499520499792putativeORF466500774504169putative 98 kDa outer membrane proteinU72499Chlamydia psittaci121545ORF467504139504600putative 98 kDa outer membrane proteinU72499Chlamydia psittaci31947ORF468504865506877putative 98 kDa outer membrane proteinU72499Chlamydia psittaci99242ORF469506790507671putative 98 kDa outer membrane proteinU72499Chlamydia psittaci73946ORF470507718510507putative 98 kDa outer membrane proteinU72499Chlamydia psittaci181342ORF471508325507912putativeORF472510660513440POMP90A precursorU65942Chlamydia psittaci183046ORF473514965513787hypotheticalD83026Bacillus subtilis48248ORF474517347515419putative 98 kDa outer membrane proteinU72499Chlamydia psittaci155451ORF475517058517363putativeORF476517798517277putative 98 kDa outer membrane proteinU72499Chlamydia psittaci22241ORF477518200517847POMP91B precursorU65943Chlamydia psittaci16242ORF478518300521146putative 98 kDa outer membrane proteinU72499Chlamydia psittaci190045ORF479521392522948POMP91AU65942Chlamydia psittaci49039ORF480523244524809putative 98 kDa outer membrane proteinU72499Chlamydia psittaci50735ORF481524379524125putativeORF482524649526238putative 98 kDa outer membrane proteinU72499Chlamydia psittaci96941ORF483526265527104putativeORF484526947526702putativeORF485526975528450putative 98 kDa outer membrane proteinU72499Chlamydia psittaci19748ORF486528408529199putative outer membrane proteinU72499Chlamydia psittaci15437ORF487530612529542putativeORF488531656530616putativeORF489533974532067putativeORF490536432534324putativeORF491537150536707putativeORF492537928537080putativeORF493538438537932putativeORF494538737538333putativeORF495539594539127putativeORF496541215539590putativeORF497542571541282putativeORF498543014542457putativeORF499543369542962putativeORF500543809546628putative 98 kDa outer membrane proteinU72499Chlamydia psittaci50689ORF501546619549525POMP91AU65942Chlamydia psittaci12850ORF502547293546994putativeORF503549699550523putative 98 kDa outer membrane proteinU72499Chlamydia psittaci9632ORF504550490551551putative 98 kDa outer membrane proteinU72499Chlamydia psittaci22333ORF505551448552623putative 98 kDa outer membrane proteinU72499Chlamydia psittaci13946ORF506552652555117putative 98 kDa outer membrane proteinU72499Chlamydia psittaci48748ORF507555029555493putativeORF508558006555673putativeORF509559694558162putativeORF510558208558573putativeORF511561692559899putativeORF512561412561708putativeORF5135639425617771,4-alpha-glucan branching enzymeX73903Streptomyces coelicolor174345ORF514564969563950putativeORF515566204564936YqeVD84432Bacillus subtilis63938ORF516567717566302putative GTPase required for high frequencyU00005Escherichia coli68641lysogenization by bacteriophage lambdaORF517568526567708putativeORF518569467568742putativeORF519571065569431putativeORF520571828571118arginine-binding periplasmic protein 1AE000188Escherichia coli19745precursorORF521572202573308putativeORF522573146575056putativeORF523575023575916carboxysome formation proteinD90901Synechocystis sp.55759ORF524577891576497putativeORF525578914578204putativeORF526579924578857putativeORF527580187579858protein kinase C inhibitorD90906Synechocystis sp.26049ORF528580017580406putativeORF529581086580187Yer156cpU18917Saccharomyces cerevisiae17634ORF530581367581828putativeORF531581678582367putativeORF532582361583428putativeORF533584690583431putativeORF534585237584950putativeORF535585626586888hypothetical proteinD64004Synechocystis sp.80545ORF536586846587907putativeORF537589049588180putativeORF538590500589301putativeORF539590755592458aminoacyl-tRNA synthetaseL25105Chlamydia trachomatis212571ORF540592526592903has homology to putative heat shockL25105Chlamydia trachomatis32459proteins of Bacillus subtilis and Clostridiumacetobutylicum; ORFA; putativeORF541592836593747Possible negative regulator of CIRCEU52216Chlamydia trachomatis96065element; Homologs in B. subtilis andClostridia spp. referred to as hrcA or orfAORF542593747594298grpEM62819Chlamydia trachomatis66171ORF543594331595947DnaK protein homolog; 71,550 Da; putativeM69227Chlamydia pneumoniae2619100ORF544595905596309DnaK protein homolog; 71,550 Da; putativeM69227Chlamydia pneumoniae674100ORF545596514597215putativeORF546597184597957vacB gene productU14003Escherichia coli30648ORF547597755598612ORF-2D11024Shigella flexneri16846ORF548598602599204homologous to DNA glycosylases;D83026Bacillus subtilis37447hypotheticalORF549599373599939putativeORF550600903602072hemolysinX73141Serpulina hyodysenteriae36236ORF551602240602587hypothetical proteinD90908Synechocystis sp.18235ORF552602637603272putativeORF553603142604512putativeORF554604627605853conserved hypothetical proteinAE000579Helicobacter pylori42340ORF555605790606620putativeORF556606571607281putativeL14679Lactococcus lactis38445ORF557609004607355putativeORF558610906609932putativeORF559611786611004diaminopimelate epimeraseD90917Synechocystis sp.20755ORF560612333611746ATP-dependent Clp protease proteolyticD90915Synechocystis sp.38944subunitORF561613897612341serine hydroxymethyltransferaseD90903Synechocystis sp.90952ORF562615179616279putativeORF563616610617383putativeORF564618796617810ORF_o328U18997Escherichia coli41345ORF565620004618826branched chain alpha-keto acidM97391Bacillus subtilis68841dehydrogenase E2ORF566619649619918putativeORF567621265620021Hypothetical proteinY14083Bacillus subtilis72737ORF568622359621265hypotheticalU32691Haemophilus influenzae29452ORF569623420622560rRNA methylaseD90913Synechocystis sp.24438ORF570624297623335hypothetical protein (SP: P39587)U67605Methanococcus jannaschii14735ORF571624773624174riboflavin synthase alpha chainAE000261Escherichia coli42450ORF572625029625484ORF 168D28752Synechococcus sp.32343ORF573625488625883YteAAF008220Bacillus subtilis17235ORF574625892626395signalpeptidase IIX78084Staphylococcus carnosus20438ORF575626444627790D-alanine permease (dagA)U32770Haemophilus influenzae56633ORF576627912628607putativeORF577628774629697putativeORF578629660631639POMP91AU65942Chlamydia psittaci57944ORF579631725633551putativeORF580633520636957putative 98 kDa outer membrane proteinU72499Chlamydia psittaci26645ORF581637232638098adhesion proteinD90903Synechocystis sp.26738ORF582640648639593GTP-binding proteinD90901Synechocystis sp.75945ORF58364097964072850S ribosomal protein L27U38804Porphyra purpurea26565ORF58464132764100750S ribosomal subunit protein L21U18997Escherichia coli21041ORF585641687642283hypothetical proteinD90906Synechocystis sp.7639ORF586643023642286assimilatory sulfite reductaseL26503Saccharomyces cerevisiae28442ORF587643330643076putativeORF588643704643351ribosomal protein S10 (rpS10)U32761Haemophilus influenzae34969ORF589645628643676translation elongation factor EF-G (fusA)AE000625Helicobacter pylori199158ORF590645783645538elongation factor G (AA 1-691)X16278Thermus aquaticus thermophilus17080ORF591646269645793ribosomal protein S7Z11567Chlamydia trachomatis73088ORF592646751646314ribosomal protein S12 (AA 1-123)X52912Cryptomonas phi48567ORF593647848647045putativeORF594648393650336ORF of prc gene (alt.)D00674Escherichia coli55442ORF595651016650420hypothetical sulfur-rich proteinU41759Chlamydia psittaci30150ORF59665295665128960 kDa CrPX53511Chlamydia pneumoniae2951100ORF597653395653126 9 kDa CrPX53511Chlamydia pneumoniae50299ORF598655740654193glutamyl-tRNA synthetase homologU41759Chlamydia psittaci225982ORF599656508655966early stage-specific transcriptionL13598Chlamydia psittaci66662experimentally demonstrated; earlyupstream open reading frame (EUO)ORF600658140657022unknownU41759Chlamydia psittaci95044ORF601660216658525RecJ recombination proteinU41759Chlamydia psittaci80773ORF602663238660248protein-export membrane protein SecDD64000Synechocystis sp.41341ORF603664461663157putativeORF604665735664635putativeORF605666212666994hypothetical proteinD64006Synechocystis sp.53858ORF606666998667921o298; This 298 aa orf is 33 pct identical (24AE000238Escherichia coli25345gaps) to 248 residues of an approx. 256 aaprotein CDSA_ECOLI SW: P06466ORF607667909668568cytidylate kinaseAE000193Escherichia coli40048ORF608668502669203hypothetical proteinD90915Synechocystis sp.22533ORF609669154670893arginyl-tRNA-synthetaseD64006Synechocystis sp.136549ORF610672226670853UDP-N-acetylglucosamine enolpyruvylU32788Haemophilus influenzae64240transferase (murZ)ORF611671137671424putativeORF612672453673001putativeORF613673072674721putativeORF614674549674262putativeORF615675518674796ORF246 gene productX59551Escherichia coli52043ORF616676083675499putativeORF617676630676067putativeORF618677016676600ORF3D10279Bacillus subtilis36163ORF619677647677015peptide release factor 2X99401Bacillus firmus42743ORF620677990678259unknownZ49939Saccharomyces cerevisiae17548ORF621679444680097unknownD26185Bacillus subtilis26338ORF622680097680897unknownD64126Bacillus subtilis50645ORF623681637680849putativeORF624681409682281putativeORF625682453682821putativeORF626682763683902sensor proteinL39904Myxococcus xanthus19048ORF627684616683969putativeORF628685169684534putativeORF629685986685117putativeORF630686278687288NtrC/NifA-like protein regulatorU17902Escherichia coli82045ORF631687483688151putativeORF632688740689501putativeORF633690242689622putativeORF634690470691126unknownZ48008Saccharomyces cerevisiae38046ORF635692600691497putativeORF636692674695064phenylalanyl-tRNA synthetase beta-subunitU32810Haemophilus influenzae59345(pheT)ORF637695049696032putativeORF638697964696585OppC-like proteinD85103Synechococcus sp.37137ORF639699803698274OppB gene productX56347Bacillus subtilis19740ORF640701926699788AppAU20909Bacillus subtilis32443ORF641703196702567putativeORF642704221703208putativeORF643704240705289ferrochelataseX73417Arabidopsis thaliana26642ORF644706070705300histidine periplasmic binding protein P29U58045Campylobacter jejuni12831ORF645706841706254conserved hypothetical proteinAE000592Helicobacter pylori15537ORF646707596706811putativeORF647708666707677ADP-glucose pyrophosphorylaseX55650Solanum tuberosum59543ORF648709793709119pyrE-F gene productX71842Arabidopsis thaliana40044ORF649711523710132transcription termination factorJ01673Escherichia coli125160ORF650712236711523putativeORF651714734712125DNA polymerase IJ04479Streptococcus pneumoniae133443ORF652715759714761protease IVU67512Methanococcus jannaschii10155ORF653717538715886adenine nucleotide translocaseZ49227Arabidopsis thaliana83239ORF654719113720243replicative DNA helicaseD26185Bacillus subtilis77644ORF655720590722422homologous to E.coli gidAX62540Pseudomonas putida157552ORF656722406723056putativeORF657723551723120nucleoside 5′-diphosphateJ05207Myxococcus xanthus45162phosphotransferase (EC 2.7.4.6)ORF658724246723626Holliday junction DNA helicase (ruvA)U32716Haemophilus influenzae29343ORF659724754724251crossover junction endodeoxyribonucleaseU32717Haemophilus influenzae29653(ruvC)ORF660725868724900putativeORF661727115726270putativeORF662728126727119glyceraldehyde-3-phosphate dehydrogenaseU83198Chlamydia trachomatis134075ORF663728594728208ribosomal protein L17L33834Chlamydia trachomatis43982ORF664729614728604RNA polymerase alpha-subunitL33834Chlamydia trachomatis135689ORF665729778729533RNA polymerase alpha-subunitL33834Chlamydia trachomatis27382ORF666730149729751ribosomal protein S11L33834Chlamydia trachomatis56290ORF667730539730174ribosomal protein S13L33834Chlamydia trachomatis54489ORF668731983730598homologL25077Chlamydia trachomatis195683ORF669732427731996ribosomal protein CtrL15eM80325Chlamydia trachomatis56377ORF670732917732423ribosomal protein CtrS5eM80325Chlamydia trachomatis70284ORF671733598733320ribosomal protein L6M60652Chlamydia trachomatis31687ORF672733869733492ribosomal protein L6M60652Chlamydia trachomatis46977ORF673734298733900ribosomal protein CtrS8eM80325Chlamydia trachomatis57282ORF674734858734319ribosomal protein CtrL5eM80325Chlamydia trachomatis73090ORF675735195734863ribosomal protein CtrL24eM80325Chlamydia trachomatis42070ORF676735578735342ribosomal protein CtrL14eM80325Chlamydia trachomatis27095ORF677735861735604ribosomal protein S17eM80325Chlamydia trachomatis32277ORF67873649273607950S ribosomal protein L16D90905Synechocystis sp.43960ORF679737192736524ribosomal protein S3D64071Actinobacillus61258actinomycetemcomitansORF680737555737211ribosomal protein L22Z21677Thermotoga maritima22848ORF68173868873783750S ribosomal subunit protein L2U18997Escherichia coli76962ORF682739048738713putativeORF683739736739065ribosomal protein L4X67014Bacillus stearothermophilus30846ORF684740477739773ribosomal protein L3Z46265Thermus aquaticus thermophilus46350ORF685740659740958putativeORF686741722740721putativeORF687742789741827methionyl-tRNA formyltransferaseD64001Synechocystis sp.51148ORF688743618742782UDP-N-acetylglucosamine acyltransferaseL22690Rickettsia rickettsii54243ORF689744092743634(3R)-hydroxymyristol acyl carrier proteinD90910Synechocystis sp.33955dehydraseORF690744604744107UDP-3-0-acyl N-acetylglcosamineD90902Synechocystis sp.28745deacetylaseORF691744953744498UDP-3-O-acyl-GlcNAc deacetylaseU67855Pseudomonas aeruginosa26251ORF692746608744986apolipoprotein N-acyltransferase (cute)U32716Haemophilus influenzae19450ORF693747085746621low homology to P14 protein ofD78189Bacillus subtilis23537Heamophilus influenzar and 14.2 kDaprotein of Escherichia coliORF694747974747219polymerase IIIM22996Bacillus subtilis18034ORF695748594748169hypothetical proteinD90914Synechocystis sp.16043ORF696749145748573putativeORF697749652749957trxAL39892Chlamydia psittaci39372ORF698750446749979spoUL39892Chlamydia psittaci55972ORF699751219750446mipL39892Chlamydia psittaci94860ORF700753042751291aspartyl-tRNA synthetaseD90910Synechocystis sp.134747ORF701754309753020histidine - tRNA ligaseZ17214Streptococcus equisimilis75744ORF702755120756175hexosephosphate transport proteinM89480Salmonella typhimurium87049ORF703756120756485hexosephosphate transport proteinM89479Escherichia coli32145ORF704756499760227DNA polymerase III alpha-subunit (dnaE)AE000646Helicobacter pylori197742ORF705761217760297putativeORF706761297761809putativeORF707761782762282putativeORF708762260762895putativeORF709762867763316hypothetical proteinD90908Synechocystis sp.17743ORF710763780763325putativeORF711763861765168DD-carboxypeptidaseM85047Bacillus subtilis29237ORF712766809765697fmu and fmv proteinD90902Synechocystis sp.13036ORF713768051766888putativeORF714768566768321putativeORF715769342768551putativeORF716770532769378putativeORF717771451770804putativeORF7187730587718473-phosphoglycerate kinaseU83197Chlamydia trachomatis154072ORF719773094773456putativeORF720774376773093putative phosphate permeaseU84890Mesembryanthemum crystallinum87045ORF721775123774380putativeORF722775398774916putativeORF723775046776077sporulation proteinM57689Bacillus subtilis69843ORF724776070777041was dppEU00039Escherichia coli56556ORF725777964777536orf288; translated orf similarity to SWISS-Y10436Coxiella burnetii25646PROT: YGI2_PSEPU hypothetical 32.4 kDaprotein of Pseudomomas putidaORF726778176777904B. subtilis genes rpmH, rnpA, 50 kd, gidAX62539Bacillus subtilis11237and gidBORF727778621779334putativeORF728781173780307f406; This 406 aa orf is 28 pct identical (12AE000263Escherichia coli60340gaps) to 264 residues of an approx. 440 aaprotein YAOA_SCHPO SW: Q10089ORF729781526781116f406; This 406 aa orf is 28 pct identical (12AE000263Escherichia coli25845gaps) to 264 residues of an approx. 440 aaprotein YAOA_SCHPO SW: Q10089ORF730782784781555f423; This 423 aa orf is 29 pct identical (1AE000263Escherichia coli19744gaps) to 172 residues of an approx. 488 aaprotein YC24_CYAPA SW: P48260ORF731783572782805hypothetical chloroplast ORF 16U38804Porphyra purpurea59752ORF732785032783581ABC transporter subunitD64004Synechocystis sp.172062ORF733786412785360putativeORF734788429786450pbpY14206Streptomyces coelicolor14855ORF735788944788528penicillin-binding protein 3X84053Pseudomonas aeruginosa14838ORF736789758788901putativeORF737790332791504major outer membrane proteinM64064Chlamydia pneumoniae202899ORF738791846792721ribosomal protein S2U60196Chlamydia trachomatis90470ORF739792724793569elongation factor TsU60196Chlamydia trachomatis102371ORF740793580794323UMP kinaseU60196Chlamydia trachomatis89172ORF741794304794843ribosome-releasing factorU60196Chlamydia trachomatis67373ORF742795217795732unknownD26185Bacillus subtilis10542ORF743795722796795unknownD26185Bacillus subtilis20833ORF744798735797053putativeL33796Vibrio cholerae38634ORF745799823798681putativeORF746799297799578putativeORF747801313799808Pkn5U40656Myxococcus xanthus34533ORF748802453801332putativeORF749803299802457putativeORF750803811803290putativeORF751805151803826YscNU02499Yersinia enterocolitica118553ORF752805860805156putativeORF753806604806332putativeORF754806913806608putativeORF755808222806903putativeORF756808751808146putativeORF757809437808673putativeORF758809939809454putativeORF759811235810213delta-aminolevulinate synthase (ECM30785Escherichia coli172402.3.1.37)ORF760811779813056DNA gyrase subunit BU35453Clostridium acetobutylicum58438ORF761812890812516putativeORF762812954813583DNA gyrase subunit BZ19108Spiroplasma citri37139ORF763813587815023gyrAX92503Mycobacterium smegmatis41455ORF764815420815746putativeORF765816036817010orf-X; hypothetical protein; Method:U48870Bacillus subtilis56947conceptual translation supplied by authorORF766817111817356unknownZ74024Mycobacterium tuberculosis11434ORF7678177918186093-deoxy-d-manno-octulosonic acid 8-Z50747Chlamydia psittaci111278phosphate synthetaseORF768818609819094protein of unknown functionZ50747Chlamydia psittaci54565ORF769819104819823ATP binding proteinU72493Chlamydia trachomatis109988ORF770820722819826putativeORF771822313821000putativeORF772823503822238putativeORF773823678825612putativeORF774825461826312putativeORF775827280826645putativeORF77682860482717176 kDa proteinL23921Chlamydia pneumoniae2179100ORF77783002682871376 kDa proteinL23921Chlamydia pneumoniae1162100ORF778831047830085mviB homologU50732Chlamydia trachomatis98258ORF779831725831051mviB homologU50732Chlamydia trachomatis74065ORF780832220833098T05H10.2Z47812Caenorhabditis elegans40734ORF781833851833396ribosomal protein S4 (rps4)AE000633Helicobacter pylori37253ORF782834068835039This ORF is homologous to a 40.0 kdL22217Mycoplasma-like organism37749hypothetical protein in the htrB 3′ regionfrom E. coli, Accession Number X61000ORF783835792835127uridine kinaseL31783Mus musculus43643ORF784837624836116ORF_f397U29581Escherichia coli9238ORF785838951840882putativeORF786840869842185exodeoxyribonuclease V (recB)U32811Haemophilus influenzae40940ORF787841989843455DNA helicase IIU39703Mycoplasma genitalium11046ORF788843242844021exodeoxyribonuclease V (recB)U32811Haemophilus influenzae19640ORF789845018843987MreC proteinM31792Escherichia coli7653ORF790846174844990aspartate aminotransferase (aspC)X03629Escherichia coli75440ORF791848509846311GreAU02878Rickettsia prowazekii19035ORF792848568849014putativeORF793849082850488NADH: ubiquinone oxidoreducatase subunitU32702Haemophilus influenzae44537A (GP: Z37111_2)ORF794851512850574porphobilinogen synthaseU38348Chlorobium vibrioforme76945ORF795852064852447putativeORF796852398853690putativeORF797855118854243geranylgeranyl pyrophosphate synthaseD85029Arabidopsis thaliana40841ORF798855751855128f147; This 147 aa orf is 26 pct identical (1AE000143Escherichia coli18736gaps) to 99 residues of an approx. 728 aaprotein E2BE_RABIT SW: P47823ORF799856551855829membrane associated regulatory proteinM28368Salmonella typhimurium17236ORF800856730858556unknown functionZ32530Chlamydia trachomatis84235ORF801858717859601exodeoxyribonuclease V (recD)U32811Haemophilus influenzae18251ORF802859591860205exonuclease V alpha subunit (AA 1-608)X04582Escherichia coli23545ORF803861132860284putativeORF80486142686116330S ribosomal protein S20Z67753Odontella sinensis15341ORF805861701862921putativeORF806863026864798major sigma factorU04442Chlamydia psittaci266194ORF807864831865256putativeORF808865226866581dihydropterin pyrophosphokinase/Y08611Pisum sativum45548dihydropteroate synthaseORF809866562867119dehydrofolate reductase, type I (folA)U32772Haemophilus influenzae21349ORF810867025867816M. jannaschii predicted coding regionU67522Methanococcus jannaschii20736MJ0768ORF811867820868497putativeORF812869743868661RecAU16739Chlamydia trachomatis151287ORF813870633870094unknown functionZ32530Chlamydia trachomatis30845ORF814871929870646unknown functionZ32530Chlamydia trachomatis141063ORF815872538872086putativeORF816873908872517putativeORF817874281874670nifR3-like gene productZ37984Azospirillum brasilense18132ORF818874582875286ORF1 gene productX62399Escherichia coli30742ORF819877857875377DNA topoisomerase IL27797Bacillus subtilis148850ORF820878446879255putativeORF821880635879268sigma factor (ntrA) (AA 1-502)X05888Azotobacter vinelandii25747ORF822882524880593DNA helicase IID90906Synechocystis sp.114050ORF823882612883319ipa-57d gene productX73124Bacillus subtilis60151ORF824884155883538hypothetical proteinD90915Synechocystis sp.34439ORF82588434088561119/20 residue stretch (32-51) identical to N-L19954Bacillus subtilis45637terminal putative signal sequence ofunknown, partly cloned B. subtilis gene.;putativeORF826885722887302heat shock proteinL12004Chlamydia trachomatis91539ORF827887587888153bas1 proteinZ34917Hordeum vulgare47450ORF828888627888220putativeORF829889330888716hypothetical proteinY14079Bacillus subtilis22355ORF830889898889323peptidoglycan-associated lipoproteinX65796Escherichia coli22250ORF831891190889898TolBU32470Haemophilus influenzae28035ORF832891828891247putativeORF833892421892017exbD peptideM28819Escherichia coli7748ORF834893116892421inner membrane protein (tolQ)U32722Haemophilus influenzae15754ORF835892521892925putativeORF836893392895419inner membrane copper tolerance proteinZ36905Escherichia coli12035ORF837895745896527unknownD26185Bacillus subtilis38141ORF838896668897558succinate dehydrogenase subunit CY08563Paenibacillus macerans25340ORF839897565899442succinate dehydrogenase subunit AY08563Paenibacillus macerans166757ORF840899420900229succinate dehydrogenase subunit BY08563Paenibacillus macerans65654ORF841903230900237putativeORF842905081903234putativeORF843906931905045sigma factor SibG regulation protein RsbUD90905Synechocystis sp.11735ORF844907248907832putativeORF845907784908128putativeORF846908132908677putativeORF847908589909320putativeORF848909405911465putativeORF849911677912360putativeORF850912303912821putativeORF851912937913983putativeORF852915128914067putativeORF853916658915303enolaseL29475Bacillus subtilis103660ORF854915627915376enolaseU43738Mycoplasma pneumoniae22665ORF855917707916853excinuclease ABC subunit B (uvrB)U32804Haemophilus influenzae72446ORF856918837917722excinuclease ABC subunit B (uvrB)U32804Haemophilus influenzae102954ORF857919868918837tryptophanyl-tRNA synthetase (trpS)U32746Haemophilus influenzae37640ORF858920434919880putativeORF859921187920438ORF8X82078Chlamydia sp.16450ORF860921959921195hypothetical proteinX62475Chlamydia psittaci51144ORF861923773921995Threonyl tRNA SynthetaseZ80360Bacillus subtilis147644ORF862922146922415putativeORF863923943923674putativeORF864924077925006putativeORF865925436925083putativeORF866926524925349putativeORF867927920926433putativeORF868928319927951putativeORF869928963928334putativeORF870929248930987DNA mismatch repair protein (mutL)U32692Haemophilus influenzae58540ORF871930995932059YqhTD84432Bacillus subtilis44539ORF872932121933515putativeORF873932881932513putativeORF874933485935746pulD (ttg start codon)M32613Klebsiella