Figure 4.

The exo-siRNA pathway in response to mosquito-borne flavivirus infection and its antagonism in humans (A) and mosquitoes (B). dsRNAs generated during viral replication in mosquitoes are recognized by the PRR Dicer-2 which cleaves the dsRNAs into 21-nucleotide virus-derived siRNAs (vsiRNAs) [122]. The vsiRNA duplex is then incorporated into Argonaute proteins (Ago2) leading to the formation of the RNA-induced silencing complex (RISC) [122]. The passenger strand of the vsiRNA duplex is eliminated from the activated RISC, while the guide strand is retained, allowing recognition of matching viral RNA sequences based on Watson-Crick base pairing, and then complementary RNAs are degraded by the endonuclease activity of Ago-2 [122]. Note that miRNAs are processed by Dicer-1 in insects, separating the miRNA and antiviral exo-siRNA pathways in insects through duplication of the Dicer gene [123]. In contrast, human RNAi is mediated by a single Dicer gene that recognizes dsRNA structures from siRNA and miRNA pathways [124]. Virus-encoded antagonists of mosquito-borne flaviviruses (DENV in purple, ZIKV in green, WNV in light blue, JEV in orange, YFV in black) are able to block these pathways in humans and mosquitoes. See main text for details.