circEPSTI1 Enables Dengue Innate Immune Evasion by Sponging miR-942-5p, a Repressor of AKT1 and the Viral Genome

Circular RNAs (circRNAs) are recently emerging transcripts that are gaining attention for their potential role in host-pathogen interactions. However, the role of circRNAs in Dengue virus (DENV) infection remains unexplored. In this study, circEPSTI1 induction was observed in DENV-infected peripheral blood mononuclear cells (PBMCs) and plasma of Dengue patients. circEPSTI1 induction is interferon-dependent, as IRF3-knockout cells completely abolished its induction. circEPSTI1 enhances DENV infection by sponging the expression of hsa-miR-942-5p. The antiviral role of hsa-miR-942-5p is mediated by bidirectional inhibition of conserved genomic sequences of the DENV genome across NS1, NS3 and NS5 and the host AKT1 signaling pathway. circEPSTI1 sponges hsa-miR-942-5p and relieves its inhibition over DENV genomic RNA and the host AKT1 signaling pathway, thus leading to increased AKT1 activation and DENV replication. These findings highlight the diagnostic and therapeutic potential of circEPSTI1 and the novel circEPSTI1-miR-942-5p-AKT1 axis that regulates the host immune response against DENV infection.