Dissecting the molecular determinants of alphavirus vector specificity

"Arboviruses (viruses transmitted by arthropods) infect more than 700 million people every year, causing a major impact on global public health. Mosquitoes of the genus Aedes, in particular Aedes aegypti, are the main vectors, capable of transmitting viruses belonging to the four major taxa of arboviruses including Flaviviruses and Alphaviruses. The Chikungunya virus (CHIKV), an alphavirus of the Semliki Forest antigenic group, is one of the most widespread and is transmitted by the Aedes aegypti mosquito, among others. Another member of this group, the O'nyong nyong virus (ONNV), is unique in that it is naturally transmitted by Anopheles mosquitoes, in particular Anopheles gambiae, which also carries malaria. ONNV was first isolated in 1959 in Uganda, and was long confused with a subtype of CHIKV due to their strong similarity. These two viruses provide a relevant model for studying vector specificity, as their respective vectors belong to subfamilies that diverged around 170 million years ago. This specificity raises key questions about the molecular determinants that govern the adaptation of viruses to their vectors. This project aims to identify the molecular mechanisms responsible for this specificity, in particular the interactions between viral proteins and host factors in mosquitoes. The aim is to gain a better understanding of how viruses adapt to new urban vectors and thus anticipate the risks of future emergences. The Mosquito Immune Responses team has proven expertise in the study of vector-pathogen interactions, with rearing facilities for Aedes aegypti and Anopheles coluzzii (formerly An. gambiae), P2/P3 facilities and experience in mosquito genetics. Previous work has highlighted the role of the nsP3 viral protein in vector specificity. Chimeric viruses show that the exchange of nsP3 between CHIKV and ONNV allows CHIKV to partially infect Anopheles. nsP3, essential for viral replication, interacts with host proteins via its hypervariable domain (HVD) and its high variability between alphaviruses suggests a key role in vector specificity. This thesis project will therefore focus on the role of nsP3 in viral infection and host specificity via three complementary experimental axes."