Streptococcus mutans (SM), a major pathogen of dental caries, may promote systemic infections after accessing the bloodstream from oral niches. In this study, we investigate pathways of complement immunity against SM, and show that the orphan regulator CovRSm modulates susceptibility to complement...

Streptococcus mutans (SM), a major pathogen of dental caries, may promote systemic infections after accessing the bloodstream from oral niches. In this study, we investigate pathways of complement immunity against SM, and show that the orphan regulator CovRSm modulates susceptibility to complement opsonization and survival in blood. SM blood isolates showed reduced susceptibility to C3b deposition compared to oral isolates. Reduced expression of covRSm in blood strains was associated with increased transcription of CovRSm-repressed genes required for SM interaction with glucan (gbpC, gbpB and epsC), sucrose-derived exopolysaccharides (EPS). Consistently, blood strains showed increased capacity to bind glucan in vitro. Deletion of covRSmin strain UA159 (UAcov) impaired C3b deposition and binding to serum IgG and C-reactive protein (CRP) as well as phagocytosis through C3b/iC3b receptors and killing by neutrophils. Opposite effects were observed in mutants of gbpC, epsC or gtfB/C/D (required for glucan synthesis). C3b deposition on UA159 was abolished in C1q-depleted serum, implying that the classical pathway is essential for complement activation on SM. Growth in sucrose-containing medium impaired binding of C3b and IgG to UA159, UAcov and blood isolates, but had absent or reduced effects on C3b deposition in gtfB/C/D, gbpC and epsC mutants. UAcov further showed increased ex vivo survival in human blood in an EPS-dependent way. Consistently, reduced survival was observed in the gbpC and epsC mutants. Finally, UAcov showed increased ability to cause bacteremia in a rat model. These results reveal that CovRSm modulates systemic virulence by regulating functions affecting SM susceptibility to complement opsonization.

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