Overcoming host restrictions to enable continuous passaging of human noroviruses in human intestinal enteroids
Kaur, G.; Crawford, S. E.; Ramani, S.; Ayyar, B. V.; Boussattach, A. I.; Zeng, X.-L.; Atmar, R. L.; Nguyen-Phuc, H.; Coarfa, C.; Estes, M. K.
Show abstract
Human noroviruses (HuNoVs), the leading cause of viral gastroenteritis, can now be cultivated in human intestinal enteroids (HIEs). 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 host restriction factors that might limit viral passaging. CXCL10, CXCL11, and CCL5 were among the most upregulated 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. TAK-779 also enhanced replication of GI.1 and GII.17 strains, but not GII.4, suggesting strain-specific host interactions or immune evasion. This breakthrough in passaging provides critical insight into HuNoV-host interactions, establishes a scalable in vitro system for virus propagation, and opens avenues for structural, biochemical and therapeutic studies.
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