pneumoniae21033ORF875935724937082epsEM96172Vibrio cholerae89055ORF876937229938410PilGU32588Neisseria gonorrhoeae28038ORF877938281938805putativeORF878938809939255putativeORF879939165939782putativeORF880939760940791putativeORF881940822941106putativeORF882940977941351putativeORF883942537941623yscTL25667Yersinia pseudotuberculosis16944ORF884942784942500yscSL25667Yersinia pseudotuberculosis17342ORF885943149942799HrcRAE000107Rhizobium sp. NGR23426552ORF886943799943029pathogenicity proteinM64094Xanthomonas campestris25241ORF887944055943732putativeM74011Yersinia enterocolitica11233ORF888944413943994putativeORF889945395944556putativeORF890945853945389putativeORF891946392945751HrcJU56662Erwinia amylovora22944ORF892947410948081putativeORF893949871948915ORF YOR196cZ75104Saccharomyces cerevisiae70244ORF894951058949868dihydrolipoamide dehydrogenase E3 subunitM57435Bacillus subtilis74539ORF895951249950959dihydrolipoamide acetyltransferase E3M73535Staphylococcus aureus16649subunitORF896951664952134putativeORF897952674952165SNFX98455Bacillus cereus22947ORF898953491952589helicaseU39680Mycoplasma genitalium30742ORF899955324953495F01G4.1Z68341Caenorhabditis elegans13357ORF900955823955281putativeORF901957082955847branched-chain amino acid carrierZ48676Lactobacillus delbrueckii29740ORF902957902957270endonuclease IIIU11289Bacillus subtilis31737ORF903959231957906homologous to E. coli 50 KX62539Bacillus subtilis80545ORF904959376960284phosphatidylserine decarboxylaseU72715Chlamydia trachomatis77651ORF905960266961669putativeORF906961856964765secretory componentU06928Caulobacter crescentus181255ORF90796685596539528.2% of identity to the Escherichia coliL47648Bacillus subtilis77841GTP-binding protein Era; putativeORF908968204966975poly(A) polymeraseL47709Bacillus subtilis38341ORF909968791968237ClpX-like proteinU18229Bacillus subtilis34039ORF910969498968731ATP-dependent protease ATPase subunitD64006Synechocystis sp.84666ORF911969858969511ClpPU16135Synechococcus sp.25754ORF912970118969762ATP-dependent clp protease proteolyticAE000591Helicobacter pylori36263component (clpP)ORF913970593970300putativeORF914971261970542putativeORF915971680971123putativeORF916971876975100SNFX98455Bacillus cereus77849ORF917975419976516MreB proteinM96343Bacillus subtilis96055ORF918976584978320phospho enol pyruvate carboxykinaseS56812Chlorobium limicola166764ORF919977680977231putativeORF920978399980738putativeORF921980756981928putativeORF922982974981931precursor protein (AA − 22 to 371)X52557Chlamydia trachomatis9750ORF923984120983119NAD + dependent glycerol-3-phosphateL47648Bacillus subtilis61843dehydrogenaseORF924985502984120AgX-1 antigen [human, infertile patient,S73498Homo sapiens25434testis, Peptide, 505 aa]ORF925987180985882ORF 4M72718Bacillus subtilis69738ORF926987172987444putativeORF927989846989049nifU-like proteinAE000542Helicobacter pylori30231ORF928991048989846putativeORF929991638990955phosphoglyceromutaseL09651Zymomonas mobilis47153ORF930991794992498ORFX13L09228Bacillus subtilis40339ORF931993619993041biotin [acetyl-CoA-carboxylase] ligaseL47709Bacillus subtilis13638ORF932993530994792rod-shape-determining proteinM22857Escherichia coli31244ORF933995970994795cadmium-transporting ATPaseD64005Synechocystis sp.35847ORF934996857995739ATPaseL28104Transposon Tn542244939ORF935997603996782putativeORF936998969997572seryl-trna synthetaseY09924Staphylococcus aureus85142ORF9379988961000023orf2, homologue to B. subtilis ribGX64395Escherichia coli59640ORF93810000871001340GTP cyclohydrolase IID90912Synechocystis sp.107852ORF93910013571001818riboflavin synthase beta subunitU27202Actinobacillus pleuropneumoniae27836ORF94010032881001873putativeORF94110034871004146putativeORF94210044851005639D-alanine glycine permease (dagA)AE000603Helicobacter pylori39433ORF94310056431005972hypothetical protein MTCY180.08Z97193Mycobacterium tuberculosis27458ORF94410067841006116similar to trithorax protein in final threeU13875Caenorhabditis elegans15546exonsORF94510075631006769yycJD78193Bacillus subtilis40638ORF94610092261007568YtpTAF008220Bacillus subtilis99247ORF94710099891009336putativeORF94810158521016337putativeORF94910165611016181putativeORF95010162971017532putativeORF95110168021016452putativeORF95210189931017701phenolhydroxylase componentU32702Haemophilus influenzae90947ORF95310194541019137ORFM63939Escherichia coli9645ORF95410207641019562pCTHom1 gene productM94254Chlamydia trachomatis118565ORF95510214051021037histone H1-like proteinM80324Chlamydia psittaci31962ORF95610218211024286phosphoproteinL25078Chlamydia trachomatis73941ORF95710246971024248putativeORF95810255691024508protoporphyrinogen oxidaseU25114Mus musculus8638ORF95910269691025590oxygen independent coprophorphyrinogenD90912Synechocystis sp.88042III oxidaseORF96010277891026947uroporphyrinogen decarboxylaseM97208Bacillus subtilis37238ORF96110311991027945transcription-repair coupling factor (trcF)U32805Haemophilus influenzae158442(mfd)ORF96210317171031172alanyl-tRNA synthetaseX95571Thiobacillus ferrooxidans7631ORF96310330571031612alanyl-tRNA synthetaseAE000353Escherichia coli88940ORF96410334251033039alanyl-tRNA synthetase (alaS)AE000629Helicobacter pylori32751ORF96510337841033200alanyl-tRNA synthetaseX59956Rhizobium leguminosarum41647ORF96610339631036038transketolaseZ73234Bacillus subtilis139844ORF96710369451036010AMP nucleosidaseAE000290Escherichia coli26542ORF96810371101037679elongation factor PU14003Escherichia coli45851ORF96910376961037944putativeORF97010389161037975putativeORF97110405821039026HSP60 chaperoninX62914Clostridium perfringens28431ORF97210409971042337PROBABLE UDP-N-AB001488Bacillus subtilis44639ACETYLMURAMOYLALANYL-D-GLUTAMYL-2, 6-DIAMINOLIGASE (EC6.3.2.15).ORF97310423571043403ORF-Y (AA 1-360)X51584Escherichia coli58245ORF97410433671044623UDP-N-acetylmuramoylalanine-D-U32793Haemophilus influenzae34842glutamate ligase (murD)ORF97510446071045362hypothetical proteinY14079Bacillus subtilis11538ORF97610453841046538spoVE gene product (AA 1-366)X51419Bacillus subtilis47935ORF97710464471047517murY13922Enterococcus hirae25645ORF97810475211049956UDP-N-acetylmuramate-alanine ligaseU32794Haemophilus influenzae75638(murC)ORF97910506111050036unknownZ74024Mycobacterium tuberculosis7844ORF98010509251050566cycY gene productU14003Escherichia coli17934ORF98110517281051090putativeORF98210517431052063hypothetical proteinD90908Synechocystis sp.13533ORF98310521011053126trna delta(2)-isopentenylpyrophosphateZ98209Mycobacterium tuberculosis44137transferaseORF98410542011053107conserved hypothetical proteinAE000579Helicobacter pylori82644ORF98510542421055555putativeORF98610554831055908putativeORF98710566091056965YqeLD84432Bacillus subtilis20238ORF98810569611058232beta-ketoacyl-ACP synthaseL13242Ricinus communis126655ORF98910582381058687diadenosine tetraphosphataseU30313Homo sapiens12242ORF99010593711058727inorganic pyrophosphatase (ppa)AE000576Helicobacter pylori20939ORF99110595261060578leucine dehydrogenase LeuDHU51099Bacillus cereus68045ORF992106155310605793′(2′),5′-bisphosphate nucleotidaseU40433Arabidopsis thaliana33543ORF99310616741062411putativeORF994106237710640772-acylglycerophosphoethanolamine acylU29581Escherichia coli38344transferase/acyl carrier protein synthetaseORF995106411610652437-keto-8-aminopelargonic acid synthetaseM29291Bacillus sphaericus20035(bioF)ORF99610674511065178priAY10304Bacillus subtilis100943ORF99710680651067376putativeORF99810682091068706putativeORF99910699581068819unknownU41759Chlamydia psittaci77741ORF100010711631070033unknownU41759Chlamydia psittaci38136ORF100110724381071332unknownU41759Chlamydia psittaci25437ORF100210729971073476putativeORF100310742391075864lysyl-tRNA synthetaseD90906Synechocystis sp.100748ORF100410767901075867cysteinyl-tRNA synthetaseL14580Bacillus subtilis39552ORF100510772681076573cys-tRNA synthetase (cysS)U32693Haemophilus influenzae43156ORF100610779991078724putativeORF100710790881078672ribonuclease P protein component (gtg startM11056Escherichia coli7846codon)ORF10081079642107994430S ribosomal subunit protein S14U18997Escherichia coli26050ORF100910805011079995F18C12.2Z75536Caenorhabditis elegans11838ORF101010807751081341putativeORF101110831581081350deoxyribodipyrimidine photolyaseJ03294Bacillus subtilis68744ORF101210846771083235DNA mismatch repair proteinU71154Aquifex pyrophilus73548ORF101310856481084632DNA mismatch repair proteinD90909Synechocystis sp.56539ORF101410861171086737DNA primase (dnaG)U32735Haemophilus influenzae30340ORF101510866921087897DnaGZ83860Mycobacterium tuberculosis22237ORF101610886461089005putativeORF101710891461089805putativeORF101810929311089890glycyl-tRNA synthetaseU20547Chlamydia trachomatis256948ORF101910931791092889putativeORF102010935841094204phosphatidylglycerophosphate synthaseU87792Bacillus subtilis16355ORF102110956191094192glycogen (starch) synthaseD90899Synechocystis sp.57440ORF102210960741096628partial ctc gene product (AA 1-186)X16518Bacillus subtilis8637ORF102310966331097082peptidyl-tRNA hydrolaseU31570Chlamydia trachomatis37853ORF102410972661097601ribosomal protein S6 (rps6)AE000630Helicobacter pylori17939ORF102510976221097867ribosomal protein S18 homolog; putativeM62820Chlamydia trachomatis32486ORF102610978861098392putative heat shock protein ORF; putativeM62820Chlamydia trachomatis19079ORF102710995211099279putativeORF102810996891101053putativeORF102911021921101107putativeORF103011049501102116glycerol-3-phosphate acyltransferaseM80571Cucumis sativus57443ORF103111065081104946ORF_f495; orfF of ECMRED, uses 2nd startU18997Escherichia coli85538ORF103211067221107249putativeORF103311074631108101PlsXU59433Bacillus subtilis28245ORF103411080411108421fatty acid/phospholipid synthesis proteinAE000540Helicobacter pylori20535(plsX)ORF103511085201113370putative 98 kDa outer membrane proteinU72499Chlamydia psittaci35244ORF103611149581113447putativeORF103711169151115071lipid A disaccharide synthetase (lpxB)U32786Haemophilus influenzae47742ORF103811181831116894poly(A) polymeraseAE000123Escherichia coli55546ORF103911188461120030putativeL12968Escherichia coli88050ORF104011200401120522glucosamine fructose-6-phosphateAE000651Helicobacter pylori39652aminotransferase (isomerizing) (glmS)ORF104111205101121430glutamine amidotransferase; glucosamine-AE000450Escherichia coli49444fructose-6-phosphate aminotransferaseORF104211213211121866L-glutamine: D-fructose-6-PU17352Thermus aquaticus thermophilus37450amidotransferase precursorORF104311221231122899tyrosine-specific transport proteinAE000284Escherichia coli28141ORF104411248421125564putativeORF104511265261125579cell division protein (ftsY)U32760Haemophilus influenzae49741ORF104611265191127676succinyl-CoA synthetase beta-subunitJ01619Escherichia coli78443ORF104711276721128571succinyl coenzyme A synthetase alphaU23408Dictyostelium discoideum97863subunitORF104811302301131336putativeORF104911314801132553putativeORF105011328301133843putativeORF105111341211134855serine protease HtrAD90905Synechocystis sp.30751ORF105211346421135592GsrA proteinD78376Yersinia enterocolitica49741ORF105311359641135653putativeORF105411371321135954R11H6.1Z93386Caenorhabditis elegans44537ORF105511371691140102Ydr430cp; CAI: 0.15U33007Saccharomyces cerevisiae55940ORF105611413651140112hypothetical 54.7 kD protein in udp 3′AE000459Escherichia coli22234region precursor (o475)ORF105711421501141356phosphatidylserine synthase (pssA)AE000614Helicobacter pylori30741ORF105811425201145660ribonucleotide reductase subunit M1K02927Mus musculus143345ORF105911456271146721ribonucleoside diphosphate reductase, betaAE000553Helicobacter pylori44332subunit (nrdB)ORF106011468621147545unknownZ95398Mycobacterium leprae19135ORF106111476661148190YtqBAF008220Bacillus subtilis26244ORF106211485141148224ORF2U01958Bacillus licheniformis13554ORF106311491361148348ORF2M31827Bacillus subtilis26840ORF106411497021149166putativeORF106511500311150591unknownZ85982Mycobacterium tuberculosis44549ORF106611507851151147ribosomal protein L20 (AA 1-119)X16188Bacillus stearothermophilus27344ORF106711511651152181phenylalany-tRNA synthetase beta subunitZ75208Bacillus subtilis77740ORF106811525221154591putativeORF106911556661154566putativeORF107011567431155670putativeORF107111568591157815hypotheticalU32723Haemophilus influenzae25242ORF107211579821160735ATP-binding proteinU01376Escherichia coli131456ORF107311626201160917polynucleotide phosphorylaseAF010578Pisum sativum141652ORF107411629701162590polyribonucleotide phophorylaseU52048Spinacia oleracea31253ORF107511635321164020orf150 gene productX95938Porphyromonas gingivalis33543ORF107611639951164294putativeORF107711655691165030putativeORF107811661081165566putativeORF107911666441166141putativeORF108011670551168374putativeORF108111692181168337methionine aminopeptidaseD64003Synechocystis sp.48854ORF108211698231169218ORF_o197U18997Escherichia coli28130ORF108311713241170572putativeORF108411720851171177hypotheticalU32720Haemophilus influenzae16244ORF108511723941173773fumaraseD64000Synechocystis sp.129257ORF108611752091173881prs-associated putative membrane proteinU02424Escherichia coli57039ORF108711755551175127hypothetical protein in pth-prs intergenicAE000219Escherichia coli27846regionORF108811757781177043hypothetical proteinZ96072Mycobacterium tuberculosis10943ORF108911771771179048putativeORF109011791561180085penicillin tolerance protein (lytB)U32781Haemophilus influenzae73154ORF109111800451180779putativeORF109211819421180788putativeORF109311822961181961putativeORF109411838441182300putativeORF109511844201183848putativeORF109611853821184366putativeORF109711858581185226putativeORF109811861641186481putativeORF109911873861186484site-specific recombinaseU92524Salmonella typhimurium40148ORF110011873701189028phophoglucoisomerase-like proteinL40822Chlamydia trachomatis115463ORF110111893211190889putativeORF110211911421192146NADP-malate dehydrogenaseL40958Flaveria bidentis77546ORF110311919741191729putativeORF110411938151192991putativeORF110511957021194248o460; This 460 aa orf is 46 pct identical (26AE000256Escherichia coli102244gaps) to 458 residues of an approx. 488 aaprotein ARCD_PSEAE SW: P18275ORF110611963031195716putativeORF110711968311196337putativeORF110811978071196746putativeORF110911987401197883putativeORF111012002321198721shikimate 5-dehydrogenaseU67551Methanococcus jannaschii24537ORF1111120128612001353-dehydroquinate synthase (aroB)U32705Haemophilus influenzae47845ORF1112120238612012592,3-dihydroxybenzoic acidL29562Vibrio anguillarum78050ORF111312029011202350putativeORF1114120416212028165-enolpyruvylshikimate 3-phosphateU67500Methanococcus jannaschii52040synthaseORF111512031771203464putativeORF111612050281204180putativeORF111712063921204878bioA gene productA02587unidentified83448ORF111812067421206086dethiobiotin synthase (bioD)U32830Haemophilus influenzae24337ORF111912078721206724L-alanine-pimelyl CoA ligaseU51868Bacillus subtilis60141ORF112012088521207851biotin sythaseU24147Arabidopsis thaliana89252ORF112112105181209742tryptophan hydroxylaseU26428Gallus gallus23734ORF112212107031211494dihydrodipicolinate reductaseU47017Pseudomonas syringae pv. tabaci34537ORF112312118701212754aspartate-semialdehyde dehydrogenaseU67476Methanococcus jannaschii44443ORF112412127421214064aspartokinase IIIU00006Escherichia coli47347ORF112512140461214858dihydrodipicolinate synthaseD64006Synechocystis sp.23840ORF112612155511216318putativeORF112712164931216849putativeORF112812171831219612putativeORF112912200681219673putativeORF113012197101220669putativeORF113112206301221376putativeORF113212216451223681unknownD26185Bacillus subtilis62143ORF113312238941224988putativeORF113412250001225830high level kasgamycin resistanceD26185Bacillus subtilis42241ORF113512278101225879hypothetical proteinD90903Synechocystis sp.112943ORF113612265281226908putativeORF113712299721228311exonuclease VII, large subunit (xseA)U32723Haemophilus influenzae66646ORF11384756947018Integrase/recombinaseAE001308Chlamydia trachomatis71672ORF11394998049117putativeORF11405335652898putativeORF11415447754884O-Sialoglycoprotein EndopeptidaseAE001307Chlamydia trachomatis31151ORF11426375363998PTS PEP PhosphotransferaseAE001306Chlamydia trachomatis19861ORF11437716477487putativeORF11447972479302Sms ProteinAE001302Chlamydia trachomatis45857ORF11458872188951putativeORF11469406794429putativeORF1147122832123341hypothetical proteinAE001303Chlamydia trachomatis39861ORF1148147536147234putativeORF1149158990159346S16 Ribosomal ProteinAE001277Chlamydia trachomatis46778ORF1150168470168979putativeORF1151169183169452putativeORF1152171785171504Cationic Amino Acid TransporterAE001278Chlamydia trachomatis26268ORF1153172518171775Cationic Amino Acid TransporterAE001278Chlamydia trachomatis53348ORF1154193599194045putativeORF1155195704196075S/T Protein KinaseAE001288Chlamydia trachomatis53682ORF1156210687210145KDO-transferaseX80061Chlamydia pneumoniae85696ORF1157211100210708putativeORF1158215420215088putativeORF1159217914218246putativeORF1160218925218701putativeORF1161223785223525IMP dehydrogenaseU13372Borrelia burgdorferi27063ORF1162224271223999putativeORF1163228691228407putativeORF1164235050235334(Methylase)AE001287Chlamydia trachomatis33166ORF1165252308253021Oligopeptide PermeaseAE001293Chlamydia trachomatis83872ORF1166258280258912Dicarboxylate TranslocatorAE001294Chlamydia trachomatis90980ORF1167261325261567putativeORF1168268195268878hypothetical proteinAE001287Chlamydia trachomatis55652ORF1169269447268881putativeORF1170271263271538putativeORF1171271957272346putativeORF1172274176274550putativeORF1173275736275314Disulfide bond OxidoreductaseAE001291Chlamydia trachomatis51973ORF1174276490276927hypothetical proteinAE001291Chlamydia trachomatis24953ORF1175277577277861hypothetical proteinAE001291Chlamydia trachomatis25652ORF1176288163287909putativeORF1177290130289789putativeORF1178290989291225putativeORF1179291372291860adenylate cyclaseAE001286Chlamydia trachomatis38848ORF1180311239311622putativeORF1181328665328384putativeORF1182337348338289sodium-dependent transporterAF017105Chlamydia psittaci111272ORF1183364764364369Prolipoprotein Diacylglycerol TransferaseAE001298Chlamydia trachomatis30054ORF1184389623390135hypothetical proteinAE001282Chlamydia trachomatis7533ORF1185393729394343ABC superfamily ATPaseAE001282Chlamydia trachomatis47352ORF1186407379407621putativeORF1187410944410708putativeORF1188427632427988putativeORF1189428172428486putativeORF1190436761437246hypothetical proteinAE001279Chlamydia trachomatis66181ORF1191460911461159putativeORF1192477597477313hypothetical proteinAE001300Chlamydia trachomatis30962ORF1193487303487001putativeORF1194487764487534Glycine Cleavage System H ProteinAE001300Chlamydia trachomatis22167ORF1195498502499017hypothetical proteinAE001275Chlamydia trachomatis20632ORF1196499795500466putativeORF1197571928572344putativeORF1198572367572131putativeORF1199588184587915hypothetical proteinAE001312Chlamydia trachomatis25662ORF1200600587600907(Metalloenzyme)AE001316Chlamydia trachomatis31461ORF1201609731608895putativeORF1202614039614755hypothetical proteinAE001317Chlamydia trachomatis47546ORF1203614823615152putativeORF1204638244638831ABC Transporter ATPaseAE001315Chlamydia trachomatis61461ORF1205638819639094(Metal Transport Protein)AE001315Chlamydia trachomatis26563ORF1206639073639636(Metal Transport Protein)AE001315Chlamydia trachomatis68769ORF1207647901648236hypothetical proteinAE001317Chlamydia trachomatis13938ORF1208678510679469phosphohydrolaseAE001320Chlamydia trachomatis99563ORF1209688178688732hypothetical proteinAE001320Chlamydia trachomatis36643ORF1210696045696563methyltransferaseAE001321Chlamydia trachomatis36949ORF1211708998708588Glucose-1-P AdenyltransferaseAE001322Chlamydia trachomatis50783ORF1212709808710089putativeORF1213718240717737Glycerol-3-P PhosphatidyltransferaseAE001323Chlamydia trachomatis57366ORF1214737828737565S19 Ribosomal ProteinAE001323Chlamydia trachomatis43994ORF1215779502780257hypothetical proteinAE001322Chlamydia trachomatis47648ORF1216806310805864hypothetical proteinAE001337Chlamydia trachomatis51267ORF1217820931820707putativeORF1218837696839096Exodeoxyribonuclease V, GammaAE001334Chlamydia trachomatis96749ORF1219883307883549putativeORF1220892010891726putativeORF1221893277893564putativeORF1222936998937225Gen. Secretion Protein EAE001327Chlamydia trachomatis25667ORF1223946865947419putativeORF1224975187975411SWF/SNF family helicaseAE001341Chlamydia trachomatis36396ORF1225985882985517hypothetical proteinAE001342Chlamydia trachomatis16633ORF1226987713987180hypothetical proteinAE001342Chlamydia trachomatis44759ORF1227988215987733Flagellar M-Ring ProteinAE001342Chlamydia trachomatis30444ORF1228988754988530Flagellar M-Ring ProteinAE001342Chlamydia trachomatis9236ORF1229992542992841hypothetical proteinAE001343Chlamydia trachomatis11239ORF1230992759993067hypothetical proteinAE001343Chlamydia trachomatis10032ORF123110042471004528D-Ala/Gly PermeaseAE001344Chlamydia trachomatis28364ORF123210150131014294235aa long hypothetical proteinAB009472Pyrococcus horikoshii10454ORF123310561471056545putativeORF123410776821078035predicted disulfide bond isomeraseAE001351Chlamydia trachomatis23346ORF123510881211088381putativeORF123610984301098852Predicted KinaseAE001352Chlamydia trachomatis38459ORF123710987981099319Predicted KinaseAE001352Chlamydia trachomatis32245ORF123811231981123515Transport PermeaseAE001354Chlamydia trachomatis31372ORF123911236061124256Tyrosine TransportAE001354Chlamydia trachomatis57758ORF124011244531124797Tyrosine TransportAE001354Chlamydia trachomatis32350ORF124111292531129567putativeORF124211649471164474hypothetical proteinAE001357Chlamydia trachomatis41256ORF124311704571170053hypothetical proteinAE001358Chlamydia trachomatis28359ORF124411723421171863ABC transporter permeaseAE001358Chlamydia trachomatis45755ORF124511921551192835putativeORF124611927591192992putativeORF124711938611194142putativeORF124811940361193779(D-Amino Acid Dehydrogenase)AE001311Chlamydia trachomatis26979ORF124912097481209053conserved hypothetical proteinAE000958Archaeoglobus fulgidus12138ORF125012151111215419putativeORF125112163021216538putativeORF125212280721227818hypothetical proteinAE001306Chlamydia trachomatis13439ORF125312283041228080xseBAL021897Mycobacterium tuberculosis8933ORF12542659926222putativeORF12552760927367putativeORF12566720666967putativeORF12577061270352putativeORF1258132703132945putativeORF1259178073178393putativeORF1260208576208349putativeORF1261209156208929putativeORF1262209263209024putativeORF1263210304210639putativeORF1264299009299452putativeORF1265352106351717putativeORF1266420182419949Flagellar Secretion ProteinAE001280Chlamydia trachomatis11543ORF1267553602553381putativeORF1268556538556807putativeORF1269594348593797putativeORF1270595169594876putativeORF1271662148662381putativeORF1272706528706893putativeORF1273803315803650putativeORF1274849551849306putativeORF1275913676913275putativeORF1276927087926836putativeORF1277930587930360putativeORF1278986531986764ORF 12M72718Bacillus subtilis10648ORF1279996229996486putativeORF128010003731000002putativeORF128110102911010037putativeORF128210111281010793106aa long hypothetical proteinAB009472Pyrococcus horikoshii15950ORF128310129241012694putativeORF128410286591028913putativeORF128510864811086762putativeORF128611186581118879PhosphoglucomutaseAE001354Chlamydia trachomatis29184ORF128711700981169835hypothetical proteinAE001358Chlamydia trachomatis18753ORF128811808281181184putativeORF128911826581183035putativeORF129011950761194795putativeORF129111958901196183putative

