PROJECT SUMMARY/ABSTRACT The global range of the mosquito, Aedes aegypti continues to expand due to a changing climate and increasing urbanization. As Ae. aegypti is the primary vector of dengue, Zika, yellow fever and chikungunya viruses, these range shifts also increase the risk of human disease. With few effective vaccines or antiviral drugs, vector control remains the best weapon against mosquitoes. Recently, the release of an insect endosymbiont, Wolbachia, into mosquito populations has emerged as a novel biocontrol strategy. Maternally inherited and with inbuilt genetic drive, Wolbachia tends to spread through insect populations. Inside the mosquito, the bacterium limits the replication of viruses, a trait called ?viral blocking?. Following release of Wolbachia into wild populations, the viral blocking effect is leading to substantial reductions in the incidence of dengue fever in humans. One concern for the long- term efficacy of Wolbachia is the emergence of resistance in mosquitoes or viruses. To design strategies to counter this likely scenario, we need to understand the genetic basis of viral blocking. While many theories have been proposed, none have been entirely satisfying. Recently, the McGraw lab used a selection experiment to create Ae. aegypti lines carrying Wolbachia with differences in blocking. In sequencing those lines, her group identified a set of novel candidate loci and a new set of hypotheses for the basis of blocking. This study also demonstrated that the strength of blocking is likely to vary across diverse mosquito genetic backgrounds. Here we propose to provide functional testing for the candidate blocking genes involved with cell adhesion, transcriptional pausing and neuronal function, for both dengue and chikungunya viruses using RNA silencing. In these experiments we will also contrast Aedes albopictus, that has long harbored a natural infection of Wolbachia, against Ae. aegypti with a recently artificially introduced Wolbachia. The nature of blocking in Ae. albopictus is a likely harbinger of the future of blocking in the artificially infected species. We will also carry out large common garden experiments to dissect the relative contribution of regional differences in mosquito and virus diversity to the strength of blocking. This project will produce novel resources for the community including a new Wolbachia infected Ae. aegypti line, a set of antibodies against key blocking association proteins and data on the efficacy of improved fluorescent reporter viruses for the study of vector competence. More broadly, this research will help to test a revised model for Wolbachia-mediated viral blocking ? knowledge fundamental for designing strategies to prolong Wolbachia?s efficacy in the field. It will also reveal the robustness of blocking to mosquito and viral genetic diversity, that will inform strategies for future Wolbachia strain deployment globally.
|Effective start/end date||8/4/21 → 7/31/22|
- National Institute of Allergy and Infectious Diseases: $491,795.00
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