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Here we show that, surprisingly, influenza-infected 129 mice have increased lung damage, morbidity and mortality, yet higher levels of IFN\u03b1\u03b2, than C57BL\/6 mice. Consistently, IFN\u03b1 treatment of influenza-infected C57BL\/6 mice increases morbidity. IFN\u03b1\u03b2 receptor deficiency in 129 mice decreases morbidity, lung damage, proinflammatory cytokines and lung-infiltrating inflammatory cells, and reduces expression of the death-inducing receptor DR5 on lung epithelia and its ligand TRAIL on inflammatory monocytes. Depletion of PDCA-1+ cells or interruption of TRAIL-DR5 interaction protects infected 129 mice. Selective lack of IFN\u03b1\u03b2 signalling in stromal cells abolishes epithelial DR5 upregulation and apoptosis, reducing host susceptibility. Hence, excessive IFN\u03b1\u03b2 signalling in response to acute influenza infection can result in uncontrolled inflammation and TRAIL-DR5-mediated epithelial cell death, which may explain morbidity and has important implications for treatment of severe disease.<\/jats:p>","DOI":"10.1038\/ncomms4864","type":"journal-article","created":{"date-parts":[[2014,5,21]],"date-time":"2014-05-21T06:47:43Z","timestamp":1400654863000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":340,"title":["Pathogenic potential of interferon \u03b1\u03b2 in acute influenza infection"],"prefix":"10.1038","volume":"5","author":[{"given":"Sophia","family":"Davidson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Crotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa M","family":"McCabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Wack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,5,21]]},"reference":[{"key":"BFncomms4864_CR1","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1016\/j.it.2009.09.004","volume":"30","author":"JS Peiris","year":"2009","unstructured":"Peiris, J. 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