title: CD4+ T cells promote the pathogenesis of Staphylococcus aureus pneumonia.
abstract: We postulated that the activation of proinflammatory signaling by methicillin-resistant Staphylococcus aureus (MRSA) strain USA300 is a major factor in the pathogenesis of severe pneumonia and a target for immunomodulation. Local activation of T cells in the lung was a conserved feature of multiple strains of S. aureus, in addition to USA300. The pattern of Vβ chain activation was consistent with known superantigens, but deletion of SelX or SEK and SEQ was not sufficient to prevent T-cell activation, indicating the participation of multiple genes. Using Rag2(-/-), Cd4(-/-), and Cd28(-/-) mice, we observed significantly improved clearance of MRSA from the airways and decreased lung pathology, compared with findings for wild-type controls. The improved outcome correlated with decreased production of proinflammatory cytokines (tumor necrosis factor, KC, interleukin 6, and interleukin 1β). Our data suggest that T-cell-mediated hypercytokinemia induced by infection with MRSA strain USA300 contributes to pathogenesis and may be a therapeutic target for improving outcomes of this common infection in a clinical setting.
authors.affiliation: Department of Pediatrics, Columbia University.
authors.forename: Dane
authors.initials: D
authors.lastname: Parker
authors.affiliation: Department of Pediatrics, Columbia University.
authors.forename: Chanelle L
authors.initials: CL
authors.lastname: Ryan
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York.
authors.forename: Francis
authors.initials: F
authors.lastname: Alonzo
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Torres
authors.affiliation: Department of Pediatrics, Columbia University.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Planet
authors.affiliation: Department of Pediatrics, Columbia University.
authors.forename: Alice S
authors.initials: AS
authors.lastname: Prince
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000172:deficiency; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology*; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency; D004195:Disease Models, Animal; D017353:Gene Deletion; D055624:Methicillin-Resistant Staphylococcus aureus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011023:Pneumonia, Staphylococcal / Q000276:immunology* / Q000473:pathology*; D018089:Superantigens / Q000235:genetics / Q000276:immunology
chemical_list: D018106:CD28 Antigens; D015704:CD4 Antigens; D016207:Cytokines; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D018089:Superantigens
keywords: MRSA; Staphylococcus aureus; T cell; lung; pneumonia