Staphylococcus aureus alpha-Hemolysin Activates the NLRP3-Inflammasome in Human and Mouse Monocytic Cells

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dc.contributor.authorCraven, Robin R.en
dc.contributor.authorGao, Xien
dc.contributor.authorAllen, Irving C.en
dc.contributor.authorGris, Denisen
dc.contributor.authorWardenburg, Juliane Bubecken
dc.contributor.authorTeKippe, Erin McElvaniaen
dc.contributor.authorTing, Jenny P.-Y.en
dc.contributor.authorDuncan, Joseph A.en
dc.date.accessioned2017-01-10T00:47:51Zen
dc.date.available2017-01-10T00:47:51Zen
dc.date.issued2009-10-14en
dc.description.abstractCommunity Acquired Methicillin Resistant Staphylococcus aureus (CA-MRSA) causes severe necrotizing infections of the skin, soft tissues, and lungs. Staphylococcal a-hemolysin is an essential virulence factor in mouse models of CA-MRSA necrotizing pneumonia. S. aureus a-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 ahemolysin, we now demonstrate that a-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 a-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 a-hemolysin results in activation of the cysteine proteinase, caspase-1. We also show that inflammasome activation by a-hemolysin works in conjunction with signaling by other CA-MRSA-derived Pathogen Associated Molecular Patterns (PAMPs) to induce secretion of pro-inflammatory cytokines IL-1b and IL-18. Additionally, ahemolysin 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.en
dc.description.versionPublished versionen
dc.format.extent? - ? (11) page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0007446en
dc.identifier.issn1932-6203en
dc.identifier.issue10en
dc.identifier.urihttp://hdl.handle.net/10919/74041en
dc.identifier.volume4en
dc.language.isoenen
dc.publisherPLOSen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000270808700009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectpanton-valentine leukocidinen
dc.subjectcommunity-associated mrsaen
dc.subjectcaspase activationen
dc.subjectendothelial-cellsen
dc.subjectcias1 mutationsen
dc.subjectwall componentsen
dc.subjectdeath pathwayen
dc.subjectcutting edgeen
dc.subjectreceptor 2en
dc.subjecttoxinen
dc.titleStaphylococcus aureus alpha-Hemolysin Activates the NLRP3-Inflammasome in Human and Mouse Monocytic Cellsen
dc.title.serialPLOS ONEen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/Veterinary Medicineen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiologyen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/CVM T&R Facultyen

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