title: TLR 2 and CD14 mediate innate immunity and lung inflammation to staphylococcal Panton-Valentine leukocidin in vivo.
abstract: The pore-forming toxin Panton-Valentine leukocidin (PVL) is carried by community-acquired methicillin-resistant Staphylococcus aureus and associated with necrotizing pneumonia together with poor prognosis of infected patients. Although the cell-death-inducing properties of PVL have previously been examined, the pulmonary immune response to PVL is largely unknown. Using an unbiased transcriptional profiling approach, we show that PVL induces only 29 genes in mouse alveolar macrophages, which are associated with TLR signaling. Further studies indicate that PVL directly binds to TLR2 and induces immune responses via NF-κB in a TLR2, CD14, MyD88, IL-1R-associated kinase 1, and TNFR-associated factor 6-dependent manner. PVL-mediated inflammation is independent of pore formation but strongly depends on the LukS subunit and is suppressed in CD14/TLR2(-/-) cells. In vivo PVL or LukS induced a robust inflammatory response in lungs, which was diminished in CD14/TLR2(-/-) mice. These results highlight the proinflammatory properties of PVL and identify CD14/TLR2 as an essential receptor complex for PVL-induced lung inflammation.
authors.affiliation: Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Ana
authors.initials: A
authors.lastname: Zivkovic
authors.forename: Omar
authors.initials: O
authors.lastname: Sharif
authors.forename: Karin
authors.initials: K
authors.lastname: Stich
authors.forename: Bianca
authors.initials: B
authors.lastname: Doninger
authors.forename: Mario
authors.initials: M
authors.lastname: Biaggio
authors.forename: Jacques
authors.initials: J
authors.lastname: Colinge
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.forename: Ildiko
authors.initials: I
authors.lastname: Mesteri
authors.forename: Parastoo
authors.initials: P
authors.lastname: Hazemi
authors.forename: Rosa
authors.initials: R
authors.lastname: Lemmens-Gruber
authors.forename: Sylvia
authors.initials: S
authors.lastname: Knapp
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D002460:Cell Line; D005098:Exotoxins / Q000633:toxicity*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D016209:Interleukin-8 / Q000096:biosynthesis / Q000378:metabolism; D007956:Leukocidins / Q000633:toxicity*; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000502:physiology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology* / Q000473:pathology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013203:Staphylococcal Infections / Q000276:immunology / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D001427:Bacterial Toxins; D005098:Exotoxins; D018836:Inflammation Mediators; D016209:Interleukin-8; D007956:Leukocidins; D018950:Lipopolysaccharide Receptors; C078284:Panton-Valentine leukocidin; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2