This renewal application describes plans to study the pathogenesis of oral streptococci in dental caries and in infective endocarditis. The long-range goal is to devise safe, effective, and reliable means for preventing or controlling oral and systemic streptococcal diseases. Previous findings have shown that fructan polymers of mutans group streptococci are important in virulence, and experiments in this application are designed to give a more complete understanding of how these polymers contribute to cariogenesis. Work will also continue on characterization of glucosyltransferases and glucan-binding proteins in S. mutans-induced dental caries. Studies on the pathogenesis of streptococcal endocarditis will focus on the virulence properties of glucans and the FimA-like proteins of S. parasanguis. There are four specific aims: (1) A novel fructan hydrolase gene will be isolated from S. mutans and characterized using allelic-exchange mutagenesis and subsequent caries testing; (2) existing and novel GTF-B epitopes will be produced as fusion proteins with the B subunit of cholera toxin and tested as vaccines for protection in gnotobiotic rats. Similar experiments will utilize fusion proteins containing epitopes from the glucan-binding protein; (3) to determine that sucrose-derived glucans, and not fructans, are endocarditis virulence determinants and that attachment of these polymers to bacteria via GTF and glucan binding protein (GBP) is critical. The occurrence of FimA-like surface proteins will be determined in streptococcal clinical isolates from plaque, endocarditis, and bacteremia. Experiments will also address the hypothesis that FimA-like genes are activated during bloodstream invasion. Antibody production to FimA protein will be studied for protection to endocarditis, for inhibition of fibrin binding by streptococci, and for enhanced clearance of streptococci from the bloodstream in animal models.
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