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Given the high social and economic cost of respiratory viruses, there is an urgent need to understand how the airways defend against virus infection. Here we use mice lacking the WD and linker domains of ATG16L1 to demonstrate that ATG16L1\u2010dependent targeting of LC3 to single\u2010membrane, non\u2010autophagosome compartments \u2013 referred to as non\u2010canonical autophagy \u2013 protects mice from lethal IAV infection. Mice with systemic loss of non\u2010canonical autophagy are exquisitely sensitive to low\u2010pathogenicity IAV where extensive viral replication throughout the lungs, coupled with cytokine amplification mediated by plasmacytoid dendritic cells, leads to fulminant pneumonia, lung inflammation and high mortality. IAV was controlled within epithelial barriers where non\u2010canonical autophagy reduced IAV fusion with endosomes and activation of interferon signalling. Conditional mouse models and ex vivo analysis showed that protection against IAV infection of lung was independent of phagocytes and other leucocytes. This establishes non\u2010canonical autophagy in airway epithelial cells as a novel innate defence that restricts IAV infection and lethal inflammation at respiratory surfaces.<\/jats:p>","DOI":"10.15252\/embj.2020105543","type":"journal-article","created":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T20:31:09Z","timestamp":1613593869000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Non\u2010canonical autophagy functions of ATG16L1 in epithelial cells limit lethal infection by influenza A virus"],"prefix":"10.1038","volume":"40","author":[{"given":"Yingxue","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parul","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Jefferson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijiao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Bone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Kipar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Bitto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine L","family":"Coombes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Pearson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9596-0068","authenticated-orcid":false,"given":"Angela","family":"Man","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Zhekova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongping","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph A","family":"Tripp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2383-9701","authenticated-orcid":false,"given":"Simon R","family":"Carding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Yamauchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2328-0052","authenticated-orcid":false,"given":"Ulrike","family":"Mayer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5347-0490","authenticated-orcid":false,"given":"Penny P","family":"Powell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8928-2037","authenticated-orcid":false,"given":"James P","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9033-2580","authenticated-orcid":false,"given":"Thomas","family":"Wileman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,15]]},"reference":[{"key":"BFEMBJ2020105543_CR1","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.chom.2015.12.002","volume":"19","author":"T Akoumianaki","year":"2016","unstructured":"Akoumianaki T, Kyrmizi I, Valsecchi I, Gresnigt MS, Samonis G, Drakos E, Boumpas D, Muszkieta L, Prevost MC, Kontoyiannis DP et al (2016) Aspergillus Cell Wall Melanin Blocks LC3\u2010Associated Phagocytosis to Promote Pathogenicity. 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