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

Author:

Lin Shih-ChingORCID,Qu Lin,Ettayebi Khalil,Crawford Sue E.,Blutt Sarah E.,Robertson Matthew J.,Zeng Xi-Lei,Tenge Victoria R.ORCID,Ayyar B. VijayalakshmiORCID,Karandikar Umesh C.,Yu Xiaomin,Coarfa Cristian,Atmar Robert L.ORCID,Ramani Sasirekha,Estes Mary K.ORCID

Abstract

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, andSTAT2. An unexpected differential response of enhanced replication and virus spread was observed for GII.3, but not the globally dominant GII.4 HuNoV inSTAT1-knockoutHIEs 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.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases

HHS | National Institutes of Health

Cancer Prevention and Research Institute of Texas

HHS | NIH | National Cancer Institute

HHS | NIH | National Institute of Environmental Health Sciences

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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