IFN-I and IL-22 mediate protective effects of intestinal viral infection.

Jessica A Neil1, Yu Matsuzawa-Ishimoto1, Elisabeth Kernbauer-Hölzl1, Samantha L Schuster1, Stela Sota1,2, Mericien Venzon1,2, Simone Dallari1, Antonio Galvao Neto3, Ashley Hine4,5, David Hudesman5, P'ng Loke4, Timothy J Nice6, Ken Cadwell7,8

  1. Kimmel Center for Biology and Medicine, Skirball Institute of Biomedical Medicine, New York University School of Medicine, New York, NY, USA.
  2. Sackler Institute of Graduate Biomedical Sciences, New York University School of Medicine, New York, NY, USA.
  3. Department of Pathology, New York University School of Medicine, New York, NY, USA.
  4. Department of Microbiology, New York University School of Medicine, New York, NY, USA.
  5. Department of Medicine, Division of Gastroenterology, New York University School of Medicine, New York, NY, USA.
  6. Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA.
  7. Kimmel Center for Biology and Medicine, Skirball Institute of Biomedical Medicine, New York University School of Medicine, New York, NY, USA. Ken.Cadwell@med.nyu.edu.
  8. Department of Microbiology, New York University School of Medicine, New York, NY, USA. Ken.Cadwell@med.nyu.edu.

Abstract

Products derived from bacterial members of the gut microbiota evoke immune signalling pathways of the host that promote immunity and barrier function in the intestine. How immune reactions to enteric viruses support intestinal homeostasis is unknown. We recently demonstrated that infection by murine norovirus (MNV) reverses intestinal abnormalities following depletion of bacteria, indicating that an intestinal animal virus can provide cues to the host that are typically attributed to the microbiota. Here, we elucidate mechanisms by which MNV evokes protective responses from the host. We identify an important role for the viral protein NS1/2 in establishing local replication and a type I interferon (IFN-I) response in the colon. We further show that IFN-I acts on intestinal epithelial cells to increase the proportion of CCR2-dependent macrophages and interleukin (IL)-22-producing innate lymphoid cells, which in turn promote pSTAT3 signalling in intestinal epithelial cells and protection from intestinal injury. In addition, we demonstrate that MNV provides a striking IL-22-dependent protection against early-life lethal infection by Citrobacter rodentium. These findings demonstrate novel ways in which a viral member of the microbiota fortifies the intestinal barrier during chemical injury and infectious challenges.

Presented by Jessica Neil

Immunology & MicrobiologyVictoria Fang2019-06 (Jun)