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Staphylococcus aureus  USA300 strains cause a highly inflammatory necrotizing pneumonia. The virulence of this strain has been attributed to its expression of multiple toxins that have diverse targets including ADAM10, NLRP3 and CD11b. We demonstrate that induction of necroptosis through RIP1/RIP3/MLKL signaling is a major consequence of  S .  aureus  toxin production. Cytotoxicity could be prevented by inhibiting either RIP1 or MLKL signaling and  S .  aureus  mutants lacking  agr ,  hla  or Hla pore formation,  lukAB  or  psms  were deficient in inducing cell death in human and murine immune cells. Toxin-associated pore formation was essential, as cell death was blocked by exogenous K+ or dextran. MLKL inhibition also blocked caspase-1 and IL-1β production, suggesting a link to the inflammasome.  Rip3    -/-   mice exhibited significantly improved staphylococcal clearance and retained an alveolar macrophage population with CD200R and CD206 markers in the setting of acute infection, suggesting increased susceptibility of these leukocytes to necroptosis. The importance of this anti-inflammatory signaling was indicated by the correlation between improved outcome and significantly decreased expression of KC, IL-6, TNF, IL-1α and IL-1β in infected mice. These findings indicate that toxin-induced necroptosis is a major cause of lung pathology in  S .  aureus  pneumonia and suggest the possibility of targeting components of this signaling pathway as a therapeutic strategy.

Toxin-Induced Necroptosis Is a Major Mechanism of Staphylococcus aureus Lung Damage