Systemic Analysis of the VI Rulence Factors of Streptococcus Parasanguinis

Streptococcus parasanguinis is a primary colonizer of the dental biofilm and an opportunistic pathogen for subacute endocarditis. In its primary niche, oral cavity, S. parasanguinis forms the basal layer of the dental plaque that allows for the adherence of additional plaque microbes to the tooth surface and the maturation of the dental plaque. Occasionally, this microbe may gain access to the bloodstream and subsequently colonize heart valves through oral trauma or surgery. Thus far, FimA, a lipoprotein of the FimCBA Mn2+/Zn2+ ATP-binding cassette transporter, is the only known virulence factor associated with the development of endocarditis, as a FimA-deficient strain is less virulent than the wild-type strain in the rat model. Preliminary studies revealed that the expression of the fim operon is subject to the regulation of FimR and additional unknown factors. Nevertheless, the precise role of FimA in the development of endocarditis is yet to be defined. To initiate a comprehensive analysis on the virulence determinants associated with the endocarditis, this proposal will focus on how S. parasanguinis establishes in the dental biofilm, evades host immune surveillance, and colonizes host tissues. Our first specific aim will analyze the impact of all cell wall anchored proteins (CWAs) in biofilm formation and binding to swine heart valves. The functions of these CWAs in pathogenesis will also be evaluated in the in vivo wax worm (Galleria mellonella) model. The second specific aim will define the regulation of fim operon expression and the FimR regulon. The impact of FimR regulon in the pathogenesis will be further analyzed in the wax worm model. Finally, a global search for genes that are differentially expressed in response to human serum will be conducted by RNA sequencing, and the functions of the identified ORFs will be analyzed. The results of this research will uncover previously unknown virulence mechanism, which is essential for the development of therapeutic approaches to control the endocarditis caused by oral streptococci.

Project ID:PC10108-0886
External Project ID:NSC101-2320-B182-030