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Author Spotlight: Investigating Viral Disruption of Intestinal Epithelial Signaling – Research Insights and Future Directions
Published on: January 19, 2024
m6A modifications regulate intestinal immunity and rotavirus infection
Anmin Wang1,2, Wanyiin Tao1,2, Jiyu Tong3
1Department 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.
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.
Insights
N6-methyladenosine (m6A) modification restricts rotavirus infection by stabilizing IRF7 mRNA, boosting interferon production in intestinal cells. This m6A-IRF7-IFN pathway is crucial for antiviral defense, especially in early life.
Area of Science:
- Epigenetics and RNA modifications
- Virology and host-pathogen interactions
- Immunology and innate immunity
Background:
- N6-methyladenosine (m6A) is a prevalent mRNA modification influencing biological processes.
- The role of m6A in intestinal antiviral immunity, particularly during rotavirus (RV) infection, remains largely unexplored.
- Understanding m6A regulation and function is critical for developing host-directed antiviral strategies.
Purpose of the Study:
- To investigate the role of m6A modification in intestinal epithelial cells (IECs) during rotavirus infection.
- To identify key m6A targets and elucidate the underlying antiviral signaling mechanisms.
- To explore the age-dependent changes in m6A modification and their implications for neonatal immunity.
Main Methods:
- Utilized genetically modified mice lacking the m6A writer enzyme METTL3 in IECs (Mettl3ΔIEC).
- Employed RNA-sequencing and m6A RNA immunoprecipitation (RIP)-sequencing to identify m6A targets.
- Assessed viral load, interferon (IFN) and IFN-stimulated gene (ISG) expression, and mRNA stability.
Main Results:
- Rotavirus infection down-regulated the m6A eraser ALKBH5, increasing global m6A levels.
- Mettl3ΔIEC mice exhibited resistance to RV infection, characterized by elevated IFN and ISG expression.
- IRF7 was identified as a key m6A target; its mRNA stability and subsequent IFN responses were enhanced in Mettl3-deficient IECs.
- IRF7 deficiency in Mettl3ΔIEC mice restored RV susceptibility and attenuated IFN/ISG responses.
- Global m6A modification significantly decreased with age in mice, particularly between 2 and 3 weeks post-birth.
Conclusions:
- A novel host antiviral signaling cascade involving m6A modification, IRF7, and IFN production restricts rotavirus infection in vivo.
- METTL3-mediated m6A modification of IRF7 is essential for robust intestinal antiviral immunity.
- Age-related decline in m6A modification may impact the developing intestinal immune system's ability to combat enteric viral infections.
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