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Human norovirus exhibits strain-specific sensitivity to host interferon pathways in human intestinal enteroids

Significance Host innate immune responses are the first line of defense against viral infections, with the outcome of infection determined by the interplay between virus and host defense mechanisms. We report transcriptomic and functional analyses of epithelial cell responses to HuNoV infection in HIE cultures. HuNoV infection triggers predominantly a type III interferon (IFN) response and upregulation of long noncoding RNAs. Exogenously added IFNs restrict HuNoV replication in a strain-independent manner, but we unexpectedly found strain-dependent effects of endogenously activated cellular IFNs. Our findings suggest strain-specific sensitivities to IFN as a factor for global dominance of pandemic strains, provide a new arsenal of stable HIE knockout lines for several IFN pathways, and highlight strain differences as a consideration for development of effective therapies. Human noroviruses (HuNoVs) are the leading cause of viral gastroenteritis worldwide; yet currently, no vaccines or FDA-approved antiviral drugs are available to counter these pathogens. To understand HuNoV biology and the epithelial response to infection, we performed transcriptomic analyses, RT-qPCR, CRISPR-Cas9 modification of human intestinal enteroid (HIE) cultures, and functional studies with two virus strains (a pandemic GII.4 and a bile acid-dependent GII.3 strain). We identified a predominant type III interferon (IFN)-mediated innate response to HuNoV infection. Replication of both strains is sensitive to exogenous addition of IFNs, suggesting the potential of IFNs as therapeutics. To obtain insight into IFN pathway genes that play a role in the antiviral response to HuNoVs, we developed knockout (KO) HIE lines for IFN alpha and lambda receptors and the signaling molecules, MAVS, STAT1, and STAT2. An unexpected differential response of enhanced replication and virus spread was observed for GII.3, but not the globally dominant GII.4 HuNoV in STAT1-knockout HIEs compared to parental HIEs. These results indicate cellular IFN responses restrict GII.3 but not GII.4 replication. The strain-specific sensitivities of innate responses against HuNoV replication provide one explanation for why GII.4 infections are more widespread and highlight strain specificity as an important factor in HuNoV biology. Genetically modified HIEs for innate immune genes are useful tools for studying immune responses to viral or microbial pathogens.