Identifying factors of resistance and susceptibility to dengue virus infection in Aedes aegypti mosquitoes

Emerging infectious diseases represent a global health problem, as demonstrated by the Covid-19 pandemic. Among them, viral pathogens transmitted by mosquitoes represent a growing threat to human health, due to global warming and globalization. For example, Aedes aegypti mosquitoes are the main vectors of dengue viruses that infect 400 million people annually. However, major knowledge gaps remain in our understanding of interactions between mosquitoes and viruses. For example, the mechanisms underlying natural variation in susceptibility to viral infection between different mosquito populations remain mostly unknown. My project aims to address this question using novel methods combining single-cell transcriptomics and metabolomics approaches. First, I will identify Ae. aegypti mosquito populations that are highly or poorly susceptible to infection with dengue viruses. Next, I will analyze infection dynamics in key mosquito organs: the mosquito midgut, which is the entry point for the virus, and the fat body which regulates metabolism. I will analyze their response to virus infection using single-cell transcriptomics and metabolomics. A joint 'Äúmulti-omics'Äù analysis of both datasets will describe, for the first time, the metabolic functions of different cellular subpopulations of the mosquito midgut and fat body upon dengue infection. It will reveal the metabolic pathways and gene expression patterns that are associated with susceptibility towards virus infection at the cellular level. Finally, the contribution of these candidate genes and metabolites to susceptibility or resistance to infection will be validated using functional assays (e.g., chemical inhibition, gene knockdown) in vivo. This project will address an important knowledge gap in virus-mosquito interactions by revealing metabolic factors underlying susceptibility towards dengue virus infections. These results might contribute to the development of innovative disease-control strategies in the future.