Neurotropic flavivirus dsRNA-protein interface in humans, mosquitoes and ticks

ended

Neurotropic flaviviruses Zika virus (ZIKV) and tick-borne encephalitis (TBEV) represent major emerging arthropod-borne viruses transmitted by two different vectors, either mosquitoes or ticks. In humans, they use cells of the immune system to spread throughout the organism and can lead to severe encephalitis. During their replication, viruses produce double-stranded RNA (dsRNA) structures which is not only a necessary by-product but also performs key regulatory functions and acts as a pathogen-associated molecular pattern recognized by the host innate immune response. However, viral adaptation to such divergent host cells and organisms and their immune response, especially in arthropods, is poorly understood. In this project, I propose to investigate and compare how neurotropic flaviviruses interact through their RNA in humans and arthropods. First, I will identify host factors involved in protein-dsRNA complexes using anti-dsRNA antibodies in a high-throughput proteomic approach from infected live arthropods and human models for immune and neuronal cells and compare the protein networks between each host. Second, I will select the most significant and relevant hits for a functional screening, further define the function of the best candidates that are either pro-viral or anti-viral, confirm their importance in most relevant models and characterize the molecular functions of the best candidates. Finally, I will identify the dsRNA structures and RNA species interacting with the best candidates, and determine the evolutionary pressure imposed on the viral genomes in each host. Altogether, this project will contribute to unravel the adaptation of neurotropic flaviviruses to their hosts throughout their cycles, both from a mechanistic and evolutionary perspective, help understand the role of the RNA in crossing species barriers and lay the grounds for new therapeutics and disease control strategies against viruses that represent an ever-increasing threat in Europe.