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

TitleHuman norovirus exhibits strain-specific sensitivity to host interferon pathways in human intestinal enteroids.
Publication TypeJournal Article
Year of Publication2020
AuthorsLin, S-C, Qu, L, Ettayebi, K, Crawford, SE, Blutt, SE, Robertson, MJ, Zeng, X-L, Tenge, VR, B Ayyar, V, Karandikar, UC, Yu, X, Coarfa, C, Atmar, RL, Ramani, S, Estes, MK
JournalProc Natl Acad Sci U S A
Volume117
Issue38
Pagination23782-23793
Date Published2020 Sep 22
ISSN1091-6490
KeywordsCaliciviridae Infections, CRISPR-Cas Systems, Host-Pathogen Interactions, Humans, Interferons, Intestines, Models, Biological, Norovirus, Organoids, Sequence Analysis, RNA, Transcriptome, Virus Replication
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, , , and An unexpected differential response of enhanced replication and virus spread was observed for GII.3, but not the globally dominant GII.4 HuNoV in 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.

DOI10.1073/pnas.2010834117
Alternate JournalProc Natl Acad Sci U S A
PubMed ID32907944
PubMed Central IDPMC7519316
Grant ListU19 AI144297 / AI / NIAID NIH HHS / United States
U19 AI116497 / AI / NIAID NIH HHS / United States
P30 DK056338 / DK / NIDDK NIH HHS / United States
HHSN272201700081C / AI / NIAID NIH HHS / United States
P30 ES030285 / ES / NIEHS NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
T32 DK007664 / DK / NIDDK NIH HHS / United States
P01 AI057788 / AI / NIAID NIH HHS / United States