title: STAT3-mediated IL-17 production by postseptic T cells exacerbates viral immunopathology of the lung.
abstract: Survivors of severe sepsis exhibit increased morbidity and mortality in response to secondary infections. Although bacterial secondary infections have been widely studied, there remains a paucity of data concerning viral infections after sepsis. In an experimental mouse model of severe sepsis (cecal ligation and puncture [CLP]) followed by respiratory syncytial virus (RSV) infection, exacerbated immunopathology was observed in the lungs of CLP mice compared with RSV-infected sham surgery mice. This virus-associated immunopathology was evidenced by increased mucus production in the lungs of RSV-infected CLP mice and correlated with increased IL-17 production in the lungs. Respiratory syncytial virus-infected CLP mice exhibited increased levels of TH2 cytokines and reduced interferon γ in the lungs and lymph nodes compared with RSV-infected sham mice. In addition, CD4 T cells from CLP mice produced increased IL-17 in vitro irrespective of the presence of exogenous cytokines or blocking antibodies. This increased IL-17 production correlated with increased STAT3 transcription factor binding to the IL-17 promoter in CD4 T cells from CLP mice. Furthermore, in vivo neutralization of IL-17 before RSV infection led to a significant reduction in virus-induced mucus production and TH2 cytokines. Taken together, these data provide evidence that postseptic CD4 T cells are primed toward IL-17 production via increased STAT3-mediated gene transcription, which may contribute to the immunopathology of a secondary viral infection.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Sumanta
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Allen
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: William F
authors.initials: WF
authors.lastname: Carson
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012136:Respiratory Syncytial Viruses; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018805:Sepsis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D020381:Interleukin-17; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D007371:Interferon-gamma