[0582]

3

TABLE 2

ORF Nos
begin
end
potential start

2
42
794
42

3
1258
1614
1261

4
1807
2418
1807

5
3393
2491
3393

6
3639
4067
3639

7
5649
4270
5649

8
7463
6012
7463

9
8051
8962
8051

10
9129
9959
9138

11
10687
10361
10639

12
10927
11232
10927

13
11246
12727
11246

14
12691
14190
12691

15
14484
17249
14484

16
16039
15770
16036

17
17845
20853
17845

18
21137
22042
21137

19
22046
23476
22046

20
23681
26110
23681

21
26109
25861
26109

22
26241
26978
26241

23
26960
27754
26960

24
27747
28577
27747

25
28887
29492
28950

26
29432
30028
29432

27
30024
31472
30024

28
31758
32288
31758

29
32201
33991
32201

30
33852
34541
33852

31
34783
36063
34783

32
36009
37529
36009

33
37881
39362
37881

34
39418
39161
39418

35
39366
40715
39366

36
43076
41094
43076

37
43800
43066
43800

38
44828
43785
44768

39
45340
44753
45340

40
45752
45372
45752

41
46996
45701
46996

42
47961
47569
47961

43
48960
48040
48960

44
51452
50133
51452

45
52606
51335
52606

46
53684
53319
53684

47
54195
53746
54195

48
55278
56453
55278

49
56493
57266
56493

50
57297
58526
57297

51
59851
58565
59851

52
61495
59924
61495

53
61324
62151
61324

54
62132
62470
62132

55
62474
63733
62474

56
63881
64186
63881

57
64611
64318
64611

58
65485
64673
65485

59
65999
65301
65999

60
66244
67281
66244

61
67265
67699
67265

62
67703
68539
67760

63
68805
70736
68805

64
69172
68831
69172

65
70642
71142
70642

66
71325
72029
71325

67
72060
73637
72060

68
74061
76175
74061

69
78351
77680
78351

70
79356
78355
79356

71
79983
79693
79983

72
80441
79938
80441

73
80475
80969
80475

74
81296
83080
81332

75
83291
83932
83291

76
84005
84769
84005

77
84975
85244
84975

78
85123
85425
85123

79
85397
85903
85397

80
85909
86583
85909

81
86626
88065
86626

82
89257
91026
89257

83
91291
93030
91291

84
93295
94086
93295

85
95285
94707
95279

86
95667
96557
95667

87
96317
97456
96317

88
98435
97968
98435

89
99460
98426
99460

90
100144
101325
100144

91
101457
101720
101457

92
101704
102273
101704

93
102356
102805
102356

94
102835
103530
102835

95
103549
104058
103549

96
104096
104491
104096

97
104601
108386
104601

98
108401
112054
108401

99
112033
112590
112033

100
112672
113682
112672

101
113726
114121
113726

102
114711
114136
114711

103
115267
115755
115267

104
115911
116543
115911

105
116736
118055
116778

106
117968
118522
117968

107
118530
119843
118530

108
119816
120457
119816

109
120451
122430
120451

110
122504
122950
122504

111
123528
126347
123528

112
126332
129166
126332

113
134690
129213
134690

114
134925
136382
134931

115
137870
136482
137867

116
137899
138240
137899

117
138239
137928
138239

118
139558
138257
139558

119
140352
139516
140352

120
140498
141841
140498

121
141855
142658
141855

122
144258
143050
144258

123
145258
144494
145258

124
145454
146749
145454

125
147318
146767
147318

126
148261
147677
148261

127
149029
152157
149029

128
154108
152201
154108

129
155135
154308
155135

130
155141
155467
155141

131
155703
156779
155703

132
156748
157635
156748

133
157653
158996
157653

134
159363
159986
159363

135
159880
160446
159880

136
160477
160839
160477

137
160898
161539
160898

138
161527
162153
161527

139
162144
162443
162144

140
162437
164098
162437

141
165451
164228
165451

142
166349
165411
166349

143
166949
168442
166949

144
169416
171029
169416

145
170857
171459
170857

146
172652
173428
172652

147
174626
173439
174626

148
174816
175613
174816

149
175598
175954
175598

150
175958
176935
175958

151
177708
176938
177708

152
177128
177376
177128

153
179472
177841
179472

154
179822
179517
179822

155
181793
179943
181793

156
182628
181876
182628

157
184420
183074
184420

158
184988
184467
184988

159
185483
185112
185483

160
185902
185483
185902

161
186174
185839
186174

162
187720
186587
187720

163
188318
190933
188318

164
191090
191635
191090

165
191547
192743
191547

166
192969
193469
192969

167
194044
193610
194044

168
194196
195809
194196

169
196088
198073
196088

170
198132
199454
198132

171
199351
202818
199351

172
204552
202999
204552

173
205648
204692
205639

174
205807
207327
205807

175
207182
207775
207182

176
207779
208267
207779

177
208267
209577
208267

178
211807
211271
211807

179
212188
211844
212188

180
214079
212448
214079

181
214907
214083
214907

182
216154
215429
216154

183
216115
216678
216115

184
216728
217282
216728

185
217267
217866
217267

186
218593
218261
218590

187
219821
218994
219821

188
221382
220309
221382

189
222719
221433
222719

190
223521
222724
223521

191
224499
225008
224499

192
225140
225559
225140

193
225555
226802
225555

194
227800
226892
227743

195
228335
228072
228335

196
229251
228643
229251

197
230983
229622
230983

198
231483
230983
231483

199
232063
231509
232063

200
232739
232053
232739

201
233166
234356
233166

202
233518
233165
233518

203
234536
235186
234536

204
235379
236689
235379

205
236680
237618
236689

206
237521
238345
237521

207
238281
238973
238281

208
238871
240115
238871

209
240191
241564
240191

210
242281
241604
242281

211
242933
242274
242933

212
243416
242976
243416

213
243500
244531
243500

214
244480
246021
244480

215
246330
247811
246330

216
247831
249174
247870

217
249437
251038
249455

218
251325
252212
251325

219
253156
254007
253156

220
253974
254852
253974

221
255258
256094
255258

222
256640
257455
256640

223
257502
258239
257502

224
257869
257501
257869

225
259248
260897
259248

226
262753
261788
262753

227
263059
262757
263059

228
264375
263182
264375

229
265985
264747
265985

230
266637
266059
266637

231
267338
266538
267338

232
267922
267473
267922

233
269647
270771
269647

234
272777
273145
272777

235
273253
273636
273253

236
273705
273977
273705

237
276016
275717
276016

238
276439
276020
276418

239
276792
277253
276792

240
277318
277599
277318

241
278578
277877
278578

242
279258
278554
279258

243
280435
279533
280435

244
281547
280849
281547

245
281696
282325
281717

246
282459
284069
282459

247
284056
284517
284056

248
284606
285775
284606

249
285592
285987
285592

250
286179
286976
286179

251
287583
287002
287583

252
287951
287451
287951

253
288499
288816
288499

254
289674
288505
289674

255
288839
289213
288839

256
289970
290254
289970

257
291931
292803
291931

258
293258
292755
293258

259
293718
293272
293718

260
294630
293953
294630

261
296153
294636
296153

262
294817
295068
294817

263
296354
297862
296354

264
298415
297879
298415

265
298777
298253
298777

266
299572
298781
299572

267
300487
299633
300487

268
301586
300702
301568

269
302440
301571
302440

270
302838
302437
302838

271
303335
302745
303335

272
304394
303852
304394

273
304606
305223
304606

274
305394
306236
305394

275
306501
307439
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664
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669
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670
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673
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674
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708
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709
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710
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711
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712
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713
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714
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715
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716
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717
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718
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719
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720
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721
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722
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723
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724
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725
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726
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727
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728
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729
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730
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731
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732
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733
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734
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735
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736
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737
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738
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739
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740
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741
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742
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743
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744
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745
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746
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747
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748
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749
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750
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751
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752
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753
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755
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756
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757
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758
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759
811235
810213
811235

760
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813056
811779

761
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812516
812890

762
812954
813583
812954

763
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815023
813587

764
815420
815746
815420

765
816036
817010
816036

766
817111
817356
817111

767
817791
818609
817797

768
818609
819094
818609

769
819104
819823
819104

770
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819826
820722

771
822313
821000
822313

772
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822238
823503

773
823678
825612
823678

774
825461
826312
825461

775
827280
826645
827280

776
828604
827171
828604

777
830026
828713
830026

778
831047
830085
831047

779
831725
831051
831725

780
832220
833098
832220

781
833851
833396
833851

782
834068
835039
834068

783
835792
835127
835792

784
837624
836116
837624

785
838951
840882
838951

786
840869
842185
840869

787
841989
843455
841989

788
843242
844021
843242

789
845018
843987
844997

790
846174
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846174

791
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846311
848509

792
848568
849014
848568

793
849082
850488
849088

794
851512
850574
851512

795
852064
852447
852064

796
852398
853690
852398

797
855118
854243
855118

798
855751
855128
855751

799
856551
855829
856551

800
856730
858556
856730

801
858717
859601
858717

802
859591
860205
859591

803
861132
860284
861132

804
861426
861163
861426

805
861701
862921
861701

806
863026
864798
863026

807
864831
865256
864831

808
865226
866581
865226

809
866562
867119
866562

810
867025
867816
867025

811
867820
868497
867820

812
869743
868661
869743

813
870633
870094
870633

814
871929
870646
871929

815
872538
872086
872538

816
873908
872517
873908

817
874281
874670
874281

818
874582
875286
874582

819
877857
875377
877857

820
878446
879255
878446

821
880635
879268
880635

822
882524
880593
882524

823
882612
883319
882612

824
884155
883538
884155

825
884340
885611
884343

826
885722
887302
885722

827
887587
888153
887587

828
888627
888220
888627

829
889330
888716
889330

830
889898
889323
889898

831
891190
889898
891190

832
891828
891247
891828

833
892421
892017
892421

834
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892421
893116

835
892521
892925
892521

836
893392
895419
893392

837
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896527
895745

838
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896668

839
897565
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897565

840
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900229
899420

841
903230
900237
903230

842
905081
903234
905081

843
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905045
906931

844
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907832
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845
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908128
907784

846
908132
908677
908132

847
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848
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911465
909405

849
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912360
911725

850
912303
912821
912303

851
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913983
912937

852
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915128

853
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854
915627
915376
915627

855
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917707

856
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917722
918837

857
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919868

858
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859
921187
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921187

860
921959
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921959

861
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921995
923773

862
922146
922415
922146

863
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923674
923943

864
924077
925006
924077

865
925436
925083
925436

866
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925349
926524

867
927920
926433
927920

868
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927951
928319

869
928963
928334
928963

870
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930987
929248

871
930995
932059
930995

872
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932175

873
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932513
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874
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875
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937082
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876
937229
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937229

877
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878
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879
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880
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940791
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881
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882
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941351
940977

883
942537
941623
942429

884
942784
942500
942763

885
943149
942799
943149

886
943799
943029
943799

887
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943732
944055

888
944413
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944404

889
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944556
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890
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891
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945751
946392

892
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948081
947431

893
949871
948915
949871

894
951058
949868
951058

895
951249
950959
951249

896
951664
952134
951664

897
952674
952165
952674

898
953491
952589
953491

899
955324
953495
955324

900
955823
955281
955823

901
957082
955847
957082

902
957902
957270
957902

903
959231
957906
959231

904
959376
960284
959376

905
960266
961669
960347

906
961856
964765
961856

907
966855
965395
966855

908
968204
966975
968204

909
968791
968237
968791

910
969498
968731
969498

911
969858
969511
969858

912
970118
969762
970118

913
970593
970300
970593

914
971261
970542
971261

915
971680
971123
971680

916
971876
975100
971876

917
975419
976516
975419

918
976584
978320
976584

919
977680
977231
977680

920
978399
980738
978399

921
980756
981928
980756

922
982974
981931
982962

923
984120
983119
984120

924
985502
984120
985502

925
987180
985882
987180

926
987172
987444
987172

927
989846
989049
989846

928
991048
989846
991048

929
991638
990955
991638

930
991794
992498
991794

931
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993041
993619

932
993530
994792
993548

933
995970
994795
995970

934
996857
995739
996857

935
997603
996782
997603

936
998969
997572
998969

937
998896
1000023
998896

938
1000087
1001340
1000087

939
1001357
1001818
1001357

940
1003288
1001873
1003288

941
1003487
1004146
1003496

942
1004485
1005639
1004689

943
1005643
1005972
1005643

944
1006784
1006116
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945
1007563
1006769
1007563

