1. Immunology and Inflammation
  2. Microbiology and Infectious Disease

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
https://doi.org/10.7554/eLife.73628
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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).

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.

Metrics

  • 1,893
    views
  • 476
    downloads
  • 30
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.73628

Categories and tags

Research organisms

Further reading

    1. Immunology and Inflammation

    CXXC-finger protein 1 associates with FOXP3 to stabilize homeostasis and suppressive functions of regulatory T cells

    Xiaoyu Meng, Yezhang Zhu ... Lie Wang
    Research Article

    FOXP3-expressing regulatory T (Treg) cells play a pivotal role in maintaining immune homeostasis and tolerance, with their activation being crucial for preventing various inflammatory responses. However, the mechanisms governing the epigenetic program in Treg cells during their dynamic activation remain unclear. In this study, we demonstrate that CXXC-finger protein 1 (CXXC1) interacts with the transcription factor FOXP3 and facilitates the regulation of target genes by modulating H3K4me3 deposition. Cxxc1 deletion in Treg cells leads to severe inflammatory disease and spontaneous T cell activation, with impaired immunosuppressive function. As a transcriptional regulator, CXXC1 promotes the expression of key Treg functional markers under steady-state conditions, which are essential for the maintenance of Treg cell homeostasis and their suppressive functions. Epigenetically, CXXC1 binds to the genomic regulatory regions of Treg program genes in mouse Treg cells, overlapping with FOXP3-binding sites. Given its critical role in Treg cell homeostasis, CXXC1 presents itself as a promising therapeutic target for autoimmune diseases.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease

    Soluble immune mediators orchestrate protective in vitro granulomatous responses across Mycobacterium tuberculosis complex lineages

    Ainhoa Arbués, Sarah Schmidiger ... Damien Portevin
    Research Article

    The members of the Mycobacterium tuberculosis complex (MTBC) causing human tuberculosis comprise 10 phylogenetic lineages that differ in their geographical distribution. The human consequences of this phylogenetic diversity remain poorly understood. Here, we assessed the phenotypic properties at the host-pathogen interface of 14 clinical strains representing five major MTBC lineages. Using a human in vitro granuloma model combined with bacterial load assessment, microscopy, flow cytometry, and multiplexed-bead arrays, we observed considerable intra-lineage diversity. Yet, modern lineages were overall associated with increased growth rate and more pronounced granulomatous responses. MTBC lineages exhibited distinct propensities to accumulate triglyceride lipid droplets—a phenotype associated with dormancy—that was particularly pronounced in lineage 2 and reduced in lineage 3 strains. The most favorable granuloma responses were associated with strong CD4 and CD8 T cell activation as well as inflammatory responses mediated by CXCL9, granzyme B, and TNF. Both of which showed consistent negative correlation with bacterial proliferation across genetically distant MTBC strains of different lineages. Taken together, our data indicate that different virulence strategies and protective immune traits associate with MTBC genetic diversity at lineage and strain level.

    1. Immunology and Inflammation

    Inflammasomes: A tale of two caspases

    Denise M Monack
    Insight

    Macrophages control intracellular pathogens like Salmonella by using two caspase enzymes at different times during infection.