The Staphylococcus aureus two-component system, SAER/S, modulates host mediators of inflammation to enhance pathogenesis

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is an opportunistic pathogen that causes diseases ranging from superficial skin infections to life-threatening invasive disease. The emergence of community-associated MRSA has caused concern, as these infections appear in healthy individuals. Increasing prevalence of antimicrobial resistance warrants the development of alternative methods of combating infections. Modulating the host immune response during infection has shown promise in research settings, but has fallen short of application in the clinic. Characterizing how Staphylococcus aureus (S. aureus) influences host mediators of inflammation is an essential step for understanding S. aureus pathogenesis and could lead to the development of novel therapies, including immuno-modulation. Previous studies demonstrated the SaeR/S two-component system of S. auerus strongly regulates exoprotein production and is essential for full virulence of this pathogen. However, the mechanisms behind the role(s) of SaeR/S in mediating pathogenesis are incompletely defined. To that end, this investigation examined the role SaeR/S in impacting host inflammatory responses during both invasive and superficial S. aureus infections. Using mutant S. aureus strains with deleted saeR/S (DeltasaeR/S), these studies show that SaeR/S is critical for promoting pathogen survival, dissemination and host mortality during peritonitis. Pro-inflammatory cytokines, such as interferon-gamma (IFNgamma), tumor necrosis factor-alpha and interleukin (IL)-6 were significantly reduced in mice infected with DeltasaeR/S. IFNgamma transcriptional activation and protein expression were significantly induced by saeR/S during skin and invasive infections. Interestingly, neutrophils were identified as the predominant source of saeR/S-induced IFNgamma expression during early S. aureus peritonitis. Robust saeR/S-influenced IFNgamma production prompted further studies investigating the role of this cytokine during S. aureus infections. IFNgamma-deficient (GKO) mice were protected during invasive infection with wild-type S. aureus as reduced bacterial burdens and reduced host cellular cytotoxicity were observed. GKO mice were protected against wild-type S. aureus skin challenge in an IL-17-dependent manner. Interestingly, both normal and GKO mice exhibited similar pathologies when infected with DeltasaeR/S during invasive and superficial infections, suggesting that IFNgamma and IL-17 impact saeR/S-mediated pathogenesis and that in the absence of saeR/S, these cytokines are inconsequential in mediating immunity. Collectively, these studies suggest that saeR/S promotes a deleterious IFNgamma response that enhances S. aureus pathogenesis.