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

Circular RNAs (circRNAs) have recently been identified as crucial regulators of gene expression in various diseases. Their role in dengue remains unexplored. In this study, circEPSTI1 induction was observed in peripheral blood mononuclear cells (PBMCs) and plasma of dengue patients. The induction of circEPSTI1 is interferon-dependent and enhances DENV infection by sponging the expression of miR-942-5p. The antiviral role of miR-942-5p is mediated by bidirectional inhibition through targeting conserved genomic sequences of the DENV genome of different subtypes across NS1, NS3, and NS5 and the host AKT1 signaling pathway. RNA-seq analysis of DENV-infected circEPSTI1 knockdown A549 cells identified SERPINE1 and AKT1 signaling pathways to be dysregulated significantly. circEPSTI1 relieves the inhibition of miR-942-5p over DENV genomic RNA and the host SERPINE1 to activate AKT1 signaling. The activation of AKT1 signaling facilitates cell survival and enhances DENV replication. The expression of SERPINE1 and circEPSTI1 was upregulated in Dengue patients, and pharmaceutical inhibition of SERPINE1 through Tiplaxtinin inhibits the DENV replication by reducing the expression of circEPSTI1. Overall, our result demonstrates the therapeutic potential of Tiplaxtinin by targeting the circ-EPSTI1-miR-942-5p-SERPINE1-AKT axis in dengue treatment.