Research Project
10171765
PROJECT SUMMARY Group A Streptococcus (GAS) is a human pathogen of global importance that primarily infects the throat (pharyngitis) or skin (impetigo), leading to ~750 million infections per year; high rates of morbidity and mortality are due to invasive disease and autoimmune complications. Despite its importance as a global pathogen, there is no vaccine available for the prevention of GAS disease. The global GAS population is highly diverse, due in large part to the high degree of antigenic heterogeneity among cell surface proteins. Diversity is amplified via the extensive horizontal gene transfer that characterizes this species to yield numerous unique combinations of surface protein antigens. Yet, a biologically relevant and standardized definition for GAS ?strain? is lacking. Historically, two serological typing schemes (M and T) were used to characterize GAS strains: M-typing is based on the short M protein surface fibril, and T-typing is based on thin elongated pili. In addition to high sequence diversity, the M protein and pili act as key virulence factors and are targets of host protective immunity. M-typing has been supplanted by emm genotyping. The proposed project seeks to develop a sequence-based typing scheme for GAS pili (i.e., T-antigens). The Specific Aim seeks to develop a pilin genotyping scheme based on adhesin and backbone pilin genes. Genome sequences from a global and diverse collection of GAS isolates are the source material for the initial database of pilin genes; sequences will undergo phylogenetic analysis and assignment to clusters. Data will be curated and made publicly available on www.pubmlst.org, a user-friendly website. Pilin type will be combined with emm type and MLST-defined sequence type to yield a definition for GAS ?strain.? The proposed work will provide an improved molecular epidemiology typing scheme for this major global pathogen. Standardization of nomenclature can facilitate ?strain? comparisons in the GAS field and enable rapid recognition of newly emerged strains. Pilin typing will also provide a foundation for future work leading to new hypotheses that address the molecular basis for pathogenesis of different types of GAS disease, and the genetic basis for new strain emergence and immune escape. The enriched molecular epidemiology data can also promote rational approaches to vaccine design and vaccination strategies. Progress towards elucidating the molecular mechanisms of pathogenesis and developing a GAS vaccine are long-term goals.
