The two‐component system VicRK regulates functions associated with <i>Streptococcus mutans</i> resistance to complement immunity

<jats:title>Summary</jats:title><jats:p><jats:italic>Streptococcus mutans</jats:italic>, a dental caries pathogen, can promote systemic infections upon reaching the bloodstream. The two‐component system (TCS) VicRK<jats:sub><jats:italic>Sm</jats:italic></jats:sub> of <jats:italic>S. mutans</jats:italic> 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<jats:sub><jats:italic>Sm</jats:italic></jats:sub> affects <jats:italic>S. mutans</jats:italic> susceptibility to blood‐mediated immunity. Compared with parent strain UA159, the <jats:italic>vicK</jats:italic><jats:sub><jats:italic>Sm</jats:italic></jats:sub> isogenic mutant (UAvic) showed reduced susceptibility to deposition of C3b of complement, low binding to serum immunoglobulin G (IgG), and low frequency of C3b/IgG‐mediated opsonophagocytosis by polymorphonuclear cells in a sucrose‐independent way (<jats:italic>P</jats:italic><.05). Reverse transcriptase quantitative polymerase chain reaction analysis comparing gene expression in UA159 and UAvic revealed that genes encoding putative peptidases of the complement (<jats:italic>pepO</jats:italic> and <jats:italic>smu.399</jats:italic>) were upregulated 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 <jats:italic>vicK</jats:italic><jats:sub><jats:italic>Sm</jats:italic></jats:sub><jats:italic>‐</jats:italic>downstream genes (<jats:italic>smaA</jats:italic>,<jats:italic> smu.2146c</jats:italic>,<jats:italic> lysM</jats:italic>,<jats:italic> atlA</jats:italic>,<jats:italic> pepO</jats:italic>,<jats:italic> smu.399</jats:italic>), only p<jats:italic>epO</jats:italic> and <jats:italic>smu.399</jats:italic> were associated with UAvic phenotypes; deletion of both genes in UA159 significantly enhanced levels of C3b deposition and opsonophagocytosis (<jats:italic>P</jats:italic><.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 <jats:italic>ex vivo</jats:italic> persistence of UAvic in blood, which was associated with growth defects of this mutant under limited nutrient conditions. Our findings revealed that <jats:italic>S. mutans</jats:italic> employs mechanisms of complement evasion through peptidases, which are controlled by VicRK<jats:sub><jats:italic>Sm</jats:italic>.</jats:sub></jats:p>