946
1009226
1007568
1009226

947
1009989
1009336
1009989

948
1015852
1016337
1015852

949
1016561
1016181
1016561

950
1016297
1017532
1016297

951
1016802
1016452
1016802

952
1018993
1017701
1018993

953
1019454
1019137
1019454

954
1020764
1019562
1020764

955
1021405
1021037
1021405

956
1021821
1024286
1021821

957
1024697
1024248
1024697

958
1025569
1024508
1025551

959
1026969
1025590
1026969

960
1027789
1026947
1027789

961
1031199
1027945
1031199

962
1031717
1031172
1031717

963
1033057
1031612
1033057

964
1033425
1033039
1033425

965
1033784
1033200
1033784

966
1033963
1036038
1033963

967
1036945
1036010
1036945

968
1037110
1037679
1037110

969
1037696
1037944
1037696

970
1038916
1037975
1038916

971
1040582
1039026
1040582

972
1040997
1042337
1040997

973
1042357
1043403
1042357

974
1043367
1044623
1043367

975
1044607
1045362
1044607

976
1045384
1046538
1045384

977
1046447
1047517
1046447

978
1047521
1049956
1047521

979
1050611
1050036
1050611

980
1050925
1050566
1050925

981
1051728
1051090
1051728

982
1051743
1052063
1051743

983
1052101
1053126
1052101

984
1054201
1053107
1054201

985
1054242
1055555
1054242

986
1055483
1055908
1055483

987
1056609
1056965
1056609

988
1056961
1058232
1056985

989
1058238
1058687
1058238

990
1059371
1058727
1059371

991
1059526
1060578
1059526

992
1061553
1060579
1061553

993
1061674
1062411
1061674

994
1062377
1064077
1062377

995
1064116
1065243
1064116

996
1067451
1065178
1067451

997
1068065
1067376
1068065

998
1068209
1068706
1068230

999
1069958
1068819
1069958

1000
1071163
1070033
1071163

1001
1072438
1071332
1072438

1002
1072997
1073476
1072997

1003
1074239
1075864
1074239

1004
1076790
1075867
1076790

1005
1077268
1076573
1077268

1006
1077999
1078724
1077999

1007
1079088
1078672
1079088

1008
1079642
1079944
1079642

1009
1080501
1079995
1080468

1010
1080775
1081341
1080775

1011
1083158
1081350
1083158

1012
1084677
1083235
1084677

1013
1085648
1084632
1085648

1014
1086117
1086737
1086117

1015
1086692
1087897
1086692

1016
1088646
1089005
1088646

1017
1089146
1089805
1089146

1018
1092931
1089890
1092931

1019
1093179
1092889
1093179

1020
1093584
1094204
1093584

1021
1095619
1094192
1095619

1022
1096074
1096628
1096074

1023
1096633
1097082
1096633

1024
1097266
1097601
1097266

1025
1097622
1097867
1097622

1026
1097886
1098392
1097886

1027
1099521
1099279
1099521

1028
1099689
1101053
1099704

1029
1102192
1101107
1102192

1030
1104950
1102116
1104950

1031
1106508
1104946
1106508

1032
1106722
1107249
1106722

1033
1107463
1108101
1107463

1034
1108041
1108421
1108041

1035
1108520
1113370
1108520

1036
1114958
1113447
1114958

1037
1116915
1115071
1116915

1038
1118183
1116894
1118183

1039
1118846
1120030
1118846

1040
1120040
1120522
1120040

1041
1120510
1121430
1120510

1042
1121321
1121866
1121321

1043
1122123
1122899
1122123

1044
1124842
1125564
1124842

1045
1126526
1125579
1126526

1046
1126519
1127676
1126519

1047
1127672
1128571
1127672

1048
1130230
1131336
1130230

1049
1131480
1132553
1131480

1050
1132830
1133843
1132830

1051
1134121
1134855
1134121

1052
1134642
1135592
1134642

1053
1135964
1135653
1135964

1054
1137132
1135954
1137132

1055
1137169
1140102
1137169

1056
1141365
1140112
1141344

1057
1142150
1141356
1142150

1058
1142520
1145660
1142520

1059
1145627
1146721
1145627

1060
1146862
1147545
1146862

1061
1147666
1148190
1147666

1062
1148514
1148224
1148514

1063
1149136
1148348
1149136

1064
1149702
1149166
1149702

1065
1150031
1150591
1150031

1066
1150785
1151147
1150785

1067
1151165
1152181
1151165

1068
1152522
1154591
1152522

1069
1155666
1154566
1155666

1070
1156743
1155670
1156740

1071
1156859
1157815
1156859

1072
1157982
1160735
1157982

1073
1162620
1160917
1162620

1074
1162970
1162590
1162970

1075
1163532
1164020
1163532

1076
1163995
1164294
1163995

1077
1165569
1165030
1165569

1078
1166108
1165566
1166108

1079
1166644
1166141
1166644

1080
1167055
1168374
1167055

1081
1169218
1168337
1169218

1082
1169823
1169218
1169823

1083
1171324
1170572
1171324

1084
1172085
1171177
1172085

1085
1172394
1173773
1172394

1086
1175209
1173881
1175209

1087
1175555
1175127
1175360

1088
1175778
1177043
1175778

1089
1177177
1179048
1177177

1090
1179156
1180085
1179156

1091
1180045
1180779
1180045

1092
1181942
1180788
1181942

1093
1182296
1181961
1182296

1094
1183844
1182300
1183844

1095
1184420
1183848
1184420

1096
1185382
1184366
1185382

1097
1185858
1185226
1185858

1098
1186164
1186481
1186185

1099
1187386
1186484
1187386

1100
1187370
1189028
1187370

1101
1189321
1190889
1189321

1102
1191142
1192146
1191142

1103
1191974
1191729
1191974

1104
1193815
1192991
1193815

1105
1195702
1194248
1195702

1106
1196303
1195716
1196303

1107
1196831
1196337
1196831

1108
1197807
1196746
1197651

1109
1198740
1197883
1198668

1110
1200232
1198721
1200232

1111
1201286
1200135
1201286

1112
1202386
1201259
1202350

1113
1202901
1202350
1202901

1114
1204162
1202816
1204162

1115
1203177
1203464
1203177

1116
1205028
1204180
1205028

1117
1206392
1204878
1206392

1118
1206742
1206086
1206742

1119
1207872
1206724
1207872

1120
1208852
1207851
1208852

1121
1210518
1209742
1210518

1122
1210703
1211494
1210703

1123
1211870
1212754
1211870

1124
1212742
1214064
1212742

1125
1214046
1214858
1214046

1126
1215551
1216318
1215551

1127
1216493
1216849
1216493

1128
1217183
1219612
1217183

1129
1220068
1219673
1220068

1130
1219710
1220669
1219710

1131
1220630
1221376
1220630

1132
1221645
1223681
1221645

1133
1223894
1224988
1223900

1134
1225000
1225830
1225000

1135
1227810
1225879
1227810

1136
1226528
1226908
1226528

1137
1229972
1228311
1229972

1138
47569
47018
47569

1139
49980
49117
49980

1140
53356
52898
53356

1141
54477
54884
54477

1142
63753
63998
63753

1143
77164
77487
77164

1144
79724
79302
79724

1145
88721
88951
88721

1146
94067
94429
94067

1147
122832
123341
122832

1148
147536
147234
147536

1149
158990
159346
158990

1150
168470
168979
168470

1151
169183
169452
169204

1152
171785
171504
171785

1153
172518
171775
172518

1154
193599
194045
193599

1155
195704
196075
195704

1156
210687
210145
210684

1157
211100
210708
211100

1158
215420
215088
215420

1159
217914
218246
217914

1160
218925
218701
218925

1161
223785
223525
223785

1162
224271
223999
224271

1163
228691
228407
228691

1164
235050
235334
235050

1165
252308
253021
252308

1166
258280
258912
258280

1167
261325
261567
261325

1168
268195
268878
268195

1169
269447
268881
269447

1170
271263
271538
271263

1171
271957
272346
271957

1172
274176
274550
274176

1173
275736
275314
275736

1174
276490
276927
276490

1175
277577
277861
277577

1176
288163
287909
288163

1177
290130
289789
290130

1178
290989
291225
290989

1179
291372
291860
291372

1180
311239
311622
311239

1181
328665
328384
328665

1182
337348
338289
337348

1183
364764
364369
364764

1184
389623
390135
389623

1185
393729
394343
393729

1186
407379
407621
407379

1187
410944
410708
410944

1188
427632
427988
427632

1189
428172
428486
428172

1190
436761
437246
436761

1191
460911
461159
460911

1192
477597
477313
477597

1193
487303
487001
487303

1194
487764
487534
487764

1195
498502
499017
498502

1196
499795
500466
499795

1197
571928
572344
571928

1198
572367
572131
572367

1199
588184
587915
588184

1200
600587
600907
600587

1201
609731
608895
609731

1202
614039
614755
614039

1203
614823
615152
614823

1204
638244
638831
638244

1205
638819
639094
638819

1206
639073
639636
639073

1207
647901
648236
647901

1208
678510
679469
678510

1209
688178
688732
688178

1210
696045
696563
696045

1211
708998
708588
708998

1212
709808
710089
709808

1213
718240
717737
718240

1214
737828
737565
737828

1215
779502
780257
779502

1216
806310
805864
806310

1217
820931
820707
820931

1218
837696
839096
837696

1219
883307
883549
883307

1220
892010
891726
892010

1221
893277
893564
893277

1222
936998
937225
936998

1223
946865
947419
946865

1224
975187
975411
975187

1225
985882
985517
985882

1226
987713
987180
987713

1227
988215
987733
988215

1228
988754
988530
988754

1229
992542
992841
992542

1230
992759
993067
992759

1231
1004247
1004528
1004268

1232
1015013
1014294
1015013

1233
1056147
1056545
1056147

1234
1077682
1078035
1077682

1235
1088121
1088381
1088121

1236
1098430
1098852
1098430

1237
1098798
1099319
1098798

1238
1123198
1123515
1123198

1239
1123606
1124256
1123606

1240
1124453
1124797
1124453

1241
1129253
1129567
1129253

1242
1164947
1164474
1164947

1243
1170457
1170053
1170457

1244
1172342
1171863
1172342

1245
1192155
1192835
1192155

1246
1192759
1192992
1192759

1247
1193861
1194142
1193861

1248
1194036
1193779
1194036

1249
1209748
1209053
1209748

1250
1215111
1215419
1215111

1251
1216302
1216538
1216302

1252
1228072
1227818
1228072

1253
1228304
1228080
1228304

1254
26599
26222
26599

1255
27609
27367
27609

1256
67206
66967
67197

1257
70612
70352
70588

1258
132703
132945
132703

1259
178073
178393
178073

1260
208576
208349
208576

1261
209156
208929
209156

1262
209263
209024
209263

1263
210304
210639
210304

1264
299009
299452
299030

1265
352106
351717
352061

1266
420182
419949
420170

1267
553602
553381
553602

1268
556538
556807
556538

1269
594348
593797
594342

1270
595169
594876
595160

1271
662148
662381
662160

1272
706528
706893
706528

1273
803315
803650
803339

1274
849551
849306
849551

1275
913676
913275
913676

1276
927087
926836
927087

1277
930587
930360
930587

1278
986531
986764
986531

1279
996229
996486
996229

1280
1000373
1000002
1000334

1281
1010291
1010037
1010273

1282
1011128
1010793
1011128

1283
1012924
1012694
1012924

1284
1028659
1028913
1028659

1285
1086481
1086762
1086481

1286
1118658
1118879
1118658

1287
1170098
1169835
1170098

1288
1180828
1181184
1180828

1289
1182658
1183035
1182658

1290
1195076
1194795
1195055

1291
1195890
1196183
1195890

1292
189042
188809
189030

1293
691250
691567
691250

1294
914544
914780
914556

1295
928525
928833
928579

1296
1040685
1040948
1040712

1297
377646
378068
377646

[0583]

4

TABLE 3

ORF 25, ORF 26, ORF 27;

ORF 28, ORF 29, ORF 30;

ORF 31, ORF 32;

ORF 33, ORF 35;

ORF 466, ORF 467;

ORF 468, ORF 469;

ORF 477, ORF 476, ORF 474;

ORF 480, ORF 482;

ORF 483, ORF 485, ORF 486, ORF 500;

ORF 503, ORF 504, ORF 505;

ORF 506, ORF 507;

ORF 1211, ORF 647;

ORF 1286, ORF 1039;

ORF 691, ORF 690;

ORF 105, ORF 106;

ORF 170, ORF 171; ORF 394, ORF 393;

ORF 453, ORF 452, ORF 451;

ORF 526, ORF 525;

ORF 757, ORF 756, ORF 755;

ORF 856, ORF 855;

ORF 958, ORF 957;

ORF 915, ORF 914, ORF 913;

ORF 543, ORF 544;

ORF 1266, ORF 380;

ORF 745, ORF 744;

ORF 777, ORF 776;

ORF 343, ORF 1297, and representative fragments.

[0584]

