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Study of the role of the epigenetic modification m6A in the amplification and fitness of the diabetogenic Coxsackievirus B in pancreatic beta cells

par Fernandes Bonfim, Maressa
Président du jury Deplus, Rachel
Promoteur Op De Beeck, Anne
Co-Promoteur Eizirik, Decio L.
Publication Non publié, 2025-10-06

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Résumé :

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the progressive destruction of pancreatic beta cells, often associated with enteroviral infections, particularly Coxsackievirus B (CVB). Among CVB serotypes, CVB1 has been linked to the induction of beta-cell autoimmunity in genetically predisposed individuals. However, the mechanisms driving serotype-specific viral fitness in pancreatic beta cells remain unclear. Here, we observed that the CVB1 genome harbors mechanisms that enable it to replicate more efficiently and induce higher cytopathogenic effects (CPE) in human pancreatic beta cells compared to CVB5. Given the role of post-transcriptional RNA modifications in regulating RNA virus infection, we investigated whether N⁶-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNA, contributes to CVB serotype-specific replication in beta cells. By using gene silencing and pharmacological inhibition approaches, we demonstrate that m6A acts as a negative regulator of CVB1 amplification, while CVB5 appears less responsive to modulation of the m6A machinery. Specifically, silencing of m6A methyltransferases METTL3 and WTAP enhanced CVB1 amplification, whereas knockdown the demethylases FTO and ALKBH5 impaired viral production. Notable, the inhibition of FTO reduced by 95% the production of infectious CVB1 in both human insulin-producing EndoC-βH1 cells and in induced pluripotent stem cell (iPSC)-derived islets. The FTO inhibitor reduced CVB1 expression within 6 hours post-infection, suggesting a direct regulation of the CVB1 genome by m6A modification. Furthermore, in the absence of viral replication, FTO inhibition decreased the translation of the incoming CVB1 genome, indicating that m6A plays a critical role in initial stages of viral RNA translation. Additionally, we observed early cleavage of m6A reader proteins YTHDF1 and YTHDF3 during CVB1 infection, suggesting that other cytoplasmic readers may mediate m6A effects on viral RNA. Together, our findings provides the first evidence that the m6A epigenetic modification machinery controls CVB1 amplification in human pancreatic beta cells, highlighting RNA methylation as a potential target for therapeutic strategies to control diabetogenic viral infections.