The two-component system VicRK regulates functions associated with Streptococcus mutans resistance to complement immunity

Summary

Streptococcus mutans, a dental caries pathogen, can promote systemic infections upon reaching the bloodstream. The two-component system (TCS) VicRK_Sm of S. mutans regulates the synthesis of and interaction with sucrose-derived exopolysaccharides (EPS), processes associated with oral and systemic virulence. In this study, we investigated the mechanisms by which VicRK_Sm affects S. mutans susceptibility to blood-mediated immunity. Compared to parent strain UA159, the vicK_Sm isogenic mutant (UAvic) showed reduced susceptibility to deposition of C3b of complement, low binding to serum IgG, and low frequency of C3b/IgG-mediated opsonophagocytosis by PMN in a sucrose-independent way (p<0.05). RT-qPCR analysis comparing gene expression in UA159 and UAvic revealed that genes encoding putative peptidases of the complement (pepO and smu.399) were up-regulated in UAvic in the presence of serum, although genes encoding murein hydrolases (SmaA and Smu.2146c) or metabolic/surface proteins involved in bacterial interactions with host components (enolase, GAPDH) were mostly affected in a serum-independent way. Among vicK_Sm-downstream genes (smaA, smu.2146c, lysM, atlA, pepO, smu.399), only pepO and smu.399 were associated with UAvic phenotypes; deletion of both genes in UA159 significantly enhanced levels of C3b deposition and opsonophagocytosis (p<0.05). Moreover, consistent with the fibronectin-binding function of PepO orthologues, UAvic showed increased binding to fibronectin. Reduced susceptibility to opsonophagocytosis was insufficient to enhance ex vivo persistence of UAvic in blood, which was associated with growth defects of this mutant under limited nutrient conditions. Our findings revealed that S. mutans employs mechanisms of complement evasion through peptidases which are controlled by VicRK_Sm.

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