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A major component of the immune response to influenza virus is the production of type I and III interferons. Here we show that the immune response to infection with influenza virus causes an increase and restructuring of the upper respiratory microbiota in wild-type (WT) mice but not in\n                    <jats:italic>\n                      Il28r\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mutant mice lacking the receptor for type III interferon. Mice lacking the IL-28 receptor fail to induce STAT1 phosphorylation and expression of its regulator, SOCS1.\n                    <jats:italic>\n                      Il28r\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mutant mice have increased expression of interleukin-22 (IL-22), as well as Ngal and RegIII\u03b3, in the nasal cavity, the source of organisms that would be aspirated to cause pneumonia. Proteomic analysis reveals changes in several cytoskeletal proteins that contribute to barrier function in the nasal epithelium that may contribute to the effects of IL-28 signaling on the microbiota. The importance of the effects of IL-28 signaling in the pathogenesis of MRSA pneumonia after influenza virus infection was confirmed by showing that WT mice nasally colonized before or after influenza virus infection had significantly higher levels of infection in the upper airways, as well as significantly greater susceptibility to MRSA pneumonia than\n                    <jats:italic>Il28r<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mutant mice did. Our results suggest that activation of the type III interferon in response to influenza virus infection has a major effect in expanding the upper airway microbiome and increasing susceptibility to lower respiratory tract infection.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n                    and influenza virus are important respiratory pathogens, and coinfection with these organisms is associated with significant morbidity and mortality. The ability of influenza virus to increase susceptibility to\n                    <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n                    infection is less well understood. We show here that influenza virus leads to a change in the upper airway microbiome in a type III interferon-dependent manner. Mice lacking the type III interferon receptor have altered STAT1 and IL-22 signaling. In coinfection studies, mice without the type III interferon receptor had significantly less nasal\n                    <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n                    colonization and subsequent pneumonia than infected WT mice did. This work demonstrates that type III interferons induced by influenza virus contribute to nasal colonization and pneumonia due to\n                    <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n                    superinfection.\n                  <\/jats:p>","DOI":"10.1128\/mbio.01939-15","type":"journal-article","created":{"date-parts":[[2016,2,9]],"date-time":"2016-02-09T21:50:22Z","timestamp":1455054622000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":96,"title":["Lambda Interferon Restructures the Nasal Microbiome and Increases Susceptibility to Staphylococcus aureus Superinfection"],"prefix":"10.1128","volume":"7","author":[{"given":"Paul J.","family":"Planet","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Infectious Diseases, Columbia University, College of Physicians and Surgeons, New York, New York, USA"},{"name":"Sackler Institute for Comparative Genomics, American Museum of Natural History, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dane","family":"Parker","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Infectious Diseases, Columbia University, College of Physicians and Surgeons, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor S.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Infectious Diseases, Columbia University, College of Physicians and Surgeons, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Infectious Diseases, Columbia University, College of Physicians and Surgeons, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justinne D.","family":"Leon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanelle","family":"Ryan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Infectious Diseases, Columbia University, College of Physicians and Surgeons, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobin J.","family":"Hammer","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah","family":"Fierer","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, Colorado, USA"},{"name":"Cooperative Institute for Research in Environmental Sciences, University of Colorado, Boulder, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily I.","family":"Chen","sequence":"additional","affiliation":[{"name":"Proteomics Shared Resource at the Herbert Irving Comprehensive Cancer Center &amp; 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