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

Autor:	Lin SC; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Qu L; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Ettayebi K; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Crawford SE; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Blutt SE; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Robertson MJ; Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030., Zeng XL; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Tenge VR; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Ayyar BV; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Karandikar UC; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Yu X; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Coarfa C; Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030.; Duncan Cancer Center-Biostatistics, Baylor College of Medicine, Houston, TX 77030.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030., Atmar RL; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.; Department of Medicine, Baylor College of Medicine, Houston, TX 77030., Ramani S; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Estes MK; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030; mestes@bcm.edu.; Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Sep 22; Vol. 117 (38), pp. 23782-23793. Date of Electronic Publication: 2020 Sep 09.
DOI:	10.1073/pnas.2010834117
Abstrakt:	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. Competing Interests: Competing interest statement: M.K.E. is named as an inventor on patents related to cloning and cultivation of the Norwalk virus genome and is a consultant to and received research funding from Takeda Vaccines, Inc. R.L.A. has received research funding from Takeda Vaccines, Inc.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu