CLIC and membrane wound repair pathways enable pandemic norovirus entry and infection.

TitleCLIC and membrane wound repair pathways enable pandemic norovirus entry and infection.
Publication TypeJournal Article
Year of Publication2023
AuthorsB Ayyar, V, Ettayebi, K, Salmen, W, Karandikar, UC, Neill, FH, Tenge, VR, Crawford, SE, Bieberich, E, Prasad, BVVenkatar, Atmar, RL, Estes, MK
JournalNat Commun
Date Published2023 Feb 28
KeywordsCell Membrane, Clathrin, Humans, Norovirus, Signal Transduction, Virus Internalization

Globally, most cases of gastroenteritis are caused by pandemic GII.4 human norovirus (HuNoV) strains with no approved therapies or vaccines available. The cellular pathways that these strains exploit for cell entry and internalization are unknown. Here, using nontransformed human jejunal enteroids (HIEs) that recapitulate the physiology of the gastrointestinal tract, we show that infectious GII.4 virions and virus-like particles are endocytosed using a unique combination of endosomal acidification-dependent clathrin-independent carriers (CLIC), acid sphingomyelinase (ASM)-mediated lysosomal exocytosis, and membrane wound repair pathways. We found that besides the known interaction of the viral capsid Protruding (P) domain with host glycans, the Shell (S) domain interacts with both galectin-3 (gal-3) and apoptosis-linked gene 2-interacting protein X (ALIX), to orchestrate GII.4 cell entry. Recognition of the viral and cellular determinants regulating HuNoV entry provides insight into the infection process of a non-enveloped virus highlighting unique pathways and targets for developing effective therapeutics.

Alternate JournalNat Commun
PubMed ID36854760
PubMed Central IDPMC9974061
Grant ListU19 AI144297 / AI / NIAID NIH HHS / United States
S10 OD028480 / OD / NIH HHS / United States
P01 AI057788 / AI / NIAID NIH HHS / United States
P30 ES030285 / ES / NIEHS NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
T32 AI055413 / AI / NIAID NIH HHS / United States
P30 DK056338 / DK / NIDDK NIH HHS / United States