@article{98c63ac140bb4bbbb83b3ce0a83ed1a3,
title = "Norovirus Cell Tropism Is Determined by Combinatorial Action of a Viral Non-structural Protein and Host Cytokine",
abstract = "Cellular tropism during persistent viral infection is commonly conferred by the interaction of a viral surface protein with a host receptor complex. Norovirus, the leading global cause of gastroenteritis, can be persistently shed during infection, but its in vivo cellular tropism and tropism determinants remain unidentified. Using murine norovirus (MNoV), we determine that a small number of intestinal epithelial cells (IECs) serve as the reservoir for fecal shedding and persistence. The viral non-structural protein NS1, rather than a viral surface protein, determines IEC tropism. Expression of NS1 from a persistent MNoV strain is sufficient for an acute MNoV strain to target IECs and persist. In addition, interferon-lambda (IFN-λ) is a key host determinant blocking MNoV infection in IECs. The inability of acute MNoV to shed and persist is rescued in Ifnlr1−/− mice, suggesting that NS1 evades IFN-λ-mediated antiviral immunity. Thus, NS1 and IFN-λ interactions govern IEC tropism and persistence of MNoV. The in vivo tropism of norovirus, a gastrointestinal pathogen, is unknown. Lee et al. discover that a small number of intestinal epithelial cells are a reservoir for persistent murine norovirus. This tropism is regulated by viral protein NS1 and host IFN-lambda, findings that provide critical insight into norovirus pathogenesis.",
keywords = "interferon-lambda, norovirus, persistence, reservoir, tropism",
author = "Sanghyun Lee and Wilen, {Craig B.} and Anthony Orvedahl and McCune, {Broc T.} and Kim, {Ki Wook} and Orchard, {Robert C.} and Peterson, {Stefan T.} and Nice, {Timothy J.} and Baldridge, {Megan T.} and Skip Virgin",
note = "Funding Information: The authors would like to thank D. Kreamalmeyer for animal care and breeding, the members of the Virgin lab for manuscript review and discussion, and the Flow Cytometry & Fluorescence Activated Cell Sorting Core Facility, the Molecular Microbiology Imaging Facility, and the Elvie L. Taylor Histology Core Facility at Washington University School of Medicine for assistance with cell sorting and immunofluorescence. The authors would also like to thank Thomas Ried for providing colonic IEC lines. H.W.V. was supported by NIH grant U19 AI109725, and the Crohn's and Colitis Foundation grant no. 326556. S.L. was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2016R1A6A3A03012352). M.T.B. was supported by NIH grant K22 AI127846-01 and DDRCC grant P30 DK052574. T.J.N. was supported by NIH training grant 5T32A100716334 and postdoctoral fellowships from the Cancer Research Institute and American Cancer Society. C.B.W. was supported by NIH grant 1K08AI128043-01. B.T.M. was supported by NCI-NIH award F31CA177194-01. K.-W.K. was supported by NIH R37 AI049653 to G.J. Randolph. A.O. was supported by Pediatric Infectious Diseases Society-St. Jude Children's Research Hospital Fellowship Program in Basic and Translational Research. Washington University holds patents related to murine norovirus. The University and H.W.V. receive income based on licenses for this MNV technology. Funding Information: The authors would like to thank D. Kreamalmeyer for animal care and breeding, the members of the Virgin lab for manuscript review and discussion, and the Flow Cytometry & Fluorescence Activated Cell Sorting Core Facility, the Molecular Microbiology Imaging Facility, and the Elvie L. Taylor Histology Core Facility at Washington University School of Medicine for assistance with cell sorting and immunofluorescence. The authors would also like to thank Thomas Ried for providing colonic IEC lines. H.W.V. was supported by NIH grant U19 AI109725 , and the Crohn's and Colitis Foundation grant no. 326556 . S.L. was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education ( NRF-2016R1A6A3A03012352 ). M.T.B. was supported by NIH grant K22 AI127846-01 and DDRCC grant P30 DK052574 . T.J.N. was supported by NIH training grant 5T32A100716334 and postdoctoral fellowships from the Cancer Research Institute and American Cancer Society . C.B.W. was supported by NIH grant 1K08AI128043-01 . B.T.M. was supported by NCI-NIH award F31CA177194-01 . K.-W.K. was supported by NIH R37 AI049653 to G.J. Randolph. A.O. was supported by Pediatric Infectious Diseases Society-St. Jude Children's Research Hospital Fellowship Program in Basic and Translational Research. Washington University holds patents related to murine norovirus. The University and H.W.V. receive income based on licenses for this MNV technology. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = oct,
day = "11",
doi = "10.1016/j.chom.2017.08.021",
language = "English",
volume = "22",
pages = "449--459.e4",
journal = "Cell Host and Microbe",
issn = "1931-3128",
number = "4",
}