title: Staphylococcus aureus α-hemolysin mediates virulence in a murine model of severe pneumonia through activation of the NLRP3 inflammasome.
abstract: Staphylococcus aureus is a dangerous pathogen that can cause necrotizing infections characterized by massive inflammatory responses and tissue destruction. Staphylococcal α-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-1β and programmed necrotic cell death. We sought to determine the role of α-hemolysin-mediated activation of NLRP3 in the pathogenesis of S. aureus pneumonia. We show that α-hemolysin activates the NLRP3 inflammasome during S. aureus pneumonia, inducing necrotic pulmonary injury. Moreover, Nlrp3(-/-) mice have less-severe pneumonia. Pulmonary injury induced by isolated α-hemolysin or live S. aureus is independent of interleukin-1β 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.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of North Carolina, Chapel Hill, USA.
authors.forename: Chahnaz
authors.initials: C
authors.lastname: Kebaier
authors.forename: Robin R
authors.initials: RR
authors.lastname: Chamberland
authors.forename: Irving C
authors.initials: IC
authors.lastname: Allen
authors.forename: Xi
authors.initials: X
authors.lastname: Gao
authors.forename: Peter M
authors.initials: PM
authors.lastname: Broglie
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Hall
authors.forename: Corey
authors.initials: C
authors.lastname: Jania
authors.forename: Claire M
authors.initials: CM
authors.lastname: Doerschuk
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Tilley
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Duncan
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism* / Q000494:pharmacology; D039481:CD11b Antigen; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006460:Hemolysin Proteins / Q000378:metabolism* / Q000494:pharmacology; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009336:Necrosis / Q000382:microbiology; D011023:Pneumonia, Staphylococcal / Q000382:microbiology*; D015398:Signal Transduction; D013211:Staphylococcus aureus / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity*
chemical_list: D001427:Bacterial Toxins; D039481:CD11b Antigen; D002352:Carrier Proteins; D006460:Hemolysin Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C021091:staphylococcal alpha-toxin