Identification of a novel two-component regulatory system that acts in global regulation of virulence factors of Staphylococcus aureus

We have previously demonstrated that the presence of oxygen is necessary fo r the production of toxic shock syndrome toxin 1 (TSST-1) by Staphylococcus aureus in vitro. To investigate the mechanism by which oxygen might regula te toxin production, we identified homologs in S. aureus of the Bacillus su btilis resDE genes. The two component regulatory system encoded by resDE, R esD-ResE, has been implicated in the global regulation of aerobic and anaer obic respiratory metabolism in B. subtilis, We have designated the S. aurer cs homologs srrAB (staphylococcal respiratory response). The effects of srr AB expression on expression of RNAIII (the effector molecule of the agr loc us) and on production of TSST-1 (an exotoxin) and protein A (a surface-asso ciated virulence factor) were investigated. Expression of RNAIII was invers ely related to expression of srrAB, Disruption of srrB resulted in increase d levels of RNAIII, while expression of srrAB in trans on a multicopy plasm id resulted in repression of RNAIII transcription, particularly in microaer obic conditions. Disruption of srrB resulted in decreased production of TSS T-1 under microaerobic conditions and, to a lesser extent, under aerobic co nditions as well. Overexpression of srrAB resulted in nearly complete repre ssion of TSST-1 production in both microaerobic and aerobic conditions. Pro tein A production by the srrB mutant was upregulated in microaerobic condit ions and decreased in aerobic conditions. Protein A production was restored to nearly wild-type levels by complementation of srrAB into the null mutan t. These results indicate that the putative two-component system encoded by srrAB, SrrA-SrrB, acts in the global regulation of staphylococcal virulenc e factors, and may repress virulence factors under low-oxygen conditions. F urthermore, srrAB may provide a mechanistic link between respiratory metabo lism, environmental signals, and regulation of virulence factors in S. aure us.