Staphylococcus aureus a-Hemolysin Mediates Virulence in a Murine Model of Severe Pneumonia Through Activation of the NLRP3

Staphylococcus aureus is a dangerous pathogen that can cause necrotizing infections characterized by massive inflammatory responses and tissue destruction. Staphylococcal a-hemolysin is an essential virulence factor in severe S. aureus pneumonia. It activates the nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 (NLRP3) inflammasome to induce production of interleukin-1b and programmed necrotic cell death. We sought to determine the role of a-hemolysin–mediated activation of NLRP3 in the pathogenesis of S. aureus pneumonia. We show that a-hemolysin activates the NLRP3 inflammasome during S. aureus pneumonia, inducing necrotic pulmonary injury. Moreover, Nlrp32/2mice have less-severe pneumonia. Pulmonary injury induced by isolated a-hemolysin or live S. aureus is independent of interleukin-1b signaling, implicating NLRP3-induced necrosis in the pathogenesis of severe infection. This work demonstrates the exploitation of host inflammatory signaling by S. aureus and suggests the NLRP3 inflammasome as a potential target for pharmacologic interventions in severe S. aureus infections. Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is now the primary cause of skin infections requiring emergency medical attention in the United States [1]. In addition, CA-MRSA can also caus