Reduction of m6A RNA methylation ameliorates antiviral response in celiac disease

m6A RNA modifications and reovirus infections have recently been involved in the development of celiac disease. Moreover, viral infections are linked to alterations in the RNA modification machinery of the host, but the link between these two events has not been studied in the context of autoimmunity driven tissue damage. Here we used an in vitro model of viral mimic combined with gliadin peptides, resembling celiac disease, together with sera and intestinal biopsies of controls and patients to describe the relationship between m6A methylation and viral infections in inducing autoimmunity related inflammation. We found elevated anti-reovirus reactivity in patients, together with higher antiviral gene expression and m6A induction. Additionally, we described a synergistic increase of IRF7 expression upon simultaneous exposure to the viral mimic and gliadin peptides is mediated by the presence of m6A motifs within its CDS and interaction with YTHDC2 reader protein. Furthermore, our findings revealed that reduction of m6A by METTL3 silencing or simvastatin treatment reduce IRF7 methylation and downstream inflammatory gene expression in vitro and ex vivo, opening new avenues for therapeutic interventions in autoimmune disorders.