m6A modifications regulate intestinal immunity and rotavirus infection

  1. Anmin Wang
  2. Wanyiin Tao
  3. Jiyu Tong
  4. Juanzi Gao
  5. Jinghao Wang
  6. Gaopeng Hou
  7. Chen Qian
  8. Guorong Zhang
  9. Runzhi Li
  10. Decai Wang
  11. Xingxing Ren
  12. Kaiguang Zhang
  13. Siyuan Ding
  14. Richard A Flavell
  15. Huabing Li
  16. Wen Pan  Is a corresponding author
  17. Shu Zhu  Is a corresponding author
  1. University of Science and Technology of China, China
  2. Shanghai Jiao Tong University, China
  3. Washington University in St. Louis, United States
  4. Yale University, United States

Abstract

N6-methyladenosine (m6A) is an abundant mRNA modification and affects many biological processes. However, how m6A levels are regulated during physiological or pathological processes such as virus infections, and the in vivo function of m6A in the intestinal immune defense against virus infections are largely unknown. Here, we uncover a novel antiviral function of m6A modification during rotavirus (RV) infection in small bowel intestinal epithelial cells (IECs). We found that rotavirus infection induced global m6A modifications on mRNA transcripts by down-regulating the m6a eraser ALKBH5. Mice lacking the m6A writer enzymes METTL3 in IECs (Mettl3ΔIEC) were resistant to RV infection and showed increased expression of interferons (IFNs) and IFN-stimulated genes (ISGs). Using RNA-sequencing and m6A RNA immuno-precipitation (RIP)-sequencing, we identified IRF7, a master regulator of IFN responses, as one of the primary m6A targets during virus infection. In the absence of METTL3, IECs showed increased Irf7 mRNA stability and enhanced type I and III IFN expression. Deficiency in IRF7 attenuated the elevated expression of IFNs and ISGs and restored susceptibility to RV infection in Mettl3ΔIEC mice. Moreover, the global m6A modification on mRNA transcripts declined with age in mice, with a significant drop from 2 weeks to 3 weeks post birth, which likely has broad implications for the development of intestinal immune system against enteric viruses early in life. Collectively, we demonstrated a novel host m6A-IRF7-IFN antiviral signaling cascade that restricts rotavirus infection in vivo.

Data availability

RNA sequencing data are available from the SRA database with accession numbers PRJNA713535.All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files is in Dryad.Source Data contain the numerical data used to generate the figures.

The following data sets were generated

Article and author information

Author details

  1. Anmin Wang

    Department of Digestive Disease, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Wanyiin Tao

    Department of Digestive Disease, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Jiyu Tong

    Department of Microbiology and Immunology, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Juanzi Gao

    Department of Digestive Disease, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Jinghao Wang

    Department of Digestive Disease, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Gaopeng Hou

    Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Chen Qian

    Department of Digestive Disease, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Guorong Zhang

    Department of Digestive Disease, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Runzhi Li

    Department of Digestive Disease, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Decai Wang

    Department of Digestive Disease, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Xingxing Ren

    Department of Digestive Disease, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Kaiguang Zhang

    Department of Digestive Disease, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Siyuan Ding

    Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Richard A Flavell

    Department of Immunobiology, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4461-0778
  15. Huabing Li

    Department of Microbiology and Immunology, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  16. Wen Pan

    Department of Digestive Disease, University of Science and Technology of China, Hefei, China
    For correspondence
    wenpan@ustc.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  17. Shu Zhu

    Institute of Immunology, University of Science and Technology of China, Hefei, China
    For correspondence
    zhushu@ustc.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8163-0869

Funding

Chinese Academy of Sciences (Strategic Priority Research Program (XDB29030101))

  • Shu Zhu

National Key Research and Development Program of China (2018YFA0508000)

  • Shu Zhu

National Natural Science Foundation of China (81822021,91842105,31770990,82061148013,81821001)

  • Shu Zhu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal studies were performed according to approved protocols by the Ethics Committee at the University of Science and Technology of China (USTCACUC202101016).

Reviewing Editor

  1. Kiyoshi Takeda, Osaka University, Japan

Publication history

  1. Received: September 6, 2021
  2. Preprint posted: September 17, 2021 (view preprint)
  3. Accepted: January 28, 2022
  4. Accepted Manuscript published: January 31, 2022 (version 1)
  5. Version of Record published: February 21, 2022 (version 2)

Copyright

© 2022, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Anmin Wang
  2. Wanyiin Tao
  3. Jiyu Tong
  4. Juanzi Gao
  5. Jinghao Wang
  6. Gaopeng Hou
  7. Chen Qian
  8. Guorong Zhang
  9. Runzhi Li
  10. Decai Wang
  11. Xingxing Ren
  12. Kaiguang Zhang
  13. Siyuan Ding
  14. Richard A Flavell
  15. Huabing Li
  16. Wen Pan
  17. Shu Zhu
(2022)
m6A modifications regulate intestinal immunity and rotavirus infection
eLife 11:e73628.
https://doi.org/10.7554/eLife.73628

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