title: IL-17-induced pulmonary pathogenesis during respiratory viral infection and exacerbation of allergic disease.
abstract: Severe respiratory syncytial virus (RSV) infections are characterized by airway epithelial cell damage, mucus hypersecretion, and Th2 cytokine production. Less is known about the role of IL-17. We observed increased IL-6 and IL-17 levels in tracheal aspirate samples from severely ill infants with RSV infection. In a mouse model of RSV infection, time-dependent increases in pulmonary IL-6, IL-23, and IL-17 expression were observed. Neutralization of IL-17 during infection and observations from IL-17(-/-) knockout mice resulted in significant inhibition of mucus production during RSV infection. RSV-infected animals treated with anti-IL-17 had reduced inflammation and decreased viral load, compared with control antibody-treated mice. Blocking IL-17 during infection resulted in significantly increased RSV-specific CD8 T cells. Factors associated with CD8 cytotoxic T lymphocytes, T-bet, IFN-γ, eomesodermin, and granzyme B were significantly up-regulated after IL-17 blockade. Additionally, in vitro analyses suggest that IL-17 directly inhibits T-bet, eomesodermin, and IFN-γ in CD8 T cells. The role of IL-17 was also investigated in RSV-induced exacerbation of allergic airway responses, in which neutralization of IL-17 led to a significant decrease in the exacerbated disease, including reduced mucus production and Th2 cytokines, with decreased viral proteins. Taken together, our data demonstrate that IL-17 plays a pathogenic role during RSV infections.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Sumanta
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Lindell
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Berlin
authors.forename: Susan B
authors.initials: SB
authors.lastname: Morris
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Shanley
authors.forename: Marc B
authors.initials: MB
authors.lastname: Hershenson
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D053804:Granzymes / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000502:physiology*; D053759:Interleukin-23 / Q000378:metabolism; D008171:Lung Diseases / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009093:Mucus / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D018357:Respiratory Syncytial Virus Infections / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000472:pathogenicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism / Q000473:pathology / Q000821:virology; D019562:Viral Load; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D020381:Interleukin-17; D053759:Interleukin-23; D012333:RNA, Messenger; D014764:Viral Proteins; D007371:Interferon-gamma; D053804:Granzymes