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

Yingxue Wang, Parul Sharma, Matthew Jefferson, Weijiao Zhang, Ben Bone, Anja Kipar, David Bitto, Janine L. Coombes, 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

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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.
Original languageEnglish
Article numbere105543
JournalThe EMBO Journal
Volume40
Issue number6
Early online date15 Feb 2021
DOIs
Publication statusPublished - 15 Mar 2021

Keywords

  • ATG16L1 WD Domain
  • cytokine storm
  • influenza
  • intrinsic defence
  • non-canonical autophagy

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