5

TABLE 4

SEQ ID NO (ORF)
Fp
Fd
Bp
Bd

2
1292
1293
3796
3797

3
1294
1295
3798
3799

4
1296
1297
3800
3801

5
1298
1299
3802
3803

6
1300
1301
3804
3805

7
1302
1303
3806
3807

8
1304
1305
3808
3809

9
1306
1307
3810
3811

10
1308
1309
3812
3813

11
1310
1311
3814
3815

12
1312
1313
3816
3817

13
1314
1315
3818
3819

14
1316
1317
3820
3821

15
1318
1319
3822
3823

16
1320
1321
3824
3825

17
1322
1323
3826
3827

18
1324
1325
3828
3829

19
1326
1327
3830
3831

20
1328
1329
3832
3833

21
1330
1331
3834
3835

22
1332
1333
3836
3837

23
1334
1335
3838
3839

24
1336
1337
3840
3841

25
1338
1339
3842
3843

26
1340
1341
3844
3845

27
1342
1343
3846
3847

28
1344
1345
3848
3849

29
1346
1347
3850
3851

30
1348
1349
3852
3853

31
1350
1351
3854
3855

32
1352
1353
3856
3857

33
1354
1355
3858
3859

34
1358
1359
3862
3863

35
1356
1357
3860
3861

36
1360
1361
3864
3865

37
1362
1363
3866
3867

38
1364
1365
3868
3869

39
1366
1367
3870
3871

40
1368
1369
3872
3873

41
1370
1371
3874
3875

42
1374
1375
3878
3879

43
1376
1377
3880
3881

44
1380
1381
3884
3885

45
1382
1383
3886
3887

46
1386
1387
3890
3891

47
1388
1389
3892
3893

48
1392
1393
3896
3897

49
1394
1395
3898
3899

50
1396
1397
3900
3901

51
1398
1399
3902
3903

52
1402
1403
3906
3907

53
1400
1401
3904
3905

54
1404
1405
3908
3909

55
1406
1407
3910
3911

56
1410
1411
3914
3915

57
1412
1413
3916
3917

58
1414
1415
3918
3919

59
1416
1417
3920
3921

60
1418
1419
3922
3923

61
1420
1421
3924
3925

62
1422
1423
3926
3927

63
1424
1425
3928
3929

64
1426
1427
3930
3931

65
1428
1429
3932
3933

66
1430
1431
3934
3935

67
1432
1433
3936
3937

68
1434
1435
3938
3939

69
1438
1439
3942
3943

70
1440
1441
3944
3945

71
1444
1445
3948
3949

72
1446
1447
3950
3951

73
1448
1449
3952
3953

74
1450
1451
3954
3955

75
1452
1453
3956
3957

76
1454
1455
3958
3959

77
1456
1457
3960
3961

78
1458
1459
3962
3963

79
1460
1461
3964
3965

80
1462
1463
3966
3967

81
1464
1465
3968
3969

82
1468
1469
3972
3973

83
1470
1471
3974
3975

84
1472
1473
3976
3977

85
1476
1477
3980
3981

86
1478
1479
3982
3983

87
1480
1481
3984
3985

88
1482
1483
3986
3987

89
1484
1485
3988
3989

90
1486
1487
3990
3991

91
1488
1489
3992
3993

92
1490
1491
3994
3995

93
1492
1493
3996
3997

94
1494
1495
3998
3999

95
1496
1497
4000
4001

96
1498
1499
4002
4003

97
1500
1501
4004
4005

98
1502
1503
4006
4007

99
1504
1505
4008
4009

100
1506
1507
4010
4011

101
1508
1509
4012
4013

102
1510
1511
4014
4015

103
1512
1513
4016
4017

104
1514
1515
4018
4019

105
1516
1517
4020
4021

106
1518
1519
4022
4023

107
1520
1521
4024
4025

108
1522
1523
4026
4027

109
1524
1525
4028
4029

110
1526
1527
4030
4031

111
1530
1531
4034
4035

112
1532
1533
4036
4037

113
1534
1535
4038
4039

114
1536
1537
4040
4041

115
1538
1539
4042
4043

116
1540
1541
4044
4045

117
1542
1543
4046
4047

118
1544
1545
4048
4049

119
1546
1547
4050
4051

120
1548
1549
4052
4053

121
1550
1551
4054
4055

122
1552
1553
4056
4057

123
1554
1555
4058
4059

124
1556
1557
4060
4061

125
1558
1559
4062
4063

126
1562
1563
4066
4067

127
1564
1565
4068
4069

128
1566
1567
4070
4071

129
1568
1569
4072
4073

130
1570
1571
4074
4075

131
1572
1573
4076
4077

132
1574
1575
4078
4079

133
1576
1577
4080
4081

134
1580
1581
4084
4085

135
1582
1583
4086
4087

136
1584
1585
4088
4089

137
1586
1587
4090
4091

138
1588
1589
4092
4093

139
1590
1591
4094
4095

140
1592
1593
4096
4097

141
1594
1595
4098
4099

142
1596
1597
4100
4101

143
1598
1599
4102
4103

144
1604
1605
4108
4109

145
1606
1607
4110
4111

146
1612
1613
4116
4117

147
1614
1615
4118
4119

148
1616
1617
4120
4121

149
1618
1619
4122
4123

150
1620
1621
4124
4125

151
1624
1625
4128
4129

152
1622
1623
4126
4127

153
1626
1627
4130
4131

154
1628
1629
4132
4133

155
1630
1631
4134
4135

156
1632
1633
4136
4137

157
1634
1635
4138
4139

158
1636
1637
4140
4141

159
1638
1639
4142
4143

160
1640
1641
4144
4145

161
1642
1643
4146
4147

162
1644
1645
4148
4149

163
1646
1647
4150
4151

164
1648
1649
4152
4153

165
1650
1651
4154
4155

166
1652
1653
4156
4157

167
1656
1657
4160
4161

168
1658
1659
4162
4163

169
1662
1663
4166
4167

170
1664
1665
4168
4169

171
1666
1667
4170
4171

172
1668
1669
4172
4173

173
1670
1671
4174
4175

174
1672
1673
4176
4177

175
1674
1675
4178
4179

176
1676
1677
4180
4181

177
1678
1679
4182
4183

178
1684
1685
4188
4189

179
1686
1687
4190
4191

180
1688
1689
4192
4193

181
1690
1691
4194
4195

182
1694
1695
4198
4199

183
1696
1697
4200
4201

184
1698
1699
4202
4203

185
1700
1701
4204
4205

186
1704
1705
4208
4209

187
1708
1709
4212
4213

188
1710
1711
4214
4215

189
1712
1713
4216
4217

190
1714
1715
4218
4219

191
1720
1721
4224
4225

192
1722
1723
4226
4227

193
1724
1725
4228
4229

194
1726
1727
4230
4231

195
1728
1729
4232
4233

196
1732
1733
4236
4237

197
1734
1735
4238
4239

198
1736
1737
4240
4241

199
1738
1739
4242
4243

200
1740
1741
4244
4245

201
1742
1743
4246
4247

202
1744
1745
4248
4249

203
1746
1747
4250
4251

204
1750
1751
4254
4255

205
1752
1753
4256
4257

206
1754
1755
4258
4259

207
1756
1757
4260
4261

208
1758
1759
4262
4263

209
1760
1761
4264
4265

210
1762
1763
4266
4267

211
1764
1765
4268
4269

212
1766
1767
4270
4271

213
1768
1769
4272
4273

214
1770
1771
4274
4275

215
1772
1773
4276
4277

216
1774
1775
4278
4279

217
1776
1777
4280
4281

218
1778
1779
4282
4283

219
1782
1783
4286
4287

220
1784
1785
4288
4289

221
1786
1787
4290
4291

222
1788
1789
4292
4293

223
1790
1791
4294
4295

224
1792
1793
4296
4297

225
1796
1797
4300
4301

226
1800
1801
4304
4305

227
1802
1803
4306
4307

228
1804
1805
4308
4309

229
1806
1807
4310
4311

230
1808
1809
4312
4313

231
1810
1811
4314
4315

232
1812
1813
4316
4317

233
1818
1819
4322
4323

234
1824
1825
4328
4329

235
1826
1827
4330
4331

236
1828
1829
4332
4333

237
1834
1835
4338
4339

238
1836
1837
4340
4341

239
1840
1841
4344
4345

240
1842
1843
4346
4347

241
1846
1847
4350
4351

242
1848
1849
4352
4353

243
1850
1851
4354
4355

244
1852
1853
4356
4357

245
1854
1855
4358
4359

246
1856
1857
4360
4361

247
1858
1859
4362
4363

248
1860
1861
4364
4365

249
1862
1863
4366
4367

250
1864
1865
4368
4369

251
1866
1867
4370
4371

252
1868
1869
4372
4373

253
1872
1873
4376
4377

254
1876
1877
4380
4381

255
1874
1875
4378
4379

256
1878
1879
4382
4383

257
1886
1887
4390
4391

258
1888
1889
4392
4393

259
1890
1891
4394
4395

260
1892
1893
4396
4397

261
1896
1897
4400
4401

262
1894
1895
4398
4399

263
1898
1899
4402
4403

264
1900
1901
4404
4405

265
1902
1903
4406
4407

266
1904
1905
4408
4409

267
1906
1907
4410
4411

268
1908
1909
4412
4413

269
1910
1911
4414
4415

270
1912
1913
4416
4417

271
1914
1915
4418
4419

272
1916
1917
4420
4421

273
1918
1919
4422
4423

274
1920
1921
4424
4425

275
1922
1923
4426
4427

276
1924
1925
4428
4429

277
1926
1927
4430
4431

278
1928
1929
4432
4433

279
1930
1931
4434
4435

280
1934
1935
4438
4439

281
1936
1937
4440
4441

282
1938
1939
4442
4443

283
1940
1941
4444
4445

284
1942
1943
4446
4447

285
1944
1945
4448
4449

286
1946
1947
4450
4451

287
1948
1949
4452
4453

288
1950
1951
4454
4455

289
1952
1953
4456
4457

290
1954
1955
4458
4459

291
1956
1957
4460
4461

292
1958
1959
4462
4463

293
1960
1961
4464
4465

294
1962
1963
4466
4467

295
1964
1965
4468
4469

296
1966
1967
4470
4471

297
1970
1971
4474
4475

298
1972
1973
4476
4477

299
1974
1975
4478
4479

300
1976
1977
4480
4481

301
1978
1979
4482
4483

302
1980
1981
4484
4485

303
1984
1985
4488
4489

304
1986
1987
4490
4491

305
1988
1989
4492
4493

306
1990
1991
4494
4495

307
1992
1993
4496
4497

308
1994
1995
4498
4499

309
1996
1997
4500
4501

310
1998
1999
4502
4503

311
2000
2001
4504
4505

312
2002
2003
4506
4507

313
2004
2005
4508
4509

314
2006
2007
4510
4511

315
2008
2009
4512
4513

316
2010
2011
4514
4515

317
2012
2013
4516
4517

318
2014
2015
4518
4519

319
2016
2017
4520
4521

320
2018
2019
4522
4523

321
2020
2021
4524
4525

322
2022
2023
4526
4527

323
2026
2027
4530
4531

324
2024
2025
4528
4529

325
2028
2029
4532
4533

326
2030
2031
4534
4535

327
2032
2033
4536
4537

328
2034
2035
4538
4539

329
2038
2039
4542
4543

330
2040
2041
4544
4545

331
2042
2043
4546
4547

332
2044
2045
4548
4549

333
2046
2047
4550
4551

334
2048
2049
4552
4553

335
2050
2051
4554
4555

336
2052
2053
4556
4557

337
2054
2055
4558
4559

338
2056
2057
4560
4561

339
2058
2059
4562
4563

340
2060
2061
4564
4565

341
2062
2063
4566
4567

342
2064
2065
4568
4569

343
2066
2067
4570
4571

344
2068
2069
4572
4573

345
2070
2071
4574
4575

346
2072
2073
4576
4577

347
2074
2075
4578
4579

348
2076
2077
4580
4581

349
2078
2079
4582
4583

350
2080
2081
4584
4585

351
2082
2083
4586
4587

352
2084
2085
4588
4589

353
2088
2089
4592
4593

354
2090
2091
4594
4595

355
2092
2093
4596
4597

356
2094
2095
4598
4599

357
2096
2097
4600
4601

358
2100
2101
4604
4605

359
2102
2103
4606
4607

360
2104
2105
4608
4609

361
2106
2107
4610
4611

362
2108
2109
4612
4613

363
2110
2111
4614
4615

364
2112
2113
4616
4617

365
2114
2115
4618
4619

366
2116
2117
4620
4621

367
2118
2119
4622
4623

368
2120
2121
4624
4625

369
2122
2123
4626
4627

370
2124
2125
4628
4629

371
2128
2129
4632
4633

372
2130
2131
4634
4635

373
2134
2135
4638
4639

374
2136
2137
4640
4641

375
2138
2139
4642
4643

376
2140
2141
4644
4645

377
2142
2143
4646
4647

378
2144
2145
4648
4649

379
2146
2147
4650
4651

380
2148
2149
4652
4653

381
2150
2151
4654
4655

382
2152
2153
4656
4657

383
2154
2155
4658
4659

384
2156
2157
4660
4661

385
2158
2159
4662
4663

386
2160
2161
4664
4665

387
2162
2163
4666
4667

388
2164
2165
4668
4669

389
2170
2171
4674
4675

390
2172
2173
4676
4677

391
2174
2175
4678
4679

392
2176
2177
4680
4681

393
2178
2179
4682
4683

394
2180
2181
4684
4685

395
2182
2183
4686
4687

396
2186
2187
4690
4691

397
2190
2191
4694
4695

398
2188
2189
4692
4693

399
2194
2195
4698
4699

400
2192
2193
4696
4697

401
2196
2197
4700
4701

402
2200
2201
4704
4705

403
2198
2199
4702
4703

404
2202
2203
4706
4707

405
2204
2205
4708
4709

406
2206
2207
4710
4711

407
2208
2209
4712
4713

408
2210
2211
4714
4715

409
2212
2213
4716
4717

410
2214
2215
4718
4719

411
2216
2217
4720
4721

412
2218
2219
4722
4723

413
2220
2221
4724
4725

414
2222
2223
4726
4727

415
2224
2225
4728
4729

416
2226
2227
4730
4731

417
2228
2229
4732
4733

418
2230
2231
4734
4735

419
2232
2233
4736
4737

420
2234
2235
4738
4739

421
2236
2237
4740
4741

422
2238
2239
4742
4743

423
2242
2243
4746
4747

424
2244
2245
4748
4749

425
2246
2247
4750
4751

426
2248
2249
4752
4753

427
2250
2251
4754
4755

428
2252
2253
4756
4757

429
2254
2255
4758
4759

430
2256
2257
4760
4761

431
2258
2259
4762
4763

432
2260
2261
4764
4765

433
2262
2263
4766
4767

434
2266
2267
4770
4771

435
2264
2265
4768
4769

436
2268
2269
4772
4773

437
2270
2271
4774
4775

438
2272
2273
4776
4777

439
2274
2275
4778
4779

440
2278
2279
4782
4783

441
2280
2281
4784
4785

442
2282
2283
4786
4787

443
2284
2285
4788
4789

444
2286
2287
4790
4791

445
2288
2289
4792
4793

446
2290
2291
4794
4795

447
2292
2293
4796
4797

448
2294
2295
4798
4799

449
2296
2297
4800
4801

450
2298
2299
4802
4803

451
2304
2305
4808
4809

452
2306
2307
4810
4811

453
2308
2309
4812
4813

454
2310
2311
4814
4815

455
2312
2313
4816
4817

456
2314
2315
4818
4819

457
2316
2317
4820
4821

458
2318
2319
4822
4823

459
2320
2321
4824
4825

460
2322
2323
4826
4827

461
2324
2325
4828
4829

462
2326
2327
4830
4831

463
2328
2329
4832
4833

464
2332
2333
4836
4837

465
2334
2335
4838
4839

466
2338
2339
4842
4843

467
2340
2341
4844
4845

468
2342
2343
4846
4847

469
2344
2345
4848
4849

470
2346
2347
4850
4851

471
2348
2349
4852
4853

472
2350
2351
4854
4855

473
2352
2353
4856
4857

474
2356
2357
4860
4861

475
2354
2355
4858
4859

476
2358
2359
4862
4863

477
2360
2361
4864
4865

478
2362
2363
4866
4867

479
2364
2365
4868
4869

480
2366
2367
4870
4871

481
2368
2369
4872
4873

482
2370
2371
4874
4875

483
2372
2373
4876
4877

484
2374
2375
4878
4879

485
2376
2377
4880
4881

486
2378
2379
4882
4883

487
2380
2381
4884
4885

488
2382
2383
4886
4887

489
2384
2385
4888
4889

490
2386
2387
4890
4891

491
2388
2389
4892
4893

492
2390
2391
4894
4895

493
2392
2393
4896
4897

494
2394
2395
4898
4899

495
2396
2397
4900
4901

496
2398
2399
4902
4903

497
2400
2401
4904
4905

498
2402
2403
4906
4907

499
2404
2405
4908
4909

500
2406
2407
4910
4911

501
2408
2409
4912
4913

502
2410
2411
4914
4915

503
2412
2413
4916
4917

504
2414
2415
4918
4919

505
2416
2417
4920
4921

506
2418
2419
4922
4923

507
2420
2421
4924
4925

508
2422
2423
4926
4927

509
2426
2427
4930
4931

510
2424
2425
4928
4929

511
2430
2431
4934
4935

512
2428
2429
4932
4933

513
2432
2433
4936
4937

514
2434
2435
4938
4939

515
2436
2437
4940
4941

516
2438
2439
4942
4943

517
2440
2441
4944
4945

518
2442
2443
4946
4947

519
2444
2445
4948
4949

520
2446
2447
4950
4951

521
2450
2451
4954
4955

522
2454
2455
4958
4959

523
2456
2457
4960
4961

524
2458
2459
4962
4963

525
2460
2461
4964
4965

526
2462
2463
4966
4967

527
2466
2467
4970
4971

528
2464
2465
4968
4969

529
2468
2469
4972
4973

530
2470
2471
4974
4975

531
2472
2473
4976
4977

532
2474
2475
4978
4979

533
2476
2477
4980
4981

534
2478
2479
4982
4983

535
2480
2481
4984
4985

536
2482
2483
4986
4987

537
2486
2487
4990
4991

538
2488
2489
4992
4993

539
2490
2491
4994
4995

540
2492
2493
4996
4997

541
2494
2495
4998
4999

542
2496
2497
5000
5001

543
2498
2499
5002
5003

544
2500
2501
5004
5005

545
2502
2503
5006
5007

546
2504
2505
5008
5009

547
2506
2507
5010
5011

548
2508
2509
5012
5013

549
2510
2511
5014
5015

550
2514
2515
5018
5019

551
2516
2517
5020
5021

552
2518
2519
5022
5023

553
2520
2521
5024
5025

554
2522
2523
5026
5027

555
2524
2525
5028
5029

556
2526
2527
5030
5031

557
2528
2529
5032
5033

558
2532
2533
5036
5037

559
2534
2535
5038
5039

560
2536
2537
5040
5041

561
2538
2539
5042
5043

562
2544
2545
5048
5049

563
2546
2547
5050
5051

564
2548
2549
5052
5053

565
2552
2553
5056
5057

566
2550
2551
5054
5055

567
2554
2555
5058
5059

568
2556
2557
5060
5061

569
2558
2559
5062
5063

570
2560
2561
5064
5065

571
2562
2563
5066
5067

572
2564
2565
5068
5069

573
2566
2567
5070
5071

574
2568
2569
5072
5073

575
2570
2571
5074
5075

576
2572
2573
5076
5077

577
2574
2575
5078
5079

578
2576
2577
5080
5081

579
2578
2579
5082
5083

580
2580
2581
5084
5085

581
2582
2583
5086
5087

582
2590
2591
5094
5095

583
2592
2593
5096
5097

584
2594
2595
5098
5099

585
2596
2597
5100
5101

586
2598
2599
5102
5103

587
2600
2601
5104
5105

588
2602
2603
5106
5107

589
2604
2605
5108
5109

590
2606
2607
5110
5111

591
2608
2609
5112
5113

592
2610
2611
5114
5115

593
2612
2613
5116
5117

594
2616
2617
5120
5121

595
2618
2619
5122
5123

596
2620
2621
5124
5125

597
2622
2623
5126
5127

598
2624
2625
5128
5129

599
2626
2627
5130
5131

600
2628
2629
5132
5133

601
2630
2631
5134
5135

602
2632
2633
5136
5137

603
2634
2635
5138
5139

604
2636
2637
5140
5141

605
2638
2639
5142
5143

606
2640
2641
5144
5145

607
2642
2643
5146
5147

608
2644
2645
5148
5149

609
2646
2647
5150
5151

610
2650
2651
5154
5155

611
2648
2649
5152
5153

612
2652
2653
5156
5157

613
2654
2655
5158
5159

614
2656
2657
5160
5161

615
2658
2659
5162
5163

616
2660
2661
5164
5165

617
2662
2663
5166
5167

618
2664
2665
5168
5169

619
2666
2667
5170
5171

620
2668
2669
5172
5173

621
2672
2673
5176
5177

622
2674
2675
5178
5179

623
2678
2679
5182
5183

624
2676
2677
5180
5181

625
2680
2681
5184
5185

626
2682
2683
5186
5187

627
2684
2685
5188
5189

628
2686
2687
5190
5191

629
2688
2689
5192
5193

630
2690
2691
5194
5195

631
2692
2693
5196
5197

632
2696
2697
5200
5201

633
2698
2699
5202
5203

634
2700
2701
5204
5205

635
2702
2703
5206
5207

636
2704
2705
5208
5209

637
2706
2707
5210
5211

638
2710
2711
5214
5215

639
2712
2713
5216
5217

640
2714
2715
5218
5219

641
2716
2717
5220
5221

642
2718
2719
5222
5223

643
2720
2721
5224
5225

644
2722
2723
5226
5227

645
2724
2725
5228
5229

646
2726
2727
5230
5231

647
2728
2729
5232
5233

648
2732
2733
5236
5237

649
2736
2737
5240
5241

650
2738
2739
5242
5243

651
2740
2741
5244
5245

652
2742
2743
5246
5247

653
2744
2745
5248
5249

654
2748
2749
5252
5253

655
2750
2751
5254
5255

656
2752
2753
5256
5257

657
2754
2755
5258
5259

658
2756
2757
5260
5261

659
2758
2759
5262
5263

660
2760
2761
5264
5265

661
2762
2763
5266
5267

662
2764
2765
5268
5269

663
2766
2767
5270
5271

664
2768
2769
5272
5273

665
2770
2771
5274
5275

666
2772
2773
5276
5277

667
2774
2775
5278
5279

668
2776
2777
5280
5281

669
2778
2779
5282
5283

670
2780
2781
5284
5285

671
2782
2783
5286
5287

672
2784
2785
5288
5289

673
2786
2787
5290
5291

674
2788
2789
5292
5293

675
2790
2791
5294
5295

676
2792
2793
5296
5297

677
2794
2795
5298
5299

678
2796
2797
5300
5301

679
2798
2799
5302
5303

680
2800
2801
5304
5305

681
2804
2805
5308
5309

682
2806
2807
5310
5311

683
2808
2809
5312
5313

684
2810
2811
5314
5315

685
2812
2813
5316
5317

686
2814
2815
5318
5319

687
2816
2817
5320
5321

688
2818
2819
5322
5323

689
2820
2821
5324
5325

690
2822
2823
5326
5327

691
2824
2825
5328
5329

692
2826
2827
5330
5331

693
2828
2829
5332
5333

694
2830
2831
5334
5335

695
2832
2833
5336
5337

696
2834
2835
5338
5339

697
2836
2837
5340
5341

698
2838
2839
5342
5343

699
2840
2841
5344
5345

700
2842
2843
5346
5347

701
2844
2845
5348
5349

702
2846
2847
5350
5351

703
2848
2849
5352
5353

704
2850
2851
5354
5355

705
2852
2853
5356
5357

706
2854
2855
5358
5359

707
2856
2857
5360
5361

708
2858
2859
5362
5363

709
2860
2861
5364
5365

710
2862
2863
5366
5367

711
2864
2865
5368
5369

712
2866
2867
5370
5371

713
2868
2869
5372
5373

714
2870
2871
5374
5375

715
2872
2873
5376
5377

716
2874
2875
5378
5379

717
2876
2877
5380
5381

718
2878
2879
5382
5383

719
2880
2881
5384
5385

720
2882
2883
5386
5387

721
2886
2887
5390
5391

722
2888
2889
5392
5393

723
2884
2885
5388
5389

724
2890
2891
5394
5395

725
2892
2893
5396
5397

726
2894
2895
5398
5399

727
2896
2897
5400
5401

728
2900
2901
5404
5405

729
2902
2903
5406
5407

730
2904
2905
5408
5409

731
2906
2907
5410
5411

732
2908
2909
5412
5413

733
2910
2911
5414
5415

734
2912
2913
5416
5417

735
2914
2915
5418
5419

736
2916
2917
5420
5421

737
2918
2919
5422
5423

738
2920
2921
5424
5425

739
2922
2923
5426
5427

740
2924
2925
5428
5429

741
2926
2927
5430
5431

742
2928
2929
5432
5433

743
2930
2931
5434
5435

744
2932
2933
5436
5437

745
2934
2935
5438
5439

746
2936
2937
5440
5441

747
2938
2939
5442
5443

748
2940
2941
5444
5445

749
2942
2943
5446
5447

750
2944
2945
5448
5449

751
2946
2947
5450
5451

752
2948
2949
5452
5453

753
2952
2953
5456
5457

754
2954
2955
5458
5459

755
2956
2957
5460
5461

756
2958
2959
5462
5463

757
2960
2961
5464
5465

758
2962
2963
5466
5467

759
2964
2965
5468
5469

760
2966
2967
5470
5471

761
2968
2969
5472
5473

762
2970
2971
5474
5475

763
2972
2973
5476
5477

764
2974
2975
5478
5479

765
2976
2977
5480
5481

766
2978
2979
5482
5483

767
2980
2981
5484
5485

768
2982
2983
5486
5487

769
2984
2985
5488
5489

770
2986
2987
5490
5491

771
2990
2991
5494
5495

772
2992
2993
5496
5497

773
2994
2995
5498
5499

774
2996
2997
5500
5501

775
2998
2999
5502
5503

776
3000
3001
5504
5505

777
3002
3003
5506
5507

778
3004
3005
5508
5509

779
3006
3007
5510
5511

780
3008
3009
5512
5513

781
3010
3011
5514
5515

782
3012
3013
5516
5517

783
3014
3015
5518
5519

784
3016
3017
5520
5521

785
3020
3021
5524
5525

786
3022
3023
5526
5527

787
3024
3025
5528
5529

788
3026
3027
5530
5531

789
3028
3029
5532
5533

790
3030
3031
5534
5535

791
3032
3033
5536
5537

792
3034
3035
5538
5539

793
3036
3037
5540
5541

794
3038
3039
5542
5543

795
3040
3041
5544
5545

796
3042
3043
5546
5547

797
3044
3045
5548
5549

798
3046
3047
5550
5551

799
3048
3049
5552
5553

800
3050
3051
5554
5555

801
3052
3053
5556
5557

802
3054
3055
5558
5559

803
3056
3057
5560
5561

804
3058
3059
5562
5563

805
3060
3061
5564
5565

806
3062
3063
5566
5567

807
3064
3065
5568
5569

808
3066
3067
5570
5571

809
3068
3069
5572
5573

810
3070
3071
5574
5575

811
3072
3073
5576
5577

812
3074
3075
5578
5579

813
3076
3077
5580
5581

814
3078
3079
5582
5583

815
3080
3081
5584
5585

816
3082
3083
5586
5587

817
3084
3085
5588
5589

818
3086
3087
5590
5591

819
3088
3089
5592
5593

820
3090
3091
5594
5595

821
3092
3093
5596
5597

822
3094
3095
5598
5599

823
3096
3097
5600
5601

824
3100
3101
5604
5605

825
3102
3103
5606
5607

826
3104
3105
5608
5609

827
3106
3107
5610
5611

828
3108
3109
5612
5613

829
3110
3111
5614
5615

830
3112
3113
5616
5617

831
3114
3115
5618
5619

832
3116
3117
5620
5621

833
3120
3121
5624
5625

834
3124
3125
5628
5629

835
3122
3123
5626
5627

836
3128
3129
5632
5633

837
3130
3131
5634
5635

838
3132
3133
5636
5637

839
3134
3135
5638
5639

840
3136
3137
5640
5641

841
3138
3139
5642
5643

842
3140
3141
5644
5645

843
3142
3143
5646
5647

844
3144
3145
5648
5649

845
3146
3147
5650
5651

846
3148
3149
5652
5653

847
3150
3151
5654
5655

848
3152
3153
5656
5657

849
3154
3155
5658
5659

850
3156
3157
5660
5661

851
3158
3159
5662
5663

852
3160
3161
5664
5665

853
3164
3165
5668
5669

854
3162
3163
5666
5667

855
3166
3167
5670
5671

856
3168
3169
5672
5673

857
3170
3171
5674
5675

858
3172
3173
5676
5677

859
3174
3175
5678
5679

860
3176
3177
5680
5681

861
3180
3181
5684
5685

862
3178
3179
5682
