2. Academic Validation
  3. m6A modifications regulate intestinal immunity and rotavirus infection

m6A modifications regulate intestinal immunity and rotavirus infection

  • Elife. 2022 Jan 31;11:e73628. doi: 10.7554/eLife.73628.
Anmin Wang 1 2,  Wanyiin Tao 1 2,  Jiyu Tong 3,  Juanzi Gao 1,  Jinghao Wang 1,  Gaopeng Hou 4,  Chen Qian 1,  Guorong Zhang 1 2,  Runzhi Li 1 2,  Decai Wang 1 2,  Xingxing Ren 1 2,  Kaiguang Zhang 1,  Siyuan Ding 4,  Richard A Flavell 5 6,  Huabing Li 3,  Wen Pan 1 2,  Shu Zhu 1 2 7 8
Affiliations

Affiliations

  • 1 Department of Digestive Disease, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 2 Institute of Immunology, the Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 3 Shanghai Institute of Immunology, Department of Microbiology and Immunology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.
  • 4 Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, United States.
  • 5 Department of Immunobiology, Yale University School of Medicine, New Haven, United States.
  • 6 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
  • 7 School of Data Science, University of Science and Technology of China, Hefei, China.
  • 8 Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China, Hefei, China.
PMID: 35098923 DOI: 10.7554/eLife.73628
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.

Keywords

IRF7; immunology; infectious disease; inflammation; innate immune; m6A; microbiology; mouse; rotavirus; virus infection; viruses.

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