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

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.

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Fig. 1: Sequence variation in NS1/2 contributes to protection from intestinal injury.
Fig. 2: NS1/2 sequence variation contributes to intestinal persistence, IFN-I signalling and epithelial cell proliferation following intestinal injury.
Fig. 3: Protection of ABX-treated mice from intestinal injury is dependent on IL-22.
Fig. 4: Protection from intestinal injury and IL-22 expression is associated with CCR2-dependent cells.
Fig. 5: IFN-I signalling in IEC is required for protection from intestinal injury.
Fig. 6: IECs react to IFN-I stimulation and promote an IL-22 response.
Fig. 7: MNV protects young mice from enteric bacterial infection.

Data availability

The data that support the findings of this study are available from the corresponding author on request. FASTQ files corresponding to the RNA–seq and 16S rRNA sequencing have been deposited in a public database (RNA–seq accession no. GSE129384 and 16S accession no. PRJNA532632).

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Acknowledgements

We wish to thank the following NYU facilities for the use of their instruments and technical assistance: Microcopy Core (grant no. RR023704), Histopathology and Immunohistochemistry Core (grant nos P30CA016087, NIH S10 OD010584-01A1 and S10 OD018338-01), the Cytometry and Cell Sorting Laboratory (grant no. P30CA016087), the Genome Technology Center (grant no. P30CA016087) and the Gnotobitoic Facility (Colton Center for Autoimmunity). We also wish to thank S. Fujii (Washington University School of Medicine in St. Louis) for his technical support in human organoid culture. This research was supported by US National Institute of Health (NIH) grant nos R01 HL123340 (K.C.), R01 DK093668 (K.C.), R01 DK103788 (K.C. and P.L.), R01 AI121244 (K.C.) and R01 AI130945 (P.L.). This work was also supported by a Vilcek Fellowship (J.A.N.), Sir Keith Murdoch Fellowship (J.A.N.), Crohn’s & Colitis Foundation Research Fellowship Award (Y.M.-I.), Faculty Scholar grant from the Howard Hughes Medical Institute (K.C.), Advanced Research Grant from the Merieux Institute (K.C.), Rainin Foundation Innovator Award (K.C.), Stony Wold-Herbert Fund (K.C.), PureTech Health (K.C.), Pfizer (K.C. and P.L.), NYU CTSI (grant no. NIH/NCATS 1UL TR001445; K.C. and P.L.) and philanthropy from Bernard Levine (K.C. and P.L.). K.C. is a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Diseases.

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J.A.N. and K.C. formulated the original hypothesis and designed the study. J.A.N. performed the experiments and analyses, and received assistance from E.K.-H. (DSS experiments), S.S. (in vitro MNV responses) and Y.M.-I. (organoids). S.L.S. and M.V. processed and analysed the samples for 16S rRNA sequencing. A.G.N. performed the histopathology analysis. P.L., D.H. and A.H. provided the human colon biopsies. S.D. performed the sorting of IECs. T.L.N. provided the cDNA clones of MNV and advice. J.A.N. and K.C. wrote the manuscript. All authors commented on the manuscript, data and conclusions.

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Correspondence to Ken Cadwell.

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K.C. has consulted for PureTech Health and AbbVie Inc. and is an inventor on US patent application 62/608,404.

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Neil, J.A., Matsuzawa-Ishimoto, Y., Kernbauer-Hölzl, E. et al. IFN-I and IL-22 mediate protective effects of intestinal viral infection. Nat Microbiol 4, 1737–1749 (2019). https://doi.org/10.1038/s41564-019-0470-1

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