Tuft-cell-intrinsic and -extrinsic mediators of norovirus tropism regulate viral immunity

Madison S Strine; Mia Madel Alfajaro; Vincent R Graziano; Jaewon Song; Leon L Hsieh; Ryan Hill; Jun Guo; Kelli L VanDussen; Robert C Orchard; Megan T Baldridge; Sanghyun Lee; Craig B Wilen

doi:10.1016/j.celrep.2022.111593

Tuft-cell-intrinsic and -extrinsic mediators of norovirus tropism regulate viral immunity

Cell Rep. 2022 Nov 8;41(6):111593. doi: 10.1016/j.celrep.2022.111593.

Authors

Affiliations

¹ Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA.
² Department of Immunology, University of Connecticut Health Center, Farmington, CT, USA.
³ Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA.
⁴ Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
⁵ Division of Infectious Diseases, Department of Medicine, Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.
⁶ Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA.
⁷ Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH, USA.
⁸ Department of Immunology, University of Texas Southwestern Medical School, Dallas, TX, USA.
⁹ Department of Medicine, Division of Infectious Diseases, Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, Saint Louis, MO, USA.
¹⁰ Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA. Electronic address: sanghyun_lee@brown.edu.
¹¹ Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA. Electronic address: craig.wilen@yale.edu.

Abstract

Murine norovirus (MNoV) is a model for human norovirus and for interrogating mechanisms of viral tropism and persistence. We previously demonstrated that the persistent strain MNoV^CR6 infects tuft cells, which are dispensable for the non-persistent strain MNoV^CW3. We now show that diverse MNoV strains require tuft cells for chronic enteric infection. We also demonstrate that interferon-λ (IFN-λ) acts directly on tuft cells to cure chronic MNoV^CR6 infection and that type I and III IFNs signal together via STAT1 in tuft cells to restrict MNoV^CW3 tropism. We then develop an enteroid model and find that MNoV^CR6 and MNoV^CW3 similarly infect tuft cells with equal IFN susceptibility, suggesting that IFN derived from non-epithelial cells signals on tuft cells in trans to restrict MNoV^CW3 tropism. Thus, tuft cell tropism enables MNoV persistence and is determined by tuft cell-intrinsic factors (viral receptor expression) and -extrinsic factors (immunomodulatory signaling by non-epithelial cells).

Keywords: CP: Immunology; CP: Microbiology; immune evasion; interferon; mucosal immunity; norovirus; tuft cells; viral persistence; viral tropism.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Caliciviridae Infections* / metabolism
Humans
Mice
Mice, Inbred C57BL
Norovirus* / physiology
Tropism
Viral Tropism

Abstract

Publication types

MeSH terms

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