@article{a4b7444859634069ab7f5d8f6b200139,
title = "Expression of Ifnlr1 on intestinal epithelial cells is critical to the antiviral effects of interferon lambda against norovirus and reovirus",
abstract = "Lambda interferon (IFN-λ) has potent antiviral effects against multiple enteric viral pathogens, including norovirus and rotavirus, in both preventing and curing infection. Because the intestine includes a diverse array of cell types, however, the cell(s) upon which IFN-λ acts to exert its antiviral effects is unclear. Here, we sought to identify IFN-λ-responsive cells by generation of mice with lineagespecific deletion of the receptor for IFN-λ, Ifnlr1. We found that expression of IFNLR1 on intestinal epithelial cells (IECs) in the small intestine and colon is required for enteric IFN-λ antiviral activity. IEC Ifnlr1 expression also determines the efficacy of IFN-λ in resolving persistent murine norovirus (MNoV) infection and regulates fecal shedding and viral titers in tissue. Thus, the expression of Ifnlr1 by IECs is necessary for the response to both endogenous and exogenous IFN-λ. We further demonstrate that IEC Ifnlr1 expression is required for the sterilizing innate immune effects of IFN-λ by extending these findings in Rag1-deficient mice. Finally, we assessed whether our findings pertained to multiple viral pathogens by infecting mice specifically lacking IEC Ifnlr1 expression with reovirus. These mice phenocopied Ifnlr1- null animals, exhibiting increased intestinal tissue titers and enhanced reovirus fecal shedding. Thus, IECs are the critical cell type responding to IFN-λ to control multiple enteric viruses. This is the first genetic evidence that supports an essential role for IECs in IFN-λ-mediated control of enteric viral infection, and these findings provide insight into the mechanism of IFN-λ-mediated antiviral activity.",
keywords = "Innate immunity, Interferons, Mucosal immunity, Norovirus, Reovirus",
author = "Baldridge, {Megan T.} and Sanghyun Lee and Brown, {Judy J.} and Nicole McAllister and Kelly Urbanek and Dermody, {Terence S.} and Nice, {Timothy J.} and Virgin, {Herbert W.}",
note = "Funding Information: We thank D. Kreamalmeyer for animal care and breeding, S. Peterson for technical assistance, members of the Virgin laboratory for manuscript review and discussion, S. Doyle and Bristol-Myers Squibb for providing Ifnlr1tm1Palu mice, and Bill Skarnes and Wendy Bushell at the Wellcome Trust Sanger Institute for providing Ifnlr1tm1a(EUCOMM)Wtsi ES cells. Experimental support was provided by the Speed Congenics Facility of the Rheumatic Diseases Core Center. H.W.V. was supported by National Institutes of Health (NIH) grant U19 AI109725 and the Crohn's and Colitis Foundation grant 326556. M.T.B. was supported by NIH training grant 5T32CA009547 and the W. M. Keck Fellowship from Washington University. T.J.N. was supported by NIH training grant 5T32A100716334 and postdoctoral fellowships from the Cancer Research Institute and American Cancer Society. S.L. was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2016R1A6A3A03012352). J.B. was supported by NIH training grant 5T32HL007751 and predoctoral fellowship F31DK108562. T.S.D. was supported by NIH grant R01 AI038296. Research reported in this publication was supported by NIH award number P30AR048335. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2017 American Society for Microbiology. All Rights Reserved. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.",
year = "2017",
doi = "10.1128/JVI.02079-16",
language = "English (US)",
volume = "91",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "7",
}