Language

English

Publication Date

2-6-2026

Journal

Science Advances

DOI

10.1126/sciadv.aeb0455

PMID

41637508

PMCID

PMC12871457

PubMedCentral® Posted Date

2-4-2026

PubMedCentral® Full Text Version

Post-print

Abstract

The establishment of human intestinal enteroids (HIEs) as a model for human norovirus (HuNoV) replication has been transformative for studying this leading cause of gastroenteritis. However, indefinite passaging of HuNoVs in HIEs remained a challenge, necessitating the use of patient stool samples as viral inocula. Using RNA-seq, we identified CXCL10, CXCL11, and CCL5 as up-regulated chemokines, suggesting their potential as host restriction factors. TAK-779, a CXCR3/CCR5/CCR2 antagonist, enhanced GII.3 HuNoV replication and viral spread in a dose- and time-dependent manner, enabling successful passaging of GII.3 HuNoV in two different HIE lines and generation of viral stocks. Sequencing passaged virus revealed one consensus change in the major capsid protein and several dynamic adaptations, suggesting emergence of variants. TAK-779 also enhanced replication of GI.1 and GII.17 strains, but not GII.4, suggesting strain-specific host interactions. This breakthrough in passaging provides insight into HuNoV-host interactions, establishes a scalable in vitro system for virus propagation, and opens avenues for structural, biochemical, and therapeutic studies.

Keywords

Humans, Norovirus, Virus Replication, Intestines, Chemokines, Caliciviridae Infections, Organoids, Host-Pathogen Interactions

Published Open-Access

yes

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