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Studies have suggested that the excessive activation of the innate immunity by IFV is responsible for severe pathologies. In this study, we focused on CARD9, a signaling adaptor known to regulate innate immune activation through multiple innate sensor proteins and investigated its role in anti-IFV defense and lung pathogenesis in a mouse model recapitulating severe influenza pneumonia with ARDS. We found that influenza pneumonia was dramatically attenuated in <jats:italic>Card9<\/jats:italic>-deficient mice, which showed improved mortality with reduced inflammatory cytokines and chemokines in the infected lungs. However, viral clearance, type-I interferon production and the development of anti-viral B and T cell immunity were not compromised by CARD9 deficiency. Syk or CARD9-deficient DCs but not macrophages showed impaired cytokine but not type-I interferon production in response to IFV <jats:italic>in vitro<\/jats:italic>, indicating a possible role for the Syk-CARD9 pathway in DCs in excessive inflammation of IFV-infected lungs. Therefore, inhibition of this pathway is an ideal therapeutic target for severe influenza pneumonia without affecting viral clearance.<\/jats:p>","DOI":"10.1038\/srep17577","type":"journal-article","created":{"date-parts":[[2015,12,2]],"date-time":"2015-12-02T10:29:20Z","timestamp":1449052160000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Loss of CARD9-mediated innate activation attenuates severe influenza pneumonia without compromising host viral immunity"],"prefix":"10.1038","volume":"5","author":[{"given":"Takayuki","family":"Uematsu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ei\u2019ichi","family":"Iizasa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noritada","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroki","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiromitsu","family":"Hara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,12,2]]},"reference":[{"key":"BFsrep17577_CR1","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.1056\/NEJMra052211","volume":"353","author":"JH Beigel","year":"2005","unstructured":"Beigel, J. 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