Identification and Characterization of the FimR Regulon in the Pathogenesis of Streptococcus parasanguinis

Streptococcus parasanguinis is among some of the most successful colonizers of the human body. The colonization of S. parasanguinis to the tooth surface is essential for the maturation of dental plaque. During oral trauma or surgery, S. parasanguinis gains access to the bloodstream, and may cause life-threatening endocarditis. However, thus far the only known virulence factor associated with endocarditis is FimA of the FimCBA Mn2+/Fe3+ ATP-binding cassette transporter. Our recent studies indicated that the expression of fimCBA is repressed by a transcriptional regulator of the Diphtheria toxin repressor family, designated FimR. Preliminary in vitro chromatin immunoprecipitation (ChIP) analysis demonstrated that FimR binds to the promoters of multiple genes, suggesting that S. parasanguinis possesses a FimR regulon. Studies also reveal that inactivation of fimR enhances the survival of S. parasanguinis within phagocytic cells, but reduces the overall capacity against lethal acidification, suggesting that the expression of FimR regulon plays different roles in the oral cavity and bloodstream. To investigate the function of the FimR regulon in the pathogenesis of S. parasanguinis, two systemic approaches, transcriptomic analysis by RNA-sequencing technology (RNA-seq) and ChIP followed by high-throughput sequencing (ChIP-seq), will be employed in our first aim to identify all members of the FimR regulon. Both the consensus binding sequence of FimR and conditions required for FimR activity will be defined. The second aim will analyze the impact of each member of the FimR regulon in the competitiveness within a pair-strain biofilm system, in the capacity against environmental stressors, and in the survival within phagocytic cells by using various recombinant strains. Finally, the toxicity of members of the FimR regulon will be tested in a wax worm (Galleria mellonella) model system and further verified in a rat endocarditis model. The result of this study will unravel previously unknown factors that are essential for the survival and pathogenesis of S. parasanguinis FW213. Such information is critical for designing therapeutic approaches to prevent and control diseases caused by S. parasanguinis.

Project ID:PC10401-0211
External Project ID:NSC102-2320-B182-031-MY3