title: Influenza A inhibits Th17-mediated host defense against bacterial pneumonia in mice.
abstract: Staphylococcus aureus is a significant cause of hospital and community acquired pneumonia and causes secondary infection after influenza A. Recently, patients with hyper-IgE syndrome, who often present with S. aureus infections of the lung and skin, were found to have mutations in STAT3, required for Th17 immunity, suggesting a potential critical role for Th17 cells in S. aureus pneumonia. Indeed, IL-17R(-/-) and IL-22(-/-) mice displayed impaired bacterial clearance of S. aureus compared with that of wild-type mice. Mice challenged with influenza A PR/8/34 H1N1 and subsequently with S. aureus had increased inflammation and decreased clearance of both virus and bacteria. Coinfection resulted in greater type I and II IFN production in the lung compared with that with virus infection alone. Importantly, influenza A coinfection resulted in substantially decreased IL-17, IL-22, and IL-23 production after S. aureus infection. The decrease in S. aureus-induced IL-17, IL-22, and IL-23 was independent of type II IFN but required type I IFN production in influenza A-infected mice. Furthermore, overexpression of IL-23 in influenza A, S. aureus-coinfected mice rescued the induction of IL-17 and IL-22 and markedly improved bacterial clearance. These data indicate a novel mechanism by which influenza A-induced type I IFNs inhibit Th17 immunity and increase susceptibility to secondary bacterial pneumonia.
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224.
authors.forename: Anupa
authors.initials: A
authors.lastname: Kudva
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224.
authors.forename: Erich V
authors.initials: EV
authors.lastname: Scheller
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224.
authors.forename: Keven M
authors.initials: KM
authors.lastname: Robinson
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224.
authors.forename: Chris R
authors.initials: CR
authors.lastname: Crowe
authors.affiliation: Department of Genetics, Lousiana State University Health Sciences Center, New Orleans, LA 70112.
authors.forename: Sun Mi
authors.initials: SM
authors.lastname: Choi
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224.
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Slight
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224.
authors.forename: Shabaana A
authors.initials: SA
authors.lastname: Khader
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Dubin
authors.affiliation: Department of Medicine, Dartmouth Medical School, Lebanon, NH 03756.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Enelow
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224.|Department of Genetics, Lousiana State University Health Sciences Center, New Orleans, LA 70112.
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224.
authors.forename: John F
authors.initials: JF
authors.lastname: Alcorn
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007370:Interferon Type I / Q000008:administration & dosage / Q000096:biosynthesis; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology*; D053759:Interleukin-23 / Q000037:antagonists & inhibitors; D007378:Interleukins / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology* / Q000821:virology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D013211:Staphylococcus aureus / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D000097043:Interleukin-22
chemical_list: D007370:Interferon Type I; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D000097043:Interleukin-22; C098680:Il17a protein, mouse