Abstract
Community Acquired Methicillin Resistant Staphylococcus aureus (CA-MRSA) causes severe necrotizing infections of the skin, soft tissues, and lungs. Staphylococcal α-hemolysin is an essential virulence factor in mouse models of CA-MRSA necrotizing pneumonia. S. aureus α-hemolysin has long been known to induce inflammatory signaling and cell death in host organisms, however the mechanism underlying these signaling events were not well understood. Using highly purified recombinant α-hemolysin, we now demonstrate that α-hemolysin activates the Nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 protein (NLRP3)-inflammasome, a host inflammatory signaling complex involved in responses to pathogens and endogenous danger signals. Non-cytolytic mutant α-hemolysin molecules fail to elicit NLRP3-inflammasome signaling, demonstrating that the responses are not due to non-specific activation of this innate immune signaling system by bacterially derived proteins. In monocyte-derived cells from humans and mice, inflammasome assembly in response to α-hemolysin results in activation of the cysteine proteinase, caspase-1. We also show that inflammasome activation by α-hemolysin works in conjunction with signaling by other CA-MRSA-derived Pathogen Associated Molecular Patterns (PAMPs) to induce secretion of pro-inflammatory cytokines IL-1β and IL-18. Additionally, α-hemolysin induces cell death in these cells through an NLRP3-dependent program of cellular necrosis, resulting in the release of endogenous pro-inflammatory molecules, like the chromatin-associated protein, High-mobility group box 1 (HMGB1). These studies link the activity of a major S. aureus virulence factor to a specific host signaling pathway. The cellular events linked to inflammasome activity have clear relevance to the disease processes associated with CA-MRSA including tissue necrosis and inflammation.
Highlights
Community Acquired Methicillin Resistant Staphylococcus aureus (CA-MRSA) is the most commonly identified cause of skin infections seen in emergency rooms in the United States [1]
We have demonstrated that highly purified recombinant S. aureus a-hemolysin is capable of inducing activation of caspase-1 through the NLRP3 inflammasome
Activation of NLRP3 by ahemolysin induces cytokine processing and programmed necrosis, both of which can explain many of the pro-inflammatory properties of a-hemolysin that have been observed in the past
Summary
CA-MRSA is the most commonly identified cause of skin infections seen in emergency rooms in the United States [1]. CAMRSA can cause severe, life threatening infections including necrotizing pneumonias and fasciitis, which are associated with very high mortality rates even in previously healthy patients [2,3]. These necrotizing infections are characterized by localized necrosis and severe inflammation. All S. aureus produce secreted exotoxin virulence factors including several cytolytic, pore-forming toxins [6]. Both ahemolysin (Hla) and Panton Valentine leukocidin (PVL) have been implicated in the pathogenesis of S. aureus necrotizing pneumonia [7,8]. A-hemolysin has been shown to be required for S. aureus strains, including CA-MRSA, to promote pneumonia in a mouse
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