The WD and linker domains of ATG16L1 required for non-canonical autophagy limit lethal influenza A virus infection at epithelial surfaces

Wang, Yingxue, Zhang, Weijiao, Jefferson, Matthew, Sharma, Parul, Bone, Benjamin, Kipar, Anja, Coombes, Janine L., Pearson, Tim, Man, Angela, Zhekova, Aleksandra, Bao, Yongping, Tripp, Ralph, Carding, Simon, Mayer, Ulrike, Powell, Penny, Stewart, James P. and Wileman, Tom (2020) The WD and linker domains of ATG16L1 required for non-canonical autophagy limit lethal influenza A virus infection at epithelial surfaces.

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Phagocytosis and autophagy represent two evolutionarily ancient pathways that provide an important defense against infection by delivering pathogens to lysosomes for degradation. Phagocytosis and autophagy are linked by non-canonical autophagy pathways that conjugate LC3 to endo-lysosome compartments to facilitate phagosome maturation and lysosome fusion. A role for non-canonical autophagy in host defence is implied from cellular studies in vitro, but critically, these studies have rarely been extended to infection of model organisms with intact epithelial barriers and complex immune systems. To address this, we developed a mouse model with specific loss of non-canonical autophagy by removing the WD and linker domain of ATG16L1 required for recruitment of LC3 to endo-lysosome compartments. The mice retain the coiled-coiled domain of ATG16L1 required for conventional autophagy and maintain tissue and immunological homeostasis. Mice with systemic loss of non-canonical autophagy are exquisitely sensitive to low-pathogenicity murine-adapted influenza A virus leading to extensive viral replication throughout the lungs, cytokine dysregulation, fulminant pneumonia and lung inflammation leading to high mortality associated with virulent strains. Conditional mouse models and ex vivo analysis showed that protection against IAV infection of lung required non-canonical autophagy within epithelial barriers but was independent of phagocytes and other leukocytes. This establishes non-canonical autophagy pathways in epithelial cells as a novel innate defence mechanism that can restrict IAV infection at mucosal surfaces.

Item Type: Article
Additional Information: This article is a preprint and has not been certified by peer review.
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Faculty of Science > School of Biological Sciences
Depositing User: LivePure Connector
Date Deposited: 19 Dec 2020 00:36
Last Modified: 30 Jun 2022 14:30
DOI: 10.1101/2020.01.15.907873

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