title: Toxin-induced necroptosis is a major mechanism of Staphylococcus aureus lung damage.
abstract: 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.
authors.affiliation: Department of Pharmacology, Columbia University Graduate School of Arts and Sciences, Columbia University, New York, New York, United States of America.
authors.forename: Kipyegon
authors.initials: K
authors.lastname: Kitur
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Dane
authors.initials: D
authors.lastname: Parker
authors.affiliation: Department of Molecular Genetics and Microbiology, Pontifical Catholic University of Chile, Santiago, Chile.
authors.forename: Pamela
authors.initials: P
authors.lastname: Nieto
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Danielle S
authors.initials: DS
authors.lastname: Ahn
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Taylor S
authors.initials: TS
authors.lastname: Cohen
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Samuel
authors.initials: S
authors.lastname: Chung
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wachtel
authors.affiliation: Department of Molecular Genetics and Microbiology, Pontifical Catholic University of Chile, Santiago, Chile.
authors.forename: Susan
authors.initials: S
authors.lastname: Bueno
authors.affiliation: Department of Pharmacology, Columbia University Graduate School of Arts and Sciences, Columbia University, New York, New York, United States of America; Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Alice
authors.initials: A
authors.lastname: Prince
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000009:adverse effects* / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D011023:Pneumonia, Staphylococcal / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D001427:Bacterial Toxins; D058847:Inflammasomes