Virulence Mechanisms of Multifunctional Borrelial Proteins

Information

  • Research Project
  • 10192642
  • ApplicationId
    10192642
  • Core Project Number
    R01AI146930
  • Full Project Number
    5R01AI146930-02
  • Serial Number
    146930
  • FOA Number
    PA-19-056
  • Sub Project Id
  • Project Start Date
    6/15/2020 - 4 years ago
  • Project End Date
    5/31/2025 - 3 months from now
  • Program Officer Name
    ILIAS, MALIHA R
  • Budget Start Date
    6/1/2021 - 3 years ago
  • Budget End Date
    5/31/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    02
  • Suffix
  • Award Notice Date
    5/18/2021 - 3 years ago
Organizations

Virulence Mechanisms of Multifunctional Borrelial Proteins

PROJECT SUMMARY Spirochetes of the Borrelia genus are the cause of several prevalent vector-borne diseases. The most well-known pathogen from this group is Borrelia burgdorferi sensu stricto, which causes over 300,000 cases of Lyme disease in the United States each year. B. garinii and B. afzelii, which belong to the B. burgdorferi sensu lato complex, are the primary agent of Lyme disease in Europe and Asia. Borrelia spirochetes are also the etiological agent of the ancient human disease relapsing fever, as well as a newly recognized infectious condition called Borrelia miyamotoi disease. Lyme-associated, relapsing fever-associated, and B. miyamotoi spirochetes have differing lifecycles and their infections are accompanied by distinct clinical presentations. However, each of these pathogens are known to encode multifunctional surface-expressed lipoproteins that interact with vertebrate host molecules. Among these proteins are a small arsenal of immunomodulators that specifically target and inactivate a primary arm of innate immunity known as the complement system. We have recently reported two independent lines of evidence that support the hypothesis that one of these pathways, known as the classical pathway, is important in controlling B. burgdorferi infections. First, we have shown that mice deficient in the pattern recognition molecule of the classical pathway, C1q, are significantly more susceptible to B. burgdorferi infection. Secondly, we have shown that the lipoprotein B. burgdorferi BBK32 is a high-affinity inhibitor of the initiating protease of the classical pathway, C1r. In Aim 1 of this project we seek to understand the C1r inhibitory activity of BBK32 sensu lato proteins at the molecular level. In Aim 2 we will determine the immunomodulatory roles and virulence contribution of three BBK32 orthologues known as FbpA, FbpB, and FbpC which are found uniquely in relapsing fever and B. miyamotoi spirochetes. In Aim 3 we will delineate the role of C1r inhibition in borrelial pathogenesis using in vivo models of disease. To achieve this, we propose a multi-disciplinary strategy that employs x-ray crystallography, biophysical approaches, and complement functional assays to pinpoint key ?hot-spot? residues on BBK32 that give rise to its potent anti-C1r activity. These data will inform the design of bbk32 mutants which will be used in mouse infectivity studies to connect structural features of BBK32, at the amino-acid level, to an in vivo phenotype. Parallel studies will use genetic deletion mutants of fbp genes from the relapsing fever- associated spirochetes B. turicatae and B. hermsii. These studies will be paired with experimental models of Lyme and relapsing fever borrelioses using C1r-/- mice to better understand the role of the classical pathway initiating protease in the control of borrelial infections. By addressing fundamental questions of how medically important Borrelia spirochetes recognize and evade host immunity, the studies proposed here stand to have a broad and significant impact on the field of bacterial pathogenesis.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R01
  • Administering IC
    AI
  • Application Type
    5
  • Direct Cost Amount
    650008
  • Indirect Cost Amount
    81111
  • Total Cost
    731119
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
    SCHOOLS OF MEDICINE
  • Funding ICs
    NIAID:731119\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    BACP
  • Study Section Name
    Bacterial Pathogenesis Study Section
  • Organization Name
    EAST CAROLINA UNIVERSITY
  • Organization Department
    MICROBIOLOGY/IMMUN/VIROLOGY
  • Organization DUNS
    607579018
  • Organization City
    GREENVILLE
  • Organization State
    NC
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    278581821
  • Organization District
    UNITED STATES