Abstract

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.

Document Type

Article

Publication Date

2-2023

Notes/Citation Information

© The Author(s) 2023

Digital Object Identifier (DOI)

https://doi.org/10.1038/s41467-023-36398-z

Funding Information

This research was supported by National Institutes of Health Grant P01 AI57788, P30 DK56338 that supports the Texas Medical Center Digestive Diseases Center and the Texas Children’s Hospital EM core, T32 AI055413 (to V.R.T.), S10 OD028480 that supported purchasing the Zeiss Laser Scanning Microscope LSM 980 with Airyscan 2 and the Robert Welch Foundation Q1279. The authors would like to acknowledge the Advanced Technology Core Laboratories (Baylor College of Medi- cine), specifically the Integrated Microscopy Core with funding from the NIH (DK56338, CA125123, ES030285), and CPRIT (RP150578, RP170719). We thank Xiaomin Yu and Hannah Johnson for technical assistance with human intestinal enteroids and imaging and Drs. Sasirekha Ramani, Joseph Hyser, and Jeanette Criglar for their helpful suggestions.

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