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.
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Data from: m6A modifications regulate intestinal immunity and rotavirus infectionDryad Digital Repository, doi:10.5061/dryad.p2ngf1vr8.
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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.
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m6A modifications regulate intestinal immunity and rotavirus infection
eLife 11:e73628.
https://doi.org/10.7554/eLife.73628