5683

863
3182
3183
5686
5687

864
3184
3185
5688
5689

865
3186
3187
5690
5691

866
3188
3189
5692
5693

867
3190
3191
5694
5695

868
3192
3193
5696
5697

869
3194
3195
5698
5699

870
3196
3197
5700
5701

871
3198
3199
5702
5703

872
3200
3201
5704
5705

873
3202
3203
5706
5707

874
3204
3205
5708
5709

875
3206
3207
5710
5711

876
3210
3211
5714
5715

877
3212
3213
5716
5717

878
3214
3215
5718
5719

879
3216
3217
5720
5721

880
3218
3219
5722
5723

881
3220
3221
5724
5725

882
3222
3223
5726
5727

883
3224
3225
5728
5729

884
3226
3227
5730
5731

885
3228
3229
5732
5733

886
3230
3231
5734
5735

887
3232
3233
5736
5737

888
3234
3235
5738
5739

889
3236
3237
5740
5741

890
3238
3239
5742
5743

891
3240
3241
5744
5745

892
3244
3245
5748
5749

893
3246
3247
5750
5751

894
3248
3249
5752
5753

895
3250
3251
5754
5755

896
3252
3253
5756
5757

897
3254
3255
5758
5759

898
3256
3257
5760
5761

899
3258
3259
5762
5763

900
3260
3261
5764
5765

901
3262
3263
5766
5767

902
3264
3265
5768
5769

903
3266
3267
5770
5771

904
3268
3269
5772
5773

905
3270
3271
5774
5775

906
3272
3273
5776
5777

907
3274
3275
5778
5779

908
3276
3277
5780
5781

909
3278
3279
5782
5783

910
3280
3281
5784
5785

911
3282
3283
5786
5787

912
3284
3285
5788
5789

913
3286
3287
5790
5791

914
3288
3289
5792
5793

915
3290
3291
5794
5795

916
3292
3293
5796
5797

917
3296
3297
5800
5801

918
3298
3299
5802
5803

919
3300
3301
5804
5805

920
3302
3303
5806
5807

921
3304
3305
5808
5809

922
3306
3307
5810
5811

923
3308
3309
5812
5813

924
3310
3311
5814
5815

925
3316
3317
5820
5821

926
3314
3315
5818
5819

927
3324
3325
5828
5829

928
3326
3327
5830
5831

929
3328
3329
5832
5833

930
3330
3331
5834
5835

931
3338
3339
5842
5843

932
3336
3337
5840
5841

933
3340
3341
5844
5845

934
3342
3343
5846
5847

935
3344
3345
5848
5849

936
3346
3347
5850
5851

937
3348
3349
5852
5853

938
3350
3351
5854
5855

939
3352
3353
5856
5857

940
3354
3355
5858
5859

941
3356
3357
5860
5861

942
3360
3361
5864
5865

943
3362
3363
5866
5867

944
3364
3365
5868
5869

945
3366
3367
5870
5871

946
3368
3369
5872
5873

947
3370
3371
5874
5875

948
3374
3375
5878
5879

949
3378
3379
5882
5883

950
3376
3377
5880
5881

951
3380
3381
5884
5885

952
3382
3383
5886
5887

953
3384
3385
5888
5889

954
3386
3387
5890
5891

955
3388
3389
5892
5893

956
3390
3391
5894
5895

957
3392
3393
5896
5897

958
3394
3395
5898
5899

959
3396
3397
5900
5901

960
3398
3399
5902
5903

961
3400
3401
5904
5905

962
3402
3403
5906
5907

963
3404
3405
5908
5909

964
3406
3407
5910
5911

965
3408
3409
5912
5913

966
3410
3411
5914
5915

967
3412
3413
5916
5917

968
3414
3415
5918
5919

969
3416
3417
5920
5921

970
3418
3419
5922
5923

971
3420
3421
5924
5925

972
3422
3423
5926
5927

973
3424
3425
5928
5929

974
3426
3427
5930
5931

975
3428
3429
5932
5933

976
3430
3431
5934
5935

977
3432
3433
5936
5937

978
3434
3435
5938
5939

979
3436
3437
5940
5941

980
3438
3439
5942
5943

981
3440
3441
5944
5945

982
3442
3443
5946
5947

983
3444
3445
5948
5949

984
3446
3447
5950
5951

985
3448
3449
5952
5953

986
3450
3451
5954
5955

987
3454
3455
5958
5959

988
3456
3457
5960
5961

989
3458
3459
5962
5963

990
3460
3461
5964
5965

991
3462
3463
5966
5967

992
3464
3465
5968
5969

993
3466
3467
5970
5971

994
3468
3469
5972
5973

995
3470
3471
5974
5975

996
3472
3473
5976
5977

997
3474
3475
5978
5979

998
3476
3477
5980
5981

999
3478
3479
5982
5983

1000
3480
3481
5984
5985

1001
3482
3483
5986
5987

1002
3484
3485
5988
5989

1003
3486
3487
5990
5991

1004
3488
3489
5992
5993

1005
3490
3491
5994
5995

1006
3494
3495
5998
5999

1007
3496
3497
6000
6001

1008
3498
3499
6002
6003

1009
3500
3501
6004
6005

1010
3502
3503
6006
6007

1011
3504
3505
6008
6009

1012
3506
3507
6010
6011

1013
3508
3509
6012
6013

1014
3510
3511
6014
6015

1015
3512
3513
6016
6017

1016
3516
3517
6020
6021

1017
3518
3519
6022
6023

1018
3520
3521
6024
6025

1019
3522
3523
6026
6027

1020
3524
3525
6028
6029

1021
3526
3527
6030
6031

1022
3528
3529
6032
6033

1023
3530
3531
6034
6035

1024
3532
3533
6036
6037

1025
3534
3535
6038
6039

1026
3536
3537
6040
6041

1027
3542
3543
6046
6047

1028
3544
3545
6048
6049

1029
3546
3547
6050
6051

1030
3548
3549
6052
6053

1031
3550
3551
6054
6055

1032
3552
3553
6056
6057

1033
3554
3555
6058
6059

1034
3556
3557
6060
6061

1035
3558
3559
6062
6063

1036
3560
3561
6064
6065

1037
3562
3563
6066
6067

1038
3564
3565
6068
6069

1039
3566
3567
6070
6071

1040
3568
3569
6072
6073

1041
3570
3571
6074
6075

1042
3572
3573
6076
6077

1043
3574
3575
6078
6079

1044
3582
3583
6086
6087

1045
3584
3585
6088
6089

1046
3586
3587
6090
6091

1047
3588
3589
6092
6093

1048
3592
3593
6096
6097

1049
3594
3595
6098
6099

1050
3596
3597
6100
6101

1051
3598
3599
6102
6103

1052
3600
3601
6104
6105

1053
3602
3603
6106
6107

1054
3604
3605
6108
6109

1055
3606
3607
6110
6111

1056
3608
3609
6112
6113

1057
3610
3611
6114
6115

1058
3612
3613
6116
6117

1059
3614
3615
6118
6119

1060
3616
3617
6120
6121

1061
3618
3619
6122
6123

1062
3620
3621
6124
6125

1063
3622
3623
6126
6127

1064
3624
3625
6128
6129

1065
3626
3627
6130
6131

1066
3628
3629
6132
6133

1067
3630
3631
6134
6135

1068
3632
3633
6136
6137

1069
3634
3635
6138
6139

1070
3636
3637
6140
6141

1071
3638
3639
6142
6143

1072
3640
3641
6144
6145

1073
3642
3643
6146
6147

1074
3644
3645
6148
6149

1075
3646
3647
6150
6151

1076
3648
3649
6152
6153

1077
3652
3653
6156
6157

1078
3654
3655
6158
6159

1079
3656
3657
6160
6161

1080
3658
3659
6162
6163

1081
3660
3661
6164
6165

1082
3662
3663
6166
6167

1083
3666
3667
6170
6171

1084
3668
3669
6172
6173

1085
3672
3673
6176
6177

1086
3674
3675
6178
6179

1087
3676
3677
6180
6181

1088
3678
3679
6182
6183

1089
3680
3681
6184
6185

1090
3682
3683
6186
6187

1091
3684
3685
6188
6189

1092
3686
3687
6190
6191

1093
3688
3689
6192
6193

1094
3690
3691
6194
6195

1095
3692
3693
6196
6197

1096
3694
3695
6198
6199

1097
3696
3697
6200
6201

1098
3698
3699
6202
6203

1099
3702
3703
6206
6207

1100
3700
3701
6204
6205

1101
3704
3705
6208
6209

1102
3706
3707
6210
6211

1103
3708
3709
6212
6213

1104
3714
3715
6218
6219

1105
3720
3721
6224
6225

1106
3722
3723
6226
6227

1107
3724
3725
6228
6229

1108
3726
3727
6230
6231

1109
3728
3729
6232
6233

1110
3730
3731
6234
6235

1111
3732
3733
6236
6237

1112
3734
3735
6238
6239

1113
3736
3737
6240
6241

1114
3740
3741
6244
6245

1115
3738
3739
6242
6243

1116
3742
3743
6246
6247

1117
3744
3745
6248
6249

1118
3746
3747
6250
6251

1119
3748
3749
6252
6253

1120
3750
3751
6254
6255

1121
3754
3755
6258
6259

1122
3756
3757
6260
6261

1123
3758
3759
6262
6263

1124
3760
3761
6264
6265

1125
3762
3763
6266
6267

1126
3766
3767
6270
6271

1127
3770
3771
6274
6275

1128
3772
3773
6276
6277

1129
3776
3777
6280
6281

1130
3774
3775
6278
6279

1131
3778
3779
6282
6283

1132
3780
3781
6284
6285

1133
3782
3783
6286
6287

1134
3784
3785
6288
6289

1135
3788
3789
6292
6293

1136
3786
3787
6290
6291

1137
3794
3795
6298
6299

1138
1372
1373
3876
3877

1139
1378
1379
3882
3883

1140
1384
1385
3888
3889

1141
1390
1391
3894
3895

1142
1408
1409
3912
3913

1143
1436
1437
3940
3941

1144
1442
1443
3946
3947

1145
1466
1467
3970
3971

1146
1474
1475
3978
3979

1147
1528
1529
4032
4033

1148
1560
1561
4064
4065

1149
1578
1579
4082
4083

1150
1600
1601
4104
4105

1151
1602
1603
4106
4107

1152
1608
1609
4112
4113

1153
1610
1611
4114
4115

1154
1654
1655
4158
4159

1155
1660
1661
4164
4165

1156
1680
1681
4184
4185

1157
1682
1683
4186
4187

1158
1692
1693
4196
4197

1159
1702
1703
4206
4207

1160
1706
1707
4210
4211

1161
1716
1717
4220
4221

1162
1718
1719
4222
4223

1163
1730
1731
4234
4235

1164
1748
1749
4252
4253

1165
1780
1781
4284
4285

1166
1794
1795
4298
4299

1167
1798
1799
4302
4303

1168
1814
1815
4318
4319

1169
1816
1817
4320
4321

1170
1820
1821
4324
4325

1171
1822
1823
4326
4327

1172
1830
1831
4334
4335

1173
1832
1833
4336
4337

1174
1838
1839
4342
4343

1175
1844
1845
4348
4349

1176
1870
1871
4374
4375

1177
1880
1881
4384
4385

1178
1882
1883
4386
4387

1179
1884
1885
4388
4389

1180
1932
1933
4436
4437

1181
1968
1969
4472
4473

1182
1982
1983
4486
4487

1183
2036
2037
4540
4541

1184
2086
2087
4590
4591

1185
2098
2099
4602
4603

1186
2126
2127
4630
4631

1187
2132
2133
4636
4637

1188
2166
2167
4670
4671

1189
2168
2169
4672
4673

1190
2184
2185
4688
4689

1191
2240
2241
4744
4745

1192
2276
2277
4780
4781

1193
2300
2301
4804
4805

1194
2302
2303
4806
4807

1195
2330
2331
4834
4835

1196
2336
2337
4840
4841

1197
2448
2449
4952
4953

1198
2452
2453
4956
4957

1199
2484
2485
4988
4989

1200
2512
2513
5016
5017

1201
2530
2531
5034
5035

1202
2540
2541
5044
5045

1203
2542
2543
5046
5047

1204
2584
2585
5088
5089

1205
2586
2587
5090
5091

1206
2588
2589
5092
5093

1207
2614
2615
5118
5119

1208
2670
2671
5174
5175

1209
2694
2695
5198
5199

1210
2708
2709
5212
5213

1211
2730
2731
5234
5235

1212
2734
2735
5238
5239

1213
2746
2747
5250
5251

1214
2802
2803
5306
5307

1215
2898
2899
5402
5403

1216
2950
2951
5454
5455

1217
2988
2989
5492
5493

1218
3018
3019
5522
5523

1219
3098
3099
5602
5603

1220
3118
3119
5622
5623

1221
3126
3127
5630
5631

1222
3208
3209
5712
5713

1223
3242
3243
5746
5747

1224
3294
3295
5798
5799

1225
3312
3313
5816
5817

1226
3318
3319
5822
5823

1227
3320
3321
5824
5825

1228
3322
3323
5826
5827

1229
3332
3333
5836
5837

1230
3334
3335
5838
5839

1231
3358
3359
5862
5863

1232
3372
3373
5876
5877

1233
3452
3453
5956
5957

1234
3492
3493
5996
5997

1235
3514
3515
6018
6019

1236
3538
3539
6042
6043

1237
3540
3541
6044
6045

1238
3576
3577
6080
6081

1239
3578
3579
6082
6083

1240
3580
3581
6084
6085

1241
3590
3591
6094
6095

1242
3650
3651
6154
6155

1243
3664
3665
6168
6169

1244
3670
3671
6174
6175

1245
3710
3711
6214
6215

1246
3712
3713
6216
6217

1247
3716
3717
6220
6221

1248
3718
3719
6222
6223

1249
3752
3753
6256
6257

1250
3764
3765
6268
6269

1251
3768
3769
6272
6273

1252
3790
3791
6294
6295

1253
3792
3793
6296
6297

1254
6300
6301
6376
6377

1255
6302
6303
6378
6379

1256
6304
6305
6380
6381

1257
6306
6307
6382
6383

1258
6308
6309
6384
6385

1259
6310
6311
6386
6387

1260
6312
6313
6388
6389

1261
6314
6315
6390
6391

1262
6316
6317
6392
6393

1263
6318
6319
6394
6395

1264
6320
6321
6396
6397

1265
6322
6323
6398
6399

1266
6324
6325
6400
6401

1267
6326
6327
6402
6403

1268
6328
6329
6404
6405

1269
6330
6331
6406
6407

1270
6332
6333
6408
6409

1271
6334
6335
6410
6411

1272
6336
6337
6412
6413

1273
6338
6339
6414
6415

1274
6340
6341
6416
6417

1275
6342
6343
6418
6419

1276
6344
6345
6420
6421

1277
6346
6347
6422
6423

1278
6348
6349
6424
6425

1279
6350
6351
6426
6427

1280
6352
6353
6428
6429

1281
6354
6355
6430
6431

1282
6356
6357
6432
6433

1283
6358
6359
6434
6435

1284
6360
6361
6436
6437

1285
6362
6363
6438
6439

1286
6364
6365
6440
6441

1287
6366
6367
6442
6443

1288
6368
6369
6444
6445

1289
6370
6371
6446
6447

1290
6372
6373
6448
6449

1291
6374
6375
6450
6451

[0585]

6

SEQ ID
or.
5′position

1292
F
1229848

1293
F
1227874

1294
F
1018

1295
F
1229162

1296
F
1588

1297
F
1229711

1298
F
2253

1299
F
369

1300
F
3381

1301
F
1508

1302
F
4042

1303
F
2126

1304
F
5735

1305
F
3843

1306
F
7832

1307
F
5909

1308
F
8887

1309
F
7010

1310
F
10139

1311
F
8175

1312
F
10640

1313
F
8799

1314
F
10997

1315
F
9037

1316
F
12458

1317
F
10572

1318
F
14187

1319
F
12365

1320
F
15529

1321
F
13629

1322
F
17626

1323
F
15699

1324
F
20909

1325
F
19006

1326
F
21800

1327
F
19927

1328
F
23462

1329
F
21557

1330
F
25637

1331
F
23729

1332
F
25997

1333
F
24071

1334
F
26727

1335
F
24828

1336
F
27528

1337
F
25628

1338
F
28643

1339
F
26765

1340
F
29202

1341
F
27313

1342
F
29793

1343
F
27835

1344
F
31488

1345
F
29639

1346
F
31957

1347
F
30050

1348
F
33570

1349
F
31666

1350
F
34564

1351
F
32664

1352
F
35783

1353
F
33875

1354
F
37597

1355
F
35741

1356
F
39135

1357
F
37236

1358
F
38939

1359
F
37038

1360
F
40872

1361
F
38972

1362
F
42825

1363
F
40923

1364
F
43563

1365
F
41652

1366
F
44531

1367
F
42623

1368
F
45150

1369
F
43250

1370
F
45478

1371
F
43579

1372
F
46755

1373
F
44874

1374
F
47347

1375
F
45386

1376
F
47818

1377
F
45897

1378
F
48893

1379
F
46995

1380
F
49907

1381
F
48000

1382
F
51088

1383
F
49169

1384
F
52651

1385
F
50721

1386
F
53065

1387
F
51176

1388
F
53516

1389
F
51611

1390
F
54242

1391
F
52351

1392
F
55058

1393
F
53159

1394
F
56274

1395
F
54348

1396
F
57078

1397
F
55156

1398
F
58343

1399
F
56392

1400
F
61103

1401
F
59177

1402
F
59701

1403
F
57802

1404
F
61887

1405
F
59971

1406
F
62255

1407
F
60348

1408
F
63515

1409
F
61557

1410
F
63657

1411
F
61761

1412
F
64088

1413
F
62196

1414
F
64422

1415
F
62537

1416
F
65072

1417
F
63140

1418
F
65978

1419
F
64088

1420
F
67046

1421
F
65146

1422
F
67466

1423
F
65580

1424
F
68569

1425
F
66686

1426
F
68609

1427
F
66688

1428
F
70423

1429
F
68479

1430
F
71099

1431
F
69206

1432
F
71829

1433
F
69935

1434
F
73745

1435
F
71931

1436
F
76942

1437
F
75022

1438
F
77404

1439
F
75556

1440
F
78133

1441
F
76192

1442
F
79079

1443
F
77122

1444
F
79471

1445
F
77481

1446
F
79670

1447
F
77816

1448
F
80236

1449
F
78356

1450
F
81108

1451
F
79182

1452
F
83024

1453
F
81158

1454
F
83786

1455
F
81886

1456
F
84739

1457
F
82821

1458
F
84866

1459
F
82967

1460
F
85175

1461
F
83240

1462
F
85690

1463
F
83790

1464
F
86397

1465
F
84507

1466
F
88470

1467
F
86563

1468
F
89038

1469
F
87121

1470
F
91017

1471
F
89146

1472
F
93075

1473
F
91147

1474
F
93846

1475
F
91948

1476
F
94410

1477
F
92561

1478
F
95447

1479
F
93541

1480
F
96074

1481
F
94197

1482
F
97706

1483
F
95841

1484
F
98142

1485
F
96292

1486
F
99925

1487
F
98011

1488
F
101229

1489
F
99338

1490
F
101429

1491
F
99552

1492
F
102137

1493
F
100237

1494
F
102600

1495
F
100657

1496
F
103330

1497
F
101429

1498
F
103877

1499
F
101966

1500
F
104336

1501
F
102469

1502
F
108182

1503
F
106280

1504
F
111814

1505
F
109911

1506
F
112412

1507
F
110553

1508
F
113442

1509
F
111571

1510
F
113891

1511
F
112010

1512
F
114990

1513
F
113112

1514
F
115684

1515
F
113776

1516
F
116526

1517
F
114656

1518
F
117731

1519
F
115825

1520
F
118292

1521
F
116389

1522
F
119593

1523
F
117685

1524
F
120231

1525
F
118292

1526
F
122278

1527
F
120382

1528
F
122610

1529
F
120682

1530
F
123309

1531
F
121390

1532
F
126113

1533
F
124213

1534
F
128975

1535
F
127091

1536
F
134603

1537
F
132806

1538
F
136249

1539
F
134352

1540
F
137680

1541
F
135756

1542
F
137680

1543
F
135799

1544
F
138035

1545
F
136135

1546
F
139266

1547
F
137363

1548
F
140208

1549
F
138351

1550
F
141636

1551
F
139735

1552
F
142808

1553
F
140900

1554
F
144272

1555
F
142372

1556
F
145217

1557
F
143335

1558
F
146527

1559
F
144645

1560
F
146965

1561
F
145086

1562
F
147455

1563
F
145501

1564
F
148810

1565
F
146904

1566
F
151964

1567
F
150062

1568
F
154064

1569
F
152113

1570
F
154888

1571
F
152963

1572
F
155418

1573
F
153558

1574
F
156528

1575
F
154606

1576
F
157433

1577
F
155516

1578
F
158771

1579
F
156842

1580
F
159105

1581
F
157219

1582
F
159657

1583
F
157761

1584
F
160240

1585
F
158316

1586
F
160675

1587
F
158778

1588
F
161289

1589
F
159402

1590
F
161918

1591
F
159979

1592
F
162214

1593
F
160297

1594
F
163996

1595
F
162045

1596
F
165189

1597
F
163288

1598
F
166730

1599
F
164828

1600
F
168243

1601
F
166327

1602
F
168907

1603
F
167064

1604
F
169129

1605
F
167294

1606
F
170632

1607
F
168692

1608
F
171229

1609
F
169381

1610
F
171553

1611
F
169614

1612
F
172433

1613
F
170533

1614
F
173217

1615
F
171316

1616
F
174567

1617
F
172680

1618
F
175342

1619
F
173479

1620
F
175709

1621
F
173752

1622
F
176909

1623
F
175009

1624
F
176704

1625
F
174761

1626
F
177608

1627
F
175709

1628
F
179259

1629
F
177384

1630
F
179719

1631
F
177800

1632
F
181629

1633
F
179743

1634
F
182851

1635
F
180952

1636
F
184230

1637
F
182335

1638
F
184870

1639
F
182962

1640
F
185241

1641
F
183348

1642
F
185611

1643
F
183685

1644
F
186336

1645
F
184445

1646
F
188059

1647
F
186171

1648
F
190828

1649
F
188956

1650
F
191294

1651
F
189428

1652
F
192686

1653
F
190788

1654
F
193380

1655
F
191474

1656
F
193388

1657
F
191474

1658
F
193977

1659
F
192059

1660
F
195480

1661
F
193585

1662
F
195868

1663
F
193969

1664
F
197913

1665
F
196013

1666
F
199088

1667
F
197213

1668
F
202776

1669
F
200876

1670
F
204467

1671
F
202497

1672
F
205584

1673
F
203664

1674
F
206940

1675
F
205063

1676
F
207560

1677
F
205587

1678
F
208048

1679
F
206139

1680
F
209923

1681
F
208023

1682
F
210455

1683
F
208569

1684
F
211049

1685
F
209147

1686
F
211596

1687
F
209705

1688
F
212226

1689
F
210311

1690
F
213832

1691
F
211960

1692
F
214866

1693
F
212921

1694
F
215173

1695
F
213307

1696
F
215800

1697
F
213957

1698
F
216489

1699
F
214549

1700
F
216980

1701
F
215100

1702
F
217665

1703
F
215793

1704
F
218039

1705
F
216071

1706
F
218476

1707
F
216560

1708
F
218769

1709
F
216809

1710
F
220020

1711
F
218128

1712
F
221210

1713
F
219275

1714
F
222497

1715
F
220601

1716
F
223292

1717
F
221403

1718
F
223775

1719
F
221877

1720
F
224250

1721
F
222377

1722
F
224906

1723
F
223008

1724
F
225283

1725
F
223418

1726
F
226670

1727
F
224770

1728
F
227849

1729
F
225937

1730
F
228185

1731
F
226269

1732
F
228393

1733
F
226512

1734
F
229334

1735
F
227499

1736
F
230761

1737
F
228846

1738
F
231287

1739
F
229334

1740
F
231731

1741
F
229927

1742
F
232865

1743
F
231027

1744
F
232865

1745
F
231027

1746
F
234315

1747
F
232394

1748
F
234823

1749
F
232865

1750
F
235154

1751
F
233245

1752
F
236429

1753
F
234520

1754
F
237268

1755
F
235271

1756
F
238047

1757
F
236162

1758
F
238636

1759
F
236736

1760
F
239957

1761
F
238047

1762
F
241373

1763
F
239482

1764
F
242017

1765
F
240072

1766
F
242740

1767
F
240829

1768
F
243281

1769
F
241373

1770
F
244244

1771
F
242345

1772
F
246052

1773
F
244179

1774
F
247581

1775
F
245697

1776
F
249216

1777
F
247244

1778
F
251003

1779
F
249137

1780
F
252064

1781
F
250189

1782
F
252900

1783
F
251000

1784
F
253718

1785
F
251855

1786
F
254993

1787
F
253138

1788
F
256414

1789
F
254509

1790
F
257283

1791
F
255383

1792
F
257279

1793
F
255379

1794
F
258061

1795
F
256107

1796
F
259005

1797
F
257128

1798
F
261075

1799
F
259195

1800
F
261551

1801
F
259650

1802
F
262535

1803
F
260611

1804
F
262960

1805
F
261060

1806
F
264509

1807
F
262614

1808
F
265837

1809
F
263925

1810
F
266239

1811
F
264367

1812
F
267185

1813
F
265286

1814
F
267909

1815
F
266037

1816
F
268594

1817
F
266756

1818
F
269299

1819
F
267505

1820
F
271044

1821
F
269121

1822
F
271737

1823
F
269838

1824
F
272558

1825
F
270645

1826
F
273007

1827
F
271098

1828
F
273463

1829
F
271500

1830
F
273922

1831
F
272057

1832
F
275083

1833
F
273094

1834
F
275495

1835
F
273554

1836
F
275739

1837
F
273878

1838
F
276229

1839
F
274371

1840
F
276548

1841
F
274638

1842
F
277098

1843
F
275178

1844
F
277358

1845
F
275448

1846
F
277609

1847
F
275739

1848
F
278314

1849
F
276386

1850
F
279310

1851
F
277385

1852
F
280627

1853
F
278702

1854
F
281471

1855
F
279559

1856
F
282239

1857
F
280288

1858
F
283832

1859
F
281933

1860
F
284384

1861
F
282486

1862
F
285373

1863
F
283473

1864
F
285919

1865
F
284059

1866
F
286742

1867
F
284879

1868
F
287216

1869
F
285329

1870
F
287671

1871
F
285751

1872
F
288273

1873
F
286323

1874
F
288618

1875
F
286685

1876
F
288273

1877
F
286323

1878
F
289723

1879
F
287836

1880
F
289508

1881
F
287667

1882
F
290750

1883
F
288858

1884
F
291142

1885
F
289253

1886
F
291702

1887
F
289812

1888
F
292522

1889
F
290633

1890
F
293035

1891
F
291142

1892
F
293731

1893
F
291786

1894
F
294530

1895
F
292670

1896
F
294367

1897
F
292513

1898
F
296092

1899
F
294209

1900
F
297611

1901
F
295757

1902
F
298027

1903
F
296092

1904
F
298555

1905
F
296582

1906
F
299403

1907
F
297511

1908
F
300409

1909
F
298579

1910
F
301332

1911
F
299433

1912
F
302215

1913
F
300282

1914
F
302492

1915
F
300618

1916
F
303627

1917
F
301730

1918
F
304350

1919
F
302487

1920
F
305173

1921
F
303226

1922
F
306244

1923
F
304350

1924
F
307232

1925
F
305310

1926
F
307799

1927
F
305877

1928
F
309173

1929
F
307301

1930
F
310158

1931
F
308306

1932
F
311020

1933
F
309118

1934
F
311031

1935
F
309126

1936
F
311552

1937
F
309658

1938
F
312510

1939
F
310614

1940
F
313134

1941
F
311255

1942
F
313674

1943
F
311717

1944
F
314490

1945
F
312633

1946
F
315306

1947
F
313355

1948
F
315932

1949
F
314033

1950
F
318434

1951
F
316516

1952
F
320876

1953
F
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1954
F
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1955
F
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1956
F
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1957
F
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1958
F
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1959
F
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1960
F
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1961
F
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1962
F
325117

1963
F
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1964
F
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1965
F
324254

