Role of WD domain of ATG16L1 and LC3 associated endocytosis in control of influenza virus infection

Wang, Yingxue (2020) Role of WD domain of ATG16L1 and LC3 associated endocytosis in control of influenza virus infection. Doctoral thesis, University of East Anglia.

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Abstract

Autophagy is a conserved self-eating process that delivers intracellular material to lysosomes for degradation (Yu, Chen, & Tooze, 2018). Autophagy is activated by multiple cellular stresses, including starvation and pathogen infection and plays crucial roles in maintaining cellular homeostasis and in controlling pathogen infection and inflammation (Florey, Gammoh, Kim, Jiang, & Overholtzer, 2015) (Levine & Kroemer, 2008). Degradation during conventional (or canonical) autophagy is facilitated by autophagy protein ATG8/LC3 (LC3) which facilitates fusion of double-membraned autophagosomes with lysosomes. Recent work has revealed non-canonical autophagy pathways that use LC3 to target single-membraned endolysosome compartments to lysosomes during the uptake of extracellular material (Heckmann, Boada-Romero, Cunha, Magne, & Green, 2017). LC3-associated phagocytosis (LAP) has been used to describe recruitment of LC3 to phagosomes in phagocytic cells, while LC3-associated endocytosis describes a similar pathway targeting endosomes in non-phagocytic cells (Heckmann et al 2019).

Conventional autophagy is a well-established as a defence against infection, but the roles played by non-canonical autophagy during infection ‘in vivo’ are less clear. This study uses a mouse model (δWD) with systemic loss of non-canonical autophagy to study the roles played by LAP and LC3-associated endocytosis during influenza A virus (IAV) infection. The δWD mice were exquisitely sensitive to IAV with elevated lung virus titres leading to exacerbated pro-inflammatory cytokine responses, fulminant pneumonia, extensive pulmonary inflammation and high mortality. Bone marrow transfers from control mice were unable to protect δWD mice from IAV. Protection against IAV infection ‘in vivo’ was therefore independent of LAP in phagocytic cells. In a reciprocal experiment LysMcre was used to delete LAP specifically from myeloid cells. These LAP-/- mice, which maintain LC3-associated endocytosis in other tissues were resistant to IAV suggesting that LC3 associated endocytosis, rather than LAP, provides a defence against IAV. Ex vivo studies suggest that this defence is most likely to take place in the epithelial cells that line the respiratory tract.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Chris White
Date Deposited: 29 Jun 2020 13:54
Last Modified: 29 Jun 2020 13:54
URI: https://ueaeprints.uea.ac.uk/id/eprint/75529
DOI:

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