Mosquito immunity against arboviruses

Abstract

Arthropod-borne viruses (arboviruses) pose a significant threat to global health, causing human disease with increasing geographic range and severity. The recent availability of the genome sequences of medically important mosquito species has kick-started investigations into the molecular basis of how mosquito vectors control arbovirus infection. Here, we discuss recent findings concerning the role of the mosquito immune system in antiviral defense, interactions between arboviruses and fundamental cellular processes such as apoptosis and autophagy, and arboviral suppression of mosquito defense mechanisms. This knowledge provides insights into co-evolutionary processes between vector and virus and also lays the groundwork for the development of novel arbovirus control strategies that target the mosquito vector.

Figure 1

Mosquito immune signaling and RNAi pathways. In Toll pathway signaling, detection of pathogen-derived ligands by pattern recognition receptors (PRRs) such as PGRP-SA and -SD triggers proteolytic cleavage of the cytokine Späetzle, which binds to and activates the Toll receptor. This triggers signaling through the adaptor proteins MyD88, Tube, and Pelle, resulting in the phosphorylation and degradation of Cactus, a negative regulator which binds to and sequesters the Rel1 transcription factor in the cytoplasm. Cactus degradation allows Rel1 translocation to the nucleus to activate transcription of Toll-pathway regulated genes. The IMD pathway is activated by ligand binding to PGRP-LCs and -LEs. This triggers signaling through IMD and various caspases and kinases, leading to a functional split in the pathway. One branch triggers JNK signaling to activate the transcription factor AP1, while the other results in the phosphorylation of the Rel2 transcription factor and its subsequent DREDD-mediated cleavage. Activated Rel2 translocates to the nucleus to activate IMD-regulated transcription. The JAK-STAT pathway is triggered by Unpaired (Upd) binding to the receptor Dome, activating the receptor-associated Hop Janus kinases, which phosphorylate each other and subsequently recruit and phosphorylate the STAT transcription factor. Phosphorylated STATs dimerize and translocate to the nucleus to activate JAK-STAT-regulated transcription. The exogenous siRNA pathway is activated when virus-derived long dsRNA is recognized and cleaved by Dcr2 into siRNAs, usually 21 bp in length. siRNAs are loaded onto the multi-protein RISC complex, which degrades one strand of the duplex and uses the other for targeted degradation of complementary single stranded viral RNA. Sensing of viral dsRNA by Dcr2 also activates TRAF, leading to Rel2 cleavage and activation via a distinct pathway. Rel2 activates transcription of Vago, a secreted peptide which subsequently triggers JAK-STAT pathway signaling. Please refer to the text for more details.