1966
F
327607

1967
F
325695

1968
F
328162

1969
F
326262

1970
F
328630

1971
F
326723

1972
F
329134

1973
F
327178

1974
F
330734

1975
F
328810

1976
F
332123

1977
F
330252

1978
F
334575

1979
F
332660

1980
F
335884

1981
F
333980

1982
F
337129

1983
F
335202

1984
F
337910

1985
F
335955

1986
F
338746

1987
F
336795

1988
F
339217

1989
F
337362

1990
F
339999

1991
F
338083

1992
F
343144

1993
F
341266

1994
F
343699

1995
F
341813

1996
F
344108

1997
F
342204

1998
F
344851

1999
F
342933

2000
F
346148

2001
F
344219

2002
F
346493

2003
F
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2004
F
346815

2005
F
344907

2006
F
347836

2007
F
345956

2008
F
350379

2009
F
348432

2010
F
350856

2011
F
348951

2012
F
352008

2013
F
350106

2014
F
353209

2015
F
351305

2016
F
354224

2017
F
352312

2018
F
354781

2019
F
352871

2020
F
355223

2021
F
353261

2022
F
355393

2023
F
353519

2024
F
358901

2025
F
357001

2026
F
356594

2027
F
354692

2028
F
359240

2029
F
357374

2030
F
359721

2031
F
357763

2032
F
361071

2033
F
359240

2034
F
363605

2035
F
361731

2036
F
364142

2037
F
362246

2038
F
364567

2039
F
362708

2040
F
365039

2041
F
363184

2042
F
365445

2043
F
363517

2044
F
367040

2045
F
365144

2046
F
368825

2047
F
366993

2048
F
369698

2049
F
367760

2050
F
370141

2051
F
368239

2052
F
372329

2053
F
370375

2054
F
372779

2055
F
370881

2056
F
373223

2057
F
371342

2058
F
373939

2059
F
372017

2060
F
374849

2061
F
372953

2062
F
375351

2063
F
373487

2064
F
376316

2065
F
374416

2066
F
377737

2067
F
375828

2068
F
379537

2069
F
377660

2070
F
380033

2071
F
378160

2072
F
380789

2073
F
378889

2074
F
381238

2075
F
379279

2076
F
382969

2077
F
381124

2078
F
383293

2079
F
381425

2080
F
385178

2081
F
383278

2082
F
386271

2083
F
384392

2084
F
386780

2085
F
384891

2086
F
389383

2087
F
387504

2088
F
389901

2089
F
388001

2090
F
390700

2091
F
388732

2092
F
391612

2093
F
389763

2094
F
392346

2095
F
390463

2096
F
392540

2097
F
390639

2098
F
393487

2099
F
391609

2100
F
393904

2101
F
392025

2102
F
394703

2103
F
392782

2104
F
395024

2105
F
393098

2106
F
395705

2107
F
393791

2108
F
397607

2109
F
395705

2110
F
398807

2111
F
396957

2112
F
399848

2113
F
397886

2114
F
400914

2115
F
399008

2116
F
401183

2117
F
399301

2118
F
401964

2119
F
400060

2120
F
403450

2121
F
401527

2122
F
404124

2123
F
402206

2124
F
405765

2125
F
403865

2126
F
407131

2127
F
405243

2128
F
407456

2129
F
405563

2130
F
408841

2131
F
406901

2132
F
410478

2133
F
408573

2134
F
410725

2135
F
408832

2136
F
412263

2137
F
410363

2138
F
414168

2139
F
412268

2140
F
415013

2141
F
413111

2142
F
415636

2143
F
413743

2144
F
417033

2145
F
415114

2146
F
417163

2147
F
415332

2148
F
418166

2149
F
416265

2150
F
420186

2151
F
418259

2152
F
420697

2153
F
418861

2154
F
421313

2155
F
419437

2156
F
422172

2157
F
420342

2158
F
423342

2159
F
421412

2160
F
424008

2161
F
422073

2162
F
424585

2163
F
422711

2164
F
426021

2165
F
424107

2166
F
427407

2167
F
425513

2168
F
427936

2169
F
426053

2170
F
428592

2171
F
426717

2172
F
430475

2173
F
428558

2174
F
431378

2175
F
429417

2176
F
431927

2177
F
430046

2178
F
432609

2179
F
430710

2180
F
433005

2181
F
431082

2182
F
433712

2183
F
431812

2184
F
436521

2185
F
434640

2186
F
436897

2187
F
435057

2188
F
439741

2189
F
437882

2190
F
438296

2191
F
436377

2192
F
440475

2193
F
438538

2194
F
440281

2195
F
438394

2196
F
440989

2197
F
439080

2198
F
442121

2199
F
440252

2200
F
442121

2201
F
440221

2202
F
442780

2203
F
440879

2204
F
443285

2205
F
441384

2206
F
444276

2207
F
442406

2208
F
444472

2209
F
442568

2210
F
444960

2211
F
443040

2212
F
445556

2213
F
443681

2214
F
447565

2215
F
445676

2216
F
448396

2217
F
446496

2218
F
450057

2219
F
448133

2220
F
450444

2221
F
448555

2222
F
450988

2223
F
449054

2224
F
452212

2225
F
450329

2226
F
453450

2227
F
451581

2228
F
454643

2229
F
452718

2230
F
456004

2231
F
454124

2232
F
456785

2233
F
454897

2234
F
457749

2235
F
455856

2236
F
458132

2237
F
456205

2238
F
459216

2239
F
457348

2240
F
460692

2241
F
458792

2242
F
460133

2243
F
458230

2244
F
461228

2245
F
459327

2246
F
462183

2247
F
460269

2248
F
463120

2249
F
461220

2250
F
464355

2251
F
462444

2252
F
464842

2253
F
463010

2254
F
465346

2255
F
463451

2256
F
466061

2257
F
464143

2258
F
466780

2259
F
464842

2260
F
467462

2261
F
465578

2262
F
469419

2263
F
467538

2264
F
471324

2265
F
469419

2266
F
470463

2267
F
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2268
F
471822

2269
F
469897

2270
F
472471

2271
F
470610

2272
F
473208

2273
F
471319

2274
F
475143

2275
F
473243

2276
F
477091

2277
F
475181

2278
F
477375

2279
F
475475

2280
F
478473

2281
F
476586

2282
F
479058

2283
F
477158

2284
F
479829

2285
F
477916

2286
F
481237

2287
F
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2288
F
481769

2289
F
479903

2290
F
482435

2291
F
480535

2292
F
483976

2293
F
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2294
F
484899

2295
F
483029

2296
F
485593

2297
F
483674

2298
F
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2299
F
484498

2300
F
486762

2301
F
484859

2302
F
487287

2303
F
485366

2304
F
487487

2305
F
485642

2306
F
488811

2307
F
486942

2308
F
488918

2309
F
487001

2310
F
489740

2311
F
487772

2312
F
490300

2313
F
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2314
F
490880

2315
F
488969

2316
F
491167

2317
F
489268

2318
F
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2319
F
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2320
F
494600

2321
F
492697

2322
F
495778

2323
F
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2324
F
496350

2325
F
494396

2326
F
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2327
F
495210

2328
F
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2329
F
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2330
F
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2331
F
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2332
F
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2333
F
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2334
F
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2335
F
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2336
F
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2337
F
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2338
F
500555

2339
F
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2340
F
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2341
F
502008

2342
F
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2343
F
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2344
F
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2345
F
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2346
F
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2347
F
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2348
F
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2349
F
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2350
F
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2351
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2352
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2353
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2354
F
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2355
F
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2356
F
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2357
F
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2358
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2359
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2360
F
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2361
F
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2362
F
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2363
F
516181

2364
F
521162

2365
F
519241

2366
F
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2367
F
521123

2368
F
523865

2369
F
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2370
F
524373

2371
F
522530

2372
F
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2373
F
524115

2374
F
526479

2375
F
524580

2376
F
526756

2377
F
524823

2378
F
528167

2379
F
526263

2380
F
529315

2381
F
527408

2382
F
530372

2383
F
528484

2384
F
531842

2385
F
529945

2386
F
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2387
F
532190

2388
F
536335

2389
F
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2390
F
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2391
F
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2392
F
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2393
F
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2394
F
538105

2395
F
536211

2396
F
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2397
F
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2398
F
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2399
F
537421

2400
F
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2401
F
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2402
F
542198

2403
F
540335

2404
F
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2405
F
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2406
F
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2407
F
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2408
F
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2409
F
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2410
F
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2411
F
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2412
F
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2413
F
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2414
F
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2415
F
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2416
F
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2417
F
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2418
F
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2419
F
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2420
F
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2421
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2422
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2423
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2424
F
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2425
F
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2426
F
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2427
F
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2428
F
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2429
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2430
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2431
F
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2432
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2433
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2434
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2435
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2436
F
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2437
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2438
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2439
F
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2440
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2441
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2442
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2443
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2444
F
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2445
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2446
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2447
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2448
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2449
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2450
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2451
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2452
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2453
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2454
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2455
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2456
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2457
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2458
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2459
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2460
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2461
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2462
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2463
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2464
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2465
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2466
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2467
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2468
F
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2469
F
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2470
F
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2471
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2472
F
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2473
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2474
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2475
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2476
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2477
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2478
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2479
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2480
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2481
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2482
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2483
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2484
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2485
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2486
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2487
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2488
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2489
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2490
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2491
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2492
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2493
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2494
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2495
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2496
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2497
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2498
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2499
F
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2500
F
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2501
F
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2502
F
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2503
F
594387

2504
F
596964

2505
F
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2506
F
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2507
F
595635

2508
F
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2509
F
596448

2510
F
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2511
F
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2512
F
600368

2513
F
598433

2514
F
600665

2515
F
598769

2516
F
602011

2517
F
600087

2518
F
602418

2519
F
600513

2520
F
602921

2521
F
601009

2522
F
604391

2523
F
602468

2524
F
605571

2525
F
603671

2526
F
606334

2527
F
604452

2528
F
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2529
F
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2530
F
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2531
F
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2532
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2533
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3235
F
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3236
F
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3237
F
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3238
F
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3239
F
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3240
F
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3241
F
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3242
F
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3243
F
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3244
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3245
F
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3246
F
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3247
F
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3248
F
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3249
F
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3250
F
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3251
F
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3252
F
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3253
F
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3254
F
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3255
F
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3256
F
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3257
F
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3258
F
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3259
F
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3260
F
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3261
F
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3262
F
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3263
F
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3264
F
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3265
F
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3266
F
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3267
F
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3268
F
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3269
F
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3270
F
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3271
F
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3272
F
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3273
F
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3274
F
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3275
F
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3276
F
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3277
F
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3278
F
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3279
F
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3280
F
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3281
F
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3282
F
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3283
F
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3284
F
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3285
F
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3286
F
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3287
F
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3288
F
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3289
F
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3290
F
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3291
F
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3292
F
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3293
F
969757

3294
F
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3295
F
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3296
F
975200

3297
F
973300

3298
F
976362

3299
F
974418

3300
F
977009

3301
F
975050

3302
F
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3303
F
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3304
F
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3305
F
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3306
F
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3307
F
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3308
F
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3309
F
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3310
F
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3311
F
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3312
F
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3313
F
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3314
F
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3315
F
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3316
F
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3317
F
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3318
F
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3319
F
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3320
F
987506

3321
F
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3322
F
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3323
F
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3324
F
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3325
F
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3326
F
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3327
F
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3328
F
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3329
F
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3330
F
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3331
F
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3332
F
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3333
F
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3334
F
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3335
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3336
F
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3337
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3338
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3339
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3340
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3341
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3342
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3343
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3344
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3345
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3346
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3347
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3348
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3349
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3350
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3351
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3352
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3353
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3354
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3355
F
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3356
F
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3357
F
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3358
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3359
F
1002132

3360
F
1004252

3361
F
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3362
F
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3363
F
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3364
F
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3365
F
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3366
F
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3367
F
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3368
F
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3369
F
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3370
F
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3371
F
1007190

3372
F
1014072

3373
F
1012172

3374
F
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3375
F
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3376
F
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3377
F
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3378
F
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3379
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3380
F
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3381
F
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3382
F
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3383
F
1015558

3384
F
1018915

3385
F
1017003

3386
F
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3387
F
1017440

3388
F
1020813

3389
F
1018915

3390
F
1021621

3391
F
1019671

3392
F
1023996

3393
F
1022107

3394
F
1024277

3395
F
1022385

3396
F
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3397
F
1023468

3398
F
1026671

3399
F
1024821

3400
F
1027688

3401
F
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3402
F
1030916

3403
F
1029047

3404
F
1031342

3405
F
1029430

3406
F
1032795

3407
F
1030916

3408
F
1032978

3409
F
1031078

3410
F
1033730

3411
F
1031839

3412
F
1035774

3413
F
1033821

3414
F
1036884

3415
F
1034954

3416
F
1037476

3417
F
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3418
F
1037714

3419
F
1035847

3420
F
1038782

3421
F
1036884

3422
F
1040777

3423
F
1038856

3424
F
1042132

3425
F
1040216

3426
F
1043148

3427
F
1041215

3428
F
1044388

3429
F
1042445

3430
F
1045164

3431
F
1043224

3432
F
1046223

3433
F
1044324

3434
F
1047299

3435
F
1045364

3436
F
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3437
F
1047914

3438
F
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3439
F
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3440
F
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3441
F
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3442
F
1051515

3443
F
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3444
F
1051828

3445
F
1049917

3446
F
1052885

3447
F
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3448
F
1053963

3449
F
1052057

3450
F
1055238

3451
F
1053362

3452
F
1055849

3453
F
1053963

3454
F
1056332

3455
F
1054465

3456
F
1056738

3457
F
1054830

3458
F
1058019

3459
F
1056110

3460
F
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3461
F
1056587

3462
F
1059300

3463
F
1057406

3464
F
1060356

3465
F
1058400

3466
F
1061455

3467
F
1059456

3468
F
1062092

3469
F
1060243

3470
F
1063884

3471
F
1061983

3472
F
1064928

3473
F
1063056

3474
F
1067125

3475
F
1065240

3476
F
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3477
F
1066075

3478
F
1068596

3479
F
1066668

3480
F
1069752

3481
F
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3482
F
1071068

3483
F
1069210

3484
F
1072701

3485
F
1070806

3486
F
1073987

3487
F
1072090

3488
F
1075643

3489
F
1073742

3490
F
1076350

3491
F
1074450

3492
F
1077354

3493
F
1075555

3494
F
1077778

3495
F
1075880

3496
F
1078445

3497
F
1076529

3498
F
1079373

3499
F
1077523

3500
F
1079715

3501
F
1077850

3502
F
1080538

3503
F
1078655

3504
F
1081108

3505
F
1079228

3506
F
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3507
F
1081108

3508
F
1084404

3509
F
1082465

3510
F
1085896

3511
F
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3512
F
1086468

3513
F
1084563

3514
F
1087889

3515
F
1085985

3516
F
1088427

3517
F
1086527

3518
F
1088927

3519
F
1087027

3520
F
1089668

3521
F
1087768

3522
F
1092655

3523
F
1090767

3524
F
1093357

3525
F
1091465

3526
F
1093957

3527
F
1092070

3528
F
1095818

3529
F
1093955

3530
F
1096359

3531
F
1094509

3532
F
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3533
F
1095114

3534
F
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3535
F
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3536
F
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3537
F
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3538
F
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3539
F
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3540
F
1098560

3541
F
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3542
F
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3543
F
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3544
F
1099454

3545
F
1097547

3546
F
1100878

3547
F
1098942

3548
F
1101839

3549
F
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3550
F
1104621

3551
F
1102789

3552
F
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3553
F
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3554
F
1107225

