Mosquitoes belonging to the Aedes genus are vectors for several important arthropod-borne viruses (arboviruses) such as dengue and Zika. We have been observing more frequent outbreaks of arboviruses worldwide while the distribution of vector mosquitoes widens. Vector population control is still a major strategy although there are limitations. Other approaches to exploit the ability of most mosquitoes to control viral infection have been proposed but we still lack understanding about the mosquito permissiveness to viruses.
In our laboratory, we are interested in understanding why Aedes mosquitoes are such efficient vectors for viruses compared to other closely related species. This is a very important question that we begin to address with an initial observation that susceptibility to viruses varies even within individual mosquitoes in the same population of the major vector Aedes aegypti. RNA interference mediated by small interfering RNAs (siRNAs) is a major antiviral defense in insects and has been shown to be highly effective against dengue virus in Aedes mosquitoes. Therefore, we pursued the hypothesis that the strength of the siRNA response would distinguish resistant and susceptible individuals from the same mosquito population. Here came our first big surprise when our data indicated that the siRNA pathway was not important for the control of dengue virus in the mosquito midgut although clearly required to restrict systemic dissemination and replication of the virus. We also observed that known components of the siRNA pathway were all expressed in the gut and silencing of exogenous and endogenous was still functional. This indicated to us that antiviral RNA interference was somewhat compromised in the midgut of mosquitoes and led us to hypothesize that a co-factor, exclusively required for the antiviral defense mediated by the siRNA pathway, would be missing. Of note here, we had previously described that, in the fruit fly Drosophila melanogaster, the PD isoform of the dsRNA binding protein Loquacious (Loqs) was essential for the siRNA pathway triggered by endogenous and exogenous dsRNAs but dispensable for the antiviral defense. In our searches for possible co-factors, we came across a gene duplication in Aedes mosquitoes that created a paralog of loqs and the closely related RNA binding protein r2d2. This new gene, which we named loqs2, was essential to control systemic dissemination of dengue and Zika viruses but was not expressed in the mosquito midgut. Ectopic expression of loqs2 in the midgut was enough to render mosquitoes resistant to infection by dengue and Zika viruses. Importantly, we observed that loqs2 is only present in Aedes mosquitoes but no other related mosquitoes such as Culex.
Our work describes a specialization of RNA interference that would make antiviral defense more efficient in Aedes mosquitoes that are, paradoxically, the most permissive vectors for the transmission of viruses. Many questions still remain, but the identification of the loqs2 gene is a first step towards shedding some light on the unique antiviral response in Aedes mosquitoes and help explain why these are such efficient vectors for viruses.
Full Paper can be found at https://www.nature.com/articles/s41564-018-0268-6.
Image showing dengue virus cycle in the mosquito by Roenick P. Olmo. Roenick Olmo, Elisa Gonçalves, Thiago Jiran and Juliana Armache contributed to this post.