Enteric viral infections have been related to the risk of developing different autoimmune disorders. Celiac disease (CeD) is an intestinal autoimmune disease in which dietary gluten is the main triggering agent, but enteroviral infections have been suggested as additional contributing environmental factors. The viral related type I interferon (IFN-I) pathway has been involved in CeD pathogenesis. Additionally, m6A RNA methylation is implicated in the control of the innate immune response to infections and has also been related to the development of autoimmunity.
We hypothesized that gluten consumption can reactivate the IFN-I pathway in patients that have been previously infected by enteric virus, and that this is regulated by an m6A-dependent mechanism. We confirmed the alterations in the IFN-I pathway and the m6A machinery in intestinal biopsies of CeD patients. Additionally, patients presented higher serum titers of antibodies against intestinal reovirus. PIC treatment, used as a viral mimic, in combination with gluten, induced an IFN-I response and altered the expression of certain m6A machinery genes with an overall increase in m6A levels in intestinal cells. Interestingly, when PIC treatment was combined with gluten, the alterations in m6A eraser ALKBH5, m6A writer METTL3 and IRF7 were stronger than those observed with PIC or gluten alone. We confirmed the methylation of IRF7 mRNA by meRIP-qPCR and observed that ALKBH5 silencing and METTL3 overexpression were able to increase IRF7 and downstream gene expression levels, verifying the involvement of m6A machinery in the regulation of this pathway. Although METTL3 overexpression decreases IRF7 mRNA stability, higher protein amounts are observed suggesting that m6A regulates its transcription.
To sum up, our results suggest that in the context of viral infection, gluten consumption may lead to the development of an autoimmune response through an alteration of the m6A machinery and the induction of innate immune pathways.