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Cell Host Microbe. 2019 Jun 12;25(6):845-857.e5. doi: 10.1016/j.chom.2019.04.005. Epub 2019 May 23.

A Secreted Viral Nonstructural Protein Determines Intestinal Norovirus Pathogenesis.

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: sanghyunlee@wustl.edu.
2
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
Departments of Laboratory Medicine and Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
4
Department of Immunology, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5
Department of Pharmacology and Center for Stem Cell and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA.
6
Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239, USA.
7
Department of Medicine, Division of Infectious Diseases, Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
8
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: virgin@wustl.edu.

Abstract

Murine norovirus (MNoV) infects a low percentage of enteric tuft cells and can persist in these cells for months following acute infection. Both tuft-cell tropism and resistance to interferon-λ (IFN-λ)-mediated clearance during persistent infection requires the viral nonstructural protein 1/2 (NS1/2). We show that processing of NS1/2 yields NS1, an unconventionally secreted viral protein that is central for IFN-λ resistance. MNoV infection globally suppresses intestinal IFN-λ responses, which is attributable to secreted NS1. MNoV NS1 secretion is triggered by caspase-3 cleavage of NS1/2, and a secreted form of human NoV NS1 is also observed. NS1 secretion is essential for intestinal infection and resistance to IFN-λ in vivo. NS1 vaccination alone protects against MNoV challenge, despite the lack of induction of neutralizing anti-capsid antibodies previously shown to confer protection. Thus, despite infecting a low number of tuft cells, NS1 secretion allows MNoV to globally suppress IFN responses and promote persistence.

KEYWORDS:

IFN-λ; NS1; norovirus; secretion; vaccine

PMID:
31130511
PMCID:
PMC6622463
[Available on 2020-06-12]
DOI:
10.1016/j.chom.2019.04.005

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