Oral Streptococcal Fitness And Virulence genes

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Project Summary Streptococcus sanguinis is a commensal oral bacterium and a pioneer colonizer of human teeth. It is associated with infective endocarditis and can enter the bloodstream through oral lesions, invasive dental procedures or routine oral activities such as chewing, flossing and brushing teeth. Recent developments in genomic technologies have created an opportunity to study streptococcal fitness genes as a whole by systems biology. This application proposes in Aim 1 to identify genes required for S. sanguinis fitness in an infective endocarditis model by screening a unique, comprehensive library of S. sanguinis genome-wide mutants. In Aim 2, a comparable analysis will be performed in saliva, serum and blood using ORF-seq analysis to clarify the findings of Aim 1 and to identify genes required for fitness, but not growth in saliva. The fitness genes in saliva and blood will be compared. Fitness genes that are located at critical hubs will be identified in network analysis and those that are conserved among oral streptococci will be identified by bioinformatics. In aim 3, the gene regulation of fitness genes will be studied in depth. This systematic analysis will provide an unprecedented understanding of streptococcal fitness genes at the molecular level and set the stage for identification of specific targets for new therapeutics or prophylactics.