Regulatory requirements for Staphylococcus aureus nitric oxide resistance

Abstract

The ability of Staphylococcus aureus to resist host innate immunity augments the severity and pervasiveness of its pathogenesis. Nitric oxide (NO?) is an innate immune radical that is critical for the efficient clearance of a wide range of microbial pathogens. Exposure of microbes to NO? typically results in growth inhibition and induction of stress regulons. S. aureus, however, induces a metabolic state in response to NO? that allows for continued replication and precludes stress regulon induction. The regulatory factors mediating this distinctive response remain largely undefined. Here, we employ a targeted transposon screen and transcriptomics to identify and characterize five regulons essential for NO? resistance in S. aureus: three virulence regulons not formerly associated with NO? resistance, SarA, CodY, and Rot, as well as two regulons with established roles, Fur and SrrAB. We provide new insights into the contributions of Fur and SrrAB during NO? stress and show that the S. aureus ΔsarA mutant, the most sensitive of the newly identified mutants, exhibits metabolic dysfunction and widespread transcriptional dysregulation following NO? exposure. Altogether, our results broadly characterize the regulatory requirements for NO? resistance in S. aureus and suggest an intriguing overlap between the regulation of NO? resistance and virulence in this well-adapted human pathogen.