3555
F
1105318

3556
F
1107814

3557
F
1105922

3558
F
1108282

3559
F
1106374

3560
F
1113162

3561
F
1111308

3562
F
1114813

3563
F
1112949

3564
F
1116611

3565
F
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3566
F
1118605

3567
F
1116725

3568
F
1119754

3569
F
1117874

3570
F
1120291

3571
F
1118385

3572
F
1121099

3573
F
1119202

3574
F
1121886

3575
F
1119982

3576
F
1122979

3577
F
1121038

3578
F
1123376

3579
F
1121486

3580
F
1124136

3581
F
1122333

3582
F
1124623

3583
F
1122723

3584
F
1125306

3585
F
1123423

3586
F
1126300

3587
F
1124399

3588
F
1127440

3589
F
1125545

3590
F
1128968

3591
F
1127134

3592
F
1129916

3593
F
1128111

3594
F
1131255

3595
F
1129330

3596
F
1132598

3597
F
1130684

3598
F
1133896

3599
F
1132002

3600
F
1134373

3601
F
1132510

3602
F
1135431

3603
F
1133531

3604
F
1135730

3605
F
1133823

3606
F
1136932

3607
F
1135040

3608
F
1139875

3609
F
1137942

3610
F
1141133

3611
F
1139231

3612
F
1142301

3613
F
1140366

3614
F
1145346

3615
F
1143505

3616
F
1146637

3617
F
1144743

3618
F
1147417

3619
F
1145547

3620
F
1147981

3621
F
1146086

3622
F
1148126

3623
F
1146211

3624
F
1148913

3625
F
1147044

3626
F
1149702

3627
F
1147890

3628
F
1150561

3629
F
1148660

3630
F
1150946

3631
F
1149046

3632
F
1152302

3633
F
1150392

3634
F
1154344

3635
F
1152371

3636
F
1155448

3637
F
1153548

3638
F
1156630

3639
F
1154729

3640
F
1157756

3641
F
1155862

3642
F
1160695

3643
F
1158788

3644
F
1162326

3645
F
1160468

3646
F
1163300

3647
F
1161413

3648
F
1163763

3649
F
1161842

3650
F
1164224

3651
F
1162283

3652
F
1164800

3653
F
1162908

3654
F
1165312

3655
F
1163427

3656
F
1165877

3657
F
1163960

3658
F
1166827

3659
F
1164936

3660
F
1168099

3661
F
1166212

3662
F
1168991

3663
F
1167093

3664
F
1169769

3665
F
1167907

3666
F
1170349

3667
F
1168446

3668
F
1170953

3669
F
1169031

3670
F
1171641

3671
F
1169703

3672
F
1172172

3673
F
1170256

3674
F
1173649

3675
F
1171759

3676
F
1174885

3677
F
1172999

3678
F
1175559

3679
F
1173649

3680
F
1176927

3681
F
1175025

3682
F
1178912

3683
F
1176985

3684
F
1179826

3685
F
1177910

3686
F
1180498

3687
F
1178666

3688
F
1181716

3689
F
1179839

3690
F
1182069

3691
F
1180140

3692
F
1183626

3693
F
1181716

3694
F
1184128

3695
F
1182244

3696
F
1185004

3697
F
1183084

3698
F
1185897

3699
F
1184029

3700
F
1187151

3701
F
1185251

3702
F
1186262

3703
F
1184361

3704
F
1189054

3705
F
1187160

3706
F
1190885

3707
F
1188990

3708
F
1191507

3709
F
1189579

3710
F
1191932

3711
F
1190008

3712
F
1192524

3713
F
1190640

3714
F
1192759

3715
F
1190869

3716
F
1193642

3717
F
1191742

3718
F
1193557

3719
F
1191657

3720
F
1194015

3721
F
1192120

3722
F
1195490

3723
F
1193560

3724
F
1196093

3725
F
1194215

3726
F
1196474

3727
F
1194592

3728
F
1197659

3729
F
1195724

3730
F
1198499

3731
F
1196578

3732
F
1199912

3733
F
1197986

3734
F
1200969

3735
F
1199133

3736
F
1202121

3737
F
1200227

3738
F
1202957

3739
F
1201058

3740
F
1202590

3741
F
1200694

3742
F
1203923

3743
F
1202049

3744
F
1204631

3745
F
1202753

3746
F
1205864

3747
F
1203964

3748
F
1206483

3749
F
1204592

3750
F
1207629

3751
F
1205727

3752
F
1208802

3753
F
1206909

3754
F
1209500

3755
F
1207557

3756
F
1210483

3757
F
1208584

3758
F
1211618

3759
F
1209745

3760
F
1212523

3761
F
1210554

3762
F
1213827

3763
F
1211927

3764
F
1214875

3765
F
1212992

3766
F
1215293

3767
F
1213430

3768
F
1216043

3769
F
1214183

3770
F
1216226

3771
F
1214374

3772
F
1216927

3773
F
1215064

3774
F
1219490

3775
F
1217534

3776
F
1219431

3777
F
1217534

3778
F
1220403

3779
F
1218475

3780
F
1221383

3781
F
1219499

3782
F
1223653

3783
F
1221767

3784
F
1224758

3785
F
1222881

3786
F
1226308

3787
F
1224409

3788
F
1225625

3789
F
1223654

3790
F
1227566

3791
F
1225677

3792
F
1227858

3793
F
1225937

3794
F
1228081

3795
F
1226189

3796
B
1019

3797
B
2954

3798
B
1843

3799
B
3739

3800
B
2694

3801
B
4545

3802
B
3694

3803
B
5513

3804
B
4290

3805
B
6238

3806
B
5924

3807
B
7846

3808
B
7687

3809
B
9583

3810
B
9189

3811
B
11095

3812
B
10261

3813
B
12119

3814
B
10982

3815
B
12839

3816
B
11463

3817
B
13355

3818
B
12950

3819
B
14850

3820
B
14425

3821
B
16332

3822
B
17477

3823
B
19400

3824
B
16296

3825
B
18161

3826
B
21128

3827
B
22976

3828
B
22265

3829
B
24185

3830
B
23701

3831
B
25599

3832
B
26350

3833
B
28258

3834
B
26350

3835
B
28258

3836
B
27241

3837
B
29113

3838
B
27977

3839
B
29896

3840
B
28804

3841
B
30700

3842
B
29727

3843
B
31642

3844
B
30253

3845
B
32158

3846
B
31775

3847
B
33657

3848
B
32511

3849
B
34422

3850
B
34214

3851
B
36114

3852
B
34765

3853
B
36664

3854
B
36289

3855
B
38186

3856
B
37759

3857
B
39682

3858
B
39585

3859
B
41496

3860
B
40942

3861
B
42840

3862
B
39640

3863
B
41543

3864
B
43329

3865
B
45196

3866
B
44025

3867
B
45979

3868
B
45048

3869
B
46970

3870
B
45582

3871
B
47472

3872
B
45979

3873
B
47901

3874
B
47216

3875
B
49128

3876
B
47791

3877
B
49689

3878
B
48196

3879
B
50126

3880
B
49180

3881
B
51105

3882
B
50231

3883
B
52149

3884
B
51697

3885
B
53619

3886
B
52917

3887
B
54735

3888
B
53619

3889
B
55476

3890
B
53910

3891
B
55816

3892
B
54416

3893
B
56326

3894
B
55107

3895
B
57009

3896
B
56693

3897
B
58586

3898
B
57489

3899
B
59394

3900
B
58749

3901
B
60649

3902
B
60086

3903
B
62002

3904
B
62375

3905
B
64275

3906
B
61715

3907
B
63633

3908
B
62699

3909
B
64601

3910
B
63981

3911
B
65858

3912
B
64268

3913
B
66227

3914
B
64423

3915
B
66309

3916
B
64834

3917
B
66756

3918
B
65705

3919
B
67611

3920
B
66228

3921
B
68163

3922
B
67538

3923
B
69404

3924
B
67961

3925
B
69841

3926
B
68796

3927
B
70662

3928
B
70984

3929
B
72885

3930
B
69392

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6038
B
1098097

6039
B
1100046

6040
B
1098615

6041
B
1100561

6042
B
1099098

6043
B
1100975

6044
B
1099614

6045
B
1101442

6046
B
1099747

6047
B
1101651

6048
B
1101298

6049
B
1103227

6050
B
1102435

6051
B
1104381

6052
B
1105179

6053
B
1107090

6054
B
1106770

6055
B
1108631

6056
B
1107502

6057
B
1109392

6058
B
1108337

6059
B
1110240

6060
B
1108653

6061
B
1110570

6062
B
1113632

6063
B
1115499

6064
B
1115225

6065
B
1117081

6066
B
1117154

6067
B
1119051

6068
B
1118403

6069
B
1120310

6070
B
1120257

6071
B
1122178

6072
B
1120776

6073
B
1122682

6074
B
1121660

6075
B
1123554

6076
B
1122120

6077
B
1123999

6078
B
1123243

6079
B
1125024

6080
B
1123752

6081
B
1125688

6082
B
1124484

6083
B
1126360

6084
B
1125020

6085
B
1126928

6086
B
1125790

6087
B
1127735

6088
B
1126747

6089
B
1128662

6090
B
1127899

6091
B
1129808

6092
B
1128819

6093
B
1130695

6094
B
1129798

6095
B
1131693

6096
B
1131563

6097
B
1133490

6098
B
1132846

6099
B
1134684

6100
B
1134070

6101
B
1136016

6102
B
1135089

6103
B
1137037

6104
B
1135815

6105
B
1137715

6106
B
1136186

6107
B
1138084

6108
B
1137365

6109
B
1139255

6110
B
1140364

6111
B
1142228

6112
B
1141611

6113
B
1143485

6114
B
1142478

6115
B
1144291

6116
B
1145907

6117
B
1147783

6118
B
1146953

6119
B
1148846

6120
B
1147769

6121
B
1149703

6122
B
1148415

6123
B
1150357

6124
B
1148758

6125
B
1150658

6126
B
1149462

6127
B
1151258

6128
B
1149932

6129
B
1151845

6130
B
1150814

6131
B
1152747

6132
B
1151409

6133
B
1153285

6134
B
1152540

6135
B
1154341

6136
B
1154863

6137
B
1156751

6138
B
1155886

6139
B
1157813

6140
B
1156963

6141
B
1158871

6142
B
1158093

6143
B
1159947

6144
B
1160998

6145
B
1162864

6146
B
1162864

6147
B
1164740

6148
B
1163244

6149
B
1165090

6150
B
1164244

6151
B
1166175

6152
B
1164517

6153
B
1166482

6154
B
1165167

6155
B
1167100

6156
B
1165789

6157
B
1167710

6158
B
1166376

6159
B
1168228

6160
B
1166872

6161
B
1168764

6162
B
1168598

6163
B
1170498

6164
B
1169447

6165
B
1171347

6166
B
1170043

6167
B
1171947

6168
B
1170689

6169
B
1172616

6170
B
1171556

6171
B
1173507

6172
B
1172305

6173
B
1174210

6174
B
1172562

6175
B
1174508

6176
B
1174018

6177
B
1175899

6178
B
1175429

6179
B
1177348

6180
B
1175793

6181
B
1177675

6182
B
1177347

6183
B
1179199

6184
B
1179316

6185
B
1181171

6186
B
1180309

6187
B
1182212

6188
B
1181048

6189
B
1182918

6190
B
1182162

6191
B
1184078

6192
B
1182528

6193
B
1184437

6194
B
1184078

6195
B
1186015

6196
B
1184698

6197
B
1186540

6198
B
1185631

6199
B
1187530

6200
B
1186079

6201
B
1188004

6202
B
1186704

6203
B
1188610

6204
B
1189251

6205
B
1191165

6206
B
1187609

6207
B
1189506

6208
B
1191165

6209
B
1193050

6210
B
1192378

6211
B
1194291

6212
B
1192265

6213
B
1194114

6214
B
1193058

6215
B
1194987

6216
B
1193224

6217
B
1195115

6218
B
1194035

6219
B
1195955

6220
B
1194384

6221
B
1196265

6222
B
1194291

6223
B
1196205

6224
B
1195955

6225
B
1197863

6226
B
1196570

6227
B
1198423

6228
B
1197051

6229
B
1198951

6230
B
1198058

6231
B
1199931

6232
B
1198960

6233
B
1200867

6234
B
1200490

6235
B
1202395

6236
B
1201512

6237
B
1203426

6238
B
1202606

6239
B
1204532

6240
B
1203139

6241
B
1205063

6242
B
1203691

6243
B
1205597

6244
B
1204382

6245
B
1206284

6246
B
1205249

6247
B
1207170

6248
B
1206651

6249
B
1208536

6250
B
1206976

6251
B
1208862

6252
B
1208092

6253
B
1210002

6254
B
1209115

6255
B
1210973

6256
B
1209979

6257
B
1211892

6258
B
1210739

6259
B
1212639

6260
B
1211761

6261
B
1213680

6262
B
1212985

6263
B
1214894

6264
B
1214299

6265
B
1216189

6266
B
1215132

6267
B
1217036

6268
B
1215714

6269
B
1217542

6270
B
1216541

6271
B
1218462

6272
B
1216828

6273
B
1218677

6274
B
1217166

6275
B
1218973

6276
B
1219876

6277
B
1221743

6278
B
1220892

6279
B
1222895

6280
B
1220288

6281
B
1222189

6282
B
1221657

6283
B
1223517

6284
B
1223930

6285
B
1225828

6286
B
1225211

6287
B
1227132

6288
B
1226090

6289
B
1227979

6290
B
1227132

6291
B
1229039

6292
B
1228061

6293
B
1229948

6294
B
1228293

6295
B
267

6296
B
1228524

6297
B
444

6298
B
267

6299
B
2068

6300
F
25997

6301
F
24032

6302
F
27128

6303
F
25189

6304
F
66744

6305
F
64845

6306
F
70130

6307
F
68200

6308
F
132477

6309
F
130559

6310
F
177854

6311
F
175906

6312
F
208127

6313
F
206180

6314
F
208688

6315
F
206807

6316
F
208732

6317
F
206877

6318
F
210051

6319
F
208141

6320
F
298801

6321
F
296907

6322
F
351495

6323
F
349572

6324
F
419727

6325
F
417822

6326
F
553133

6327
F
551247

6328
F
556301

6329
F
554410

6330
F
593567

6331
F
591675

6332
F
594641

6333
F
592748

6334
F
661934

6335
F
660041

6336
F
706309

6337
F
704409

6338
F
803092

6339
F
801192

6340
F
849060

6341
F
847142

6342
F
913050

6343
F
911152

6344
F
926614

6345
F
924714

6346
F
930121

6347
F
928238

6348
F
986297

6349
F
984362

6350
F
996001

6351
F
994109

6352
F
999731

6353
F
997877

6354
F
1009782

6355
F
1007891

6356
F
1010540

6357
F
1008671

6358
F
1012465

6359
F
1010540

6360
F
1028431

6361
F
1026524

6362
F
1086215

6363
F
1084362

6364
F
1118417

6365
F
1116527

6366
F
1169595

6367
F
1167713

6368
F
1180592

6369
F
1178709

6370
F
1182406

6371
F
1180498

6372
F
1194573

6373
F
1192667

6374
F
1195654

6375
F
1193753

6376
B
26870

6377
B
28721

6378
B
27835

6379
B
29730

6380
B
67456

6381
B
69351

6382
B
70820

6383
B
72708

6384
B
133173

6385
B
135068

6386
B
178637

6387
B
180518

6388
B
208864

6389
B
210727

6390
B
209376

6391
B
211305

6392
B
209483

6393
B
211383

6394
B
210875

6395
B
212766

6396
B
299694

6397
B
301582

6398
B
352312

6399
B
354200

6400
B
420390

6401
B
422291

6402
B
553822

6403
B
555736

6404
B
557050

6405
B
558930

6406
B
594583

6407
B
596527

6408
B
595405

6409
B
597289

6410
B
662614

6411
B
664530

6412
B
707138

6413
B
709063

6414
B
803951

6415
B
805790

6416
B
849771

6417
B
851730

6418
B
913917

6419
B
915796

6420
B
927331

6421
B
929238

6422
B
930857

6423
B
932735

6424
B
986987

6425
B
988912

6426
B
996771

6427
B
998623

6428
B
1000593

6429
B
1002496

6430
B
1010541

6431
B
1012452

6432
B
1011365

6433
B
1013249

6434
B
1013146

6435
B
1015044

6436
B
1029168

6437
B
1031036

6438
B
1087041

6439
B
1088885

6440
B
1119102

6441
B
1121033

6442
B
1170355

6443
B
1172218

6444
B
1181427

6445
B
1183338

6446
B
1183263

6447
B
1185158

6448
B
1195296

6449
B
1197175

6450
B
1196406

6451
B
1198306

[0586]

7

TABLE 6

Chromosomal

clone Name
SEQ ID NO (B)
SEQ ID NO (F)
region

790313H3#
6452
6648
A

790331B1#
6453
6649
A

790233A9#
6454
6650
A

790031G7#
6455
6651
A

890021E4#
6456
6652
A

790021E11#
6457
6653
A

790332G10#
6458
6654
A

790271B6#
6459
6655
A

790253H6#
6460
6656
A

790214E8#
6461
6657
A

790352D2#
6462
6658
A

790373F2#
6463
6659
A

790424A7#
6464
6660
A

790282F3#
6465
6661
A

790272F5#
6466
6662
A

790424F6#
6467
6663
A

890033H11#
6468
6664
A

790264H10#
6469
6665
A

790293A5#
6470
6666
A

790391E8#
6471
6667
A

890022B8#
6472
6668
A

790332B9#
6473
6669
A

790251B9#
6474
6670
A

790344E8#
6475
6671
B

790323F3#
6476
6672
B

790231G2#
6477
6673
B

790341C5#
6478
6674
B

790332H9#
6479
6675
B

890013A8#
6480
6676
B

790394F2#
6481
6677
B

790222G5#
6482
6678
B

790402A10#
6483
6679
B

790283F6#
6484
6680
B

790041H11#
6485
6681
B

790381C7#
6486
6682
B

790213E1#
6487
6683
B

790211C4#
6488
6684
B

790251B5#
6489
6685
B

790043H9#
6490
6686
B

790303F7#
6491
6687
B

790251G5#
6492
6688
B

790044H7#
6493
6689
B

790022E4#
6494
6690
B

790252A8#
6495
6691
B

790313E9#
6496
6692
B

790264G2#
6497
6693
B

790372A4#
6498
6694
B

790411C2#
6499
6695
B

790322B7#
6500
6696
B

790254F7#
6501
6697
B

790323B12#
6502
6698
B

790263E5#
6503
6699
B

790223C8#
6504
6700
B

790231H2#
6505
6701
B

790324E12#
6506
6702
B

790271D7#
6507
6703
B

790222E8#
6508
6704
B

790083G7#
6509
6705
B

790241D3#
6510
6706
B

790303C8#
6511
6707
B

790283F10#
6512
6708
B

790241B7#
6513
6709
B

790373F10#
6514
6710
B

790362F9#
6515
6711
B

790263H8#
6516
6712
B

790393D10#
6517
6713
B

790313D12#
6518
6714
B

890024C6#
6519
6715
B

890024B10#
6520
6716
B

790212E2#
6521
6717
B

790362E10#
6522
6718
B

790344G11#
6523
6719
B

890011D2#
6524
6720
B

790341B11#
6525
6721
B

790064E10#
6526
6722
B

790212E1#
6527
6723
B

790213G5#
6528
6724
B

790331F2#
6529
6725
B

890024B9#
6530
6726
B

790421F5#
6531
6727
B

890014D11#
6532
6728
B

790373F3#
6533
6729
B

790293D4#
6534
6730
B

790211A3#
6535
6731
B

790211H8#
6536
6732
B

790264E7#
6537
6733
B

790292B11#
6538
6734
B

790312A2#
6539
6735
B

890012D5#
6540
6736
B

790012D12#
6541
6737
B

790291E10#
6542
6738
B

790241C9#
6543
6739
B

790343F1#
6544
6740
B

790241D7#
6545
6741
B

790031H7#
6546
6742
B

790081C4#
6547
6743
B

790013B7#
6548
6744
B

790213F3#
6549
6745
B

790292F9#
6550
6746
B

790423F4#
6551
6747
B

790331F3#
6552
6748
B

790222B10#
6553
6749
B

790261G12#
6554
6750
B

790423G10#
6555
6751
B

790392A9#
6556
6752
B

790331B5#
6557
6753
B

790323H3#
6558
6754
B

890014H8#
6559
6755
B

790231B6#
6560
6756
B

790252F7#
6561
6757
B

790392C10#
6562
6758
B

790021D4#
6563
6759
B

790052D10#
6564
6760
B

790261E3#
6565
6761
B

890023E10#
6566
6762
B

790244B7#
6567
6763
B

790383E1#
6568
6764
B

790401B11#
6569
6765
B

790411B5#
6570
6766
B

790423A11#
6571
6767
B

790031A4#
6572
6768
B

790241G3#
6573
6769
B

790044F7#
6574
6770
B

790252B10#
6575
6771
B

790293F9#
6576
6772
B

790282H3#
6577
6773
B

790381C10#
6578
6774
B

790024H5#
6579
6775
B

790354H7#
6580
6776
B

790411F9#
6581
6777
B

790324G10#
6582
6778
B

790014A5#
6583
6779
B

790381F3#
6584
6780
B

790424D3#
6585
6781
B

790394A10#
6586
6782
B

790423C10#
6587
6783
B

790214D6#
6588
6784
B

790214C4#
6589
6785
B

790014F11#
6590
6786
B

790352F10#
6591
6787
B

790381H6#
6592
6788
B

790282G5#
6593
6789
B

790263C8#
6594
6790
B

890022B4#
6595
6791
B

790283C6#
6596
6792
B

790293B2#
6597
6793
B

790073A3#
6598
6794
B

790313E10#
6599
6795
B

790361D3#
6600
6796
B

790014A11#
6601
6797
B

790254G2#
6602
6798
B

790381C61#
6603
6799
B

790424E3#
6604
6800
B

790421G8#
6605
6801
B

790013C3#
6606
6802
B

790263E8#
6607
6803
B

790373C1#
6608
6804
B

790041C1#
6609
6805
B

790344A7#
6610
6806
B

790271D6#
6611
6807
B

790342H2#
6612
6808
B

890021A6#
6613
6809
B

790381E7#
6614
6810
C

790013G10#
6615
6811
C

790254A4#
6616
6812
C

790213D8#
6617
6813
C

790052A4#
6618
6814
C

790213D3#
6619
6815
C

790394D2#
6620
6816
C

790214D2#
6621
6817
C

790014A4#
6622
6818
C

790324H4#
6623
6819
C

790082B4#
6624
6820
C

790324A6#
6625
6821
C

790424A12#
6626
6822
C

790044G8#
6627
6823
C

790323C6#
6628
6824
C

790312G4#
6629
6825
C

790053C11#
6630
6826
C

890022B7#
6631
6827
C

790392A2#
6632
6828
C

890023D8#
6633
6829
C

790301F1#
6634
6830
C

790343A11#
6635
6831
C

790421A2#
6636
6832
C

790271G2#
6637
6833
C

790302G12#
6638
6834
C

790341E5#
6639
6835
C

790283B6#
6640
6836
C

790222A4#
6641
6837
C

790241B8#
6642
6838
C

790014C2#
6643
6839
C

790402C1#
6644
6840
C

790264E9#
6645
6841
C

790242G4#
6646
6842
C

790422F3#
6647
6843
C

[0587]

8

TABLE 7

SEQ ID
or.
5′position

6452
B
29372

6453
B
30198

6454
B
31007

6455
B
31126

6456
B
32735

6457
B
32264

6458
B
32898

6459
B
33582

6460
B
33519

6461
B
34836

6462
B
35795

6463
B
35548

6464
B
35825

6465
B
37239

6466
B
36761

6467
B
37045

6468
B
36761

6469
B
37958

6470
B
38636

6471
B
39813

6472
B
41140

6473
B
40575

6474
B
40526

6475
B
501495

6476
B
502410

6477
B
502586

6478
B
503233

6479
B
503749

6480
B
504488

6481
B
504206

6482
B
504310

6483
B
505455

6484
B
505877

6485
B
506655

6486
B
506513

6487
B
507532

6488
B
507742

6489
B
508050

6490
B
507771

6491
B
509120

6492
B
509646

6493
B
510137

6494
B
510953

6495
B
511165

6496
B
511526

6497
B
511993

6498
B
513012

6499
B
512983

6500
B
512781

6501
B
514155

6502
B
515036

6503
B
515287

6504
B
516292

6505
B
516234

6506
B
516337

6507
B
517347

6508
B
517005

6509
B
516888

6510
B
516234

6511
B
517560

6512
B
517337

6513
B
518756

6514
B
518943

6515
B
519833

6516
B
520123

6517
B
520574

6518
B
520888

6519
B
522154

6520
B
523041

6521
B
522052

6522
B
522217

6523
B
523035

6524
B
524995

6525
B
523567

6526
B
523477

6527
B
523967

6528
B
525211

6529
B
525215

6530
B
526133

6531
B
525674

6532
B
526561

6533
B
526697

6534
B
526715

6535
B
526844

6536
B
527261

6537
B
527503

6538
B
528775

6539
B
528249

6540
B
530307

6541
B
527772

6542
B
529406

6543
B
527752

6544
B
529829

6545
B
529907

6546
B
529574

6547
B
529635

6548
B
530391

6549
B
531516

6550
B
532154

6551
B
532606

6552
B
533407

6553
B
533664

6554
B
533916

6555
B
534707

6556
B
533482

6557
B
534614

6558
B
534935

6559
B
536823

6560
B
535986

6561
B
536143

6562
B
537505

6563
B
537618

6564
B
538165

6565
B
538702

6566
B
540278

6567
B
539156

6568
B
539619

6569
B
540115

6570
B
540724

6571
B
541484

6572
B
540968

6573
B
542062

6574
B
541898

6575
B
543100

6576
B
543846

6577
B
543820

6578
B
544382

6579
B
545158

6580
B
545678

6581
B
545905

6582
B
546683

6583
B
547718

6584
B
547184

6585
B
547684

6586
B
547342

6587
B
548946

6588
B
549071

6589
B
550054

6590
B
549989

6591
B
550426

6592
B
550055

6593
B
550132

6594
B
550132

6595
B
551400

6596
B
551572

6597
B
551468

6598
B
550849

6599
B
552137

6600
B
552325

6601
B
552583

6602
B
553033

6603
B
553629

6604
B
553960

6605
B
553914

6606
B
554354

6607
B
555783

6608
B
555687

6609
B
556441

6610
B
557054

6611
B
556627

6612
B
557292

6613
B
557050

6614
B
815995

6615
B
817104

6616
B
817104

6617
B
816920

6618
B
820464

6619
B
821017

6620
B
821379

6621
B
821504

6622
B
822723

6623
B
823298

6624
B
823380

6625
B
824414

6626
B
824204

6627
B
825288

6628
B
825346

6629
B
825403

6630
B
826237

6631
B
824995

6632
B
826838

6633
B
828146

6634
B
827878

6635
B
827571

6636
B
828472

6637
B
828484

6638
B
828691

6639
B
829507

6640
B
829169

6641
B
828763

6642
B
829769

6643
B
831582

6644
B
830481

6645
B
831468

6646
B
831670

6647
B
832293

6648
F
28484

6649
F
29043

6650
F
29656

6651
F
30157

6652
F
30712

6653
F
31175

6654
F
31658

6655
F
31902

6656
F
32638

6657
F
33203

6658
F
33804

6659
F
34164

6660
F
34426

6661
F
35131

6662
F
35675

6663
F
36097

6664
F
36641

6665
F
36835

6666
F
37236

6667
F
38287

6668
F
38711

6669
F
39117

6670
F
39798

6671
F
500539

6672
F
501016

6673
F
501319

6674
F
501632

6675
F
502155

6676
F
502623

6677
F
503025

6678
F
503681

6679
F
504389

6680
F
504744

6681
F
505468

6682
F
505652

6683
F
505822

6684
F
505833

6685
F
506933

6686
F
507220

6687
F
507559

6688
F
508216

6689
F
508619

6690
F
509329

6691
F
509783

6692
F
510383

6693
F
510729

6694
F
511188

6695
F
511773

6696
F
511869

6697
F
512946

6698
F
513202

6699
F
513821

6700
F
514322

6701
F
514811

6702
F
515101

6703
F
515611

6704
F
515911

6705
F
516123

6706
F
516169

6707
F
516215

6708
F
516305

6709
F
517240

6710
F
517993

6711
F
518174

6712
F
518756

6713
F
519133

6714
F
519646

6715
F
520201

6716
F
520563

6717
F
521015

6718
F
521162

6719
F
521543

6720
F
521739

6721
F
522328

6722
F
522567

6723
F
522915

6724
F
523300

6725
F
523791

6726
F
523959

6727
F
524369

6728
F
524801

6729
F
525085

6730
F
525241

6731
F
525738

6732
F
526263

6733
F
526628

6734
F
526779

6735
F
527004

6736
F
527230

6737
F
527381

6738
F
527545

6739
F
527691

6740
F
527932

6741
F
527995

6742
F
528167

6743
F
528610

6744
F
529063

6745
F
529710

6746
F
531140

6747
F
531488

6748
F
531842

6749
F
532064

6750
F
532350

6751
F
532794

6752
F
533117

6753
F
533536

6754
F
533868

6755
F
534200

6756
F
534844

6757
F
535213

6758
F
535678

6759
F
535970

6760
F
536504

6761
F
537013

6762
F
537710

6763
F
538047

6764
F
538353

6765
F
538718

6766
F
539188

6767
F
539471

6768
F
539910

6769
F
540774

6770
F
540962

6771
F
541721

6772
F
542198

6773
F
542644

6774
F
543180

6775
F
543877

6776
F
544601

6777
F
544866

6778
F
545442

6779
F
545948

6780
F
546209

6781
F
546585

6782
F
546960

6783
F
547114

6784
F
547726

6785
F
548045

6786
F
548480

6787
F
548561

6788
F
548775

6789
F
549037

6790
F
549153

6791
F
549597

6792
F
550049

6793
F
550520

6794
F
550890

6795
F
550997

6796
F
551040

6797
F
551247

6798
F
551854

6799
F
552333

6800
F
552603

6801
F
552823

6802
F
553207

6803
F
553898

6804
F
554298

6805
F
554767

6806
F
555323

6807
F
555595

6808
F
555965

6809
F
556248

6810
F
815116

6811
F
815376

6812
F
815849

6813
F
816098

6814
F
818726

6815
F
819337

6816
F
820080

6817
F
820750

6818
F
821170

6819
F
821815

6820
F
822490

6821
F
822789

6822
F
823244

6823
F
823762

6824
F
823964

6825
F
824245

6826
F
824609

6827
F
824948

6828
F
825490

6829
F
826064

6830
F
826405

6831
F
826480

6832
F
827089

6833
F
827418

6834
F
827496

6835
F
827730

6836
F
828180

6837
F
828348

6838
F
828729

6839
F
830099

6840
F
830281

6841
F
830491

6842
F
830550

6843
F
830576

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	Number	Date	Country
Parent	09198452	Nov 1998	US
Child	10289762	Nov 2002	US

Chlamydia pneumoniae polynucleotides and uses thereof

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