Tripartite interactions between the mosquito's immune system, gut microbiome and the dengue virus

The dengue virus is one of the most important arboviral pathogens and the causative agent of dengue fever, dengue hemorrhagic fever and dengue shock syndrome. The increasing incidence of morbidity and mortality due to dengue in the tropics and subtropics is having a worldly impact on public health. Although arthropod immune responses to viral pathogens have been studied in Drosophila, less is known about the immune responses mounted by the mosquito Aedes aegypti to dengue virus infection. However, several factors have facilitated the analyses of this interaction, particularly the Ae. aegypti whole genome sequence availability and the subsequent development of an Ae. aegypti oligonucleotide microarray. In this thesis work, we have: 1 Conducted RNAi-based reverse genetic assays and high-throughput gene expression analysis to study the implication of the mosquito immune pathways in the response against dengue virus infection. Additional infection and functional assays showed that the Toll pathway is an effective regulator of the anti-dengue defense, acting against different dengue serotypes at different stages of infection, and in Ae. aegypti of diverse geographic origins. In conjunction, our studies of the dengue infection –responsive transcriptome profile in different tissues and at different infection stages reveals complex and dynamic interactions between the mosquito and the dengue virus that would determine the likelihood of infection and duration of the extrinsic incubation period. Our assays are the first ones that evaluate the implication of a putative mosquito innate immune pathway in the control of infection with an arbovirus. 2. Studied the tripartite interactions between the mosquito, the dengue virus and its midgut microbiota. Some bacterial isolates significantly affect vector competence by reducing dengue virus infection of the mosquito midgut through different mechanisms. Conversely, the elicitation of the mosquito immune system by dengue virus infection affects the mosquito's gut microbiota. This thesis work contributes to a better understanding of the mosquito immune system and the microbiota-mosquito interactions that influence viral pathogen infection.;Keywords: Toll pathway, dengue virus, mosquito microbiome, tripartite interactions.