Quorum-sensingagrsystem ofStaphylococcus aureusprimes gene expression for protection from lethal oxidative stress

Theagrquorum-sensing system linksStaphylococcus aureusmetabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H₂O₂, a crucial host defense againstS. aureus. We now report that protection byagrsurprisingly extends beyond post-exponential growth to the exit from stationary phase when theagrsystem is no longer turned on. Thus,agrcan be considered a constitutive protective factor. Deletion ofagrincreased both respiration and fermentation but decreased ATP levels and growth, suggesting that Δagrcells assume a hyperactive metabolic state in response to reduced metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in theagrmutant than in wild-type cells, thereby explaining elevated susceptibility of Δagrstrains to lethal H₂O₂doses. Increased survival of wild-typeagrcells during H₂O₂exposure requiredsodA, which detoxifies superoxide. Additionally, pretreatment ofS. aureuswith respiration-reducing menadione protected Δagrcells from killing by H₂O₂. Thus, genetic deletion and pharmacologic experiments indicate thatagrhelps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived “memory” ofagr-mediated protection, which is uncoupled fromagractivation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Nox2^−/−) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.