Molecular Mechanism of Virulence Regulation in Streptococcus Pyogenes

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Pathogenic bacteria survive in complex and hostile environments in the host. Several host- and microbiota-derived factors curb pathogen growth during infection. Successful pathogens respond by exploiting the cues in their immediate environment to coordinate spatiotemporal production of virulence factors. Our preliminary data indicate that the human pathogen group A streptococcus (GAS) is engaged in arms race with a commensal bacterium during oropharyngeal infection. The commensal bacteria produce a previously unknown antimicrobial metabolite with a novel chemical scaffold that may contribute to host defense against GAS colonization in human oropharynx. As a countermeasure, GAS employs secreted cysteine protease SpeB, a major virulence factor, to overcome commensal defenses by proteolytically degrading the antimicrobial metabolites. Despite our experimental evidence suggesting antagonism between GAS and commensal bacterium, the factors and mechanisms that regulate antimicrobial metabolite production in the commensal and their influence on SpeB production by GAS are unknown. Recently, we discovered a novel GAS quorum sensing pathway comprised of a new class of bacterial quorum sensing signal, a leaderless secreted peptide, and an intracellular receptor that controls the temporal expression of speB during infection. Interestingly, the commensal bacterium also employs a leaderless peptide-dependent quorum sensing pathway to control the antimicrobial metabolite production. However, our preliminary data suggest that GAS hijacks the commensal peptide signal to induce its endogenous quorum sensing pathway and activate SpeB production. This finding is highly relevant to GAS pathogenesis as the interspecies signaling facilitates virulence factor production in a suboptimal host environment and promotes GAS virulence. Using a multidisciplinary approach combining microbiological, genetic, biochemical and imaging methodologies, and animal infection studies, we will dissect the molecular details of intra- and inter- species signaling, characterize the mechanism of antagonism between the two bacterial species, determine its impact on GAS pathogenesis, and elucidate the mechanism of intercellular signaling by leaderless peptides in four specific aims. The results from this study will elucidate how the peptide signaling pathways are tailored for the physiological needs of the producing bacteria and how a pathogen gain survival advantage by hijacking the non-cognate signal from a commensal microbe to trigger virulence factor production and cause disease. The proposed research is significant as it investigates a critical process in disease pathogenesis of a major human pathogen and is likely to elucidate novel translational strategies to combat GAS infections.