senses human neutrophils via PerR to coordinate the expression of the toxin LukAB.

is a gram-positive pathogen that poses a major health concern, in part due to its large array of virulence factors that allow infection and evasion of the immune system. One of these virulence factors is the bicomponent pore-forming leukocidin LukAB. The regulation of expression is not completely understood, especially in the presence of immune cells such as human polymorphonuclear neutrophils (hPMNs). Here, we screened for transcriptional regulators of during the infection of primary hPMNs. We uncovered that PerR, a peroxide sensor, is vital for hPMN-mediated induction of and that PerR upregulates cytotoxicity during the infection of hPMNs. Exposure of to hydrogen peroxide (HO) alone also results in increased promoter activity, a phenotype dependent on PerR. Collectively, our data suggest that uses PerR to sense the HO produced by hPMNs to stimulate the expression of , allowing the bacteria to withstand these critical innate immune cells.IMPORTANCE utilizes a diverse set of virulence factors, such as leukocidins, to subvert human neutrophils, but how these toxins are regulated is incompletely defined. Here, we identified the peroxide-sensitive repressor, PerR, as a required protein involved in the induction of in the presence of primary human neutrophils, a phenotype directly linked to the ability of PerR to sense HO. Thus, we show that coordinates sensing and resistance to oxidative stress with toxin production to promote pathogen survival.