Secreted Vago restricts West Nile virus infection in Culex mosquito cells by activating the Jak-STAT pathway

Abstract

Although West Nile virus (WNV) and other arthropod-borne viruses are a major public health problem, the mechanisms of antiviral immunity in mosquitoes are poorly understood. Dicer-2, responsible for the RNAi-mediated response through the C-terminal RNase-III domain, also contains an N-terminal DExD/H-box helicase domain similar to mammalian RIG-I/MDA5 which, in Drosophila, was found to be required for activation of an antiviral gene, Vago. Here we show that the Culex orthologue of Vago (CxVago) is up-regulated in response to WNV infection in a Dicer-2-dependent manner. Further, our data show that CxVago is a secreted peptide that restricts WNV infection by activation of the Jak-STAT pathway. Thus, Vago appears to function as an IFN-like antiviral cytokine in mosquitoes.innate immunity | insect cytokine

Making connections in insect innate immunity

“…As insects appear to lack an adaptive immune response characteristic of vertebrates, this controlling response occurs through activation of apparently simple, linear innate immunity pathways. However, in PNAS, Paradkar et al (3) describe a mechanism connecting two of these innate immunity pathways (the RNAi pathway and the Jak-STAT pathway) in mosquitoes through the action of a secreted signaling molecule, Vago, leading to an antiviral state in uninfected, responsive cells. This work provides evidence of an integrated, versatile insect immune system capable of communication between pathways and cells to give rise to an effective response.…”

Antiviral responses of arthropod vectors: an update on recent advances

“…In fact, evidence suggests that there are significant differences between the different arbovirus families which need to be taken into consideration. Some (or possibly all) flaviviruses have the ability to suppress RNAi [59,101]; thus it is not surprising that other innate immunity pathways such as JAK/STAT and Toll are involved in controlling flavivirus infection in mosquitoes [92,115,130]. In contrast, alphaviruses are not known to actively suppress RNAi and use only decoy mechanisms to evade the RNAi response [111].…”

“…It has been suggested that Dcr-2 is also involved in signalling. Like RIG-I or Mda-5 in mammalian cells, Dcr-2 detects dsRNA as foreign and activates signalling which, at least in mosquitoes, results in increased expression of vago, a cytokine with an interferon-like function [92].…”

“…JAK/STAT pathway activation inhibits replication of the flaviviruses DENV and WNV in, respectively, A. aegypti mosquitoes [115] and C. quinquefasciatus Hsu cells [92]. Upon flavivirus infection, mosquito Dcr-2 recognises viral dsRNA in a similar manner to RIG-I and Mda-5 in mammals and initiates a signalling cascade leading to the expression and secretion of Vago [92], a small cytokine with a function similar to interferon in the mammalian system. Secreted Vago binds to an unknown receptor on neighbouring cells leading to the signalling cascade shown in Fig.…”

“…Activated STAT acts as a transcription factor inducing expression of antimicrobial peptides (AMPs) such as two DENV restriction factors [115] and vir-1 [92]. However, treatment with poly I:C (a synthetic analogue of dsRNA) or BTV dsRNA did not lead to vago upregulation and STAT activation in C. quinquefasciatus cells [92], and infection of U4.4 cells with the alphavirus SFV did not lead to activation of STAT [33]. Taken together, these findings suggest that activation of STAT may be a specific anti-flaviviral response.…”