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Non-canonical autophagy functions of ATG16L1 in epithelial cells limit lethal infection by influenza A virus.

Wang, Yingxue; Sharma, Parul; Jefferson, Matthew; Zhang, Weijiao; Bone, Ben; Kipar, Anja; Bitto, David; Coombes, Janine L.; Pearson, Timothy; Man, Angela; Zhekova, Alex; Bao, Yongping; Tripp, Ralph A.; Carding, Simon R.; Yamauchi, Yohei; Mayer, Ulrike; Powell, Penny P.; Stewart, James P.; Wileman, Thomas

Authors

Yingxue Wang

Parul Sharma

Matthew Jefferson

Weijiao Zhang

Ben Bone

Anja Kipar

David Bitto

Timothy Pearson

Angela Man

Alex Zhekova

Yongping Bao

Ralph A. Tripp

Simon R. Carding

Yohei Yamauchi

Ulrike Mayer

Penny P. Powell

James P. Stewart

Thomas Wileman



Abstract

Influenza A virus (IAV) and SARS-CoV-2 (COVID-19) cause pandemic infections where cytokine storm syndrome and lung inflammation lead to high mortality. 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-dependent targeting of LC3 to single-membrane, non-autophagosome compartments – referred to as non-canonical autophagy – protects mice from lethal IAV infection. Mice with systemic loss of non-canonical autophagy are exquisitely sensitive to low-pathogenicity 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-canonical 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-canonical autophagy in airway epithelial cells as a novel innate defence that restricts IAV infection and lethal inflammation at respiratory surfaces.

Citation

WANG, Y., SHARMA, P., JEFFERSON, M. et al. 2021. Non-canonical autophagy functions of ATG16L1in epithelial cells limit lethal infection by influenzaA virus. EMBO journal [online], 40(6), article e105543. Available from: https://doi.org/10.15252/embj.202010554

Journal Article Type Article
Acceptance Date Jan 8, 2021
Online Publication Date Feb 15, 2021
Publication Date Mar 15, 2021
Deposit Date Aug 8, 2023
Publicly Available Date Aug 14, 2023
Journal EMBO journal
Print ISSN 0261-4189
Electronic ISSN 1460-2075
Publisher EMBO Press
Peer Reviewed Peer Reviewed
Volume 40
Issue 6
Article Number e105543
DOI https://doi.org/10.15252/embj.2020105543
Keywords ATG16L1 WD domain; Cytokine storm; Influenza; Intrinsic defence; Non-canonical autophagy
Public URL https://rgu-repository.worktribe.com/output/2035125

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