Abstract
Usutu (USUV) and West-Nile (WNV) virus are emerging arboviruses mainly transmitted by Culex genus mosquitoes. In human, the infection can lead to neurological impairments following invasion of the central nervous system (CNS) by viruses, for example, through the blood-brain barrier (BBB). This thesis project aims to characterize access and infection mechanisms of the BBB by USUV and WNV. Neuroinflammation associated to these infections is an important part of the pathogenesis, consequently immune cell role and their interactions with the BBB have been studied. This work has shown the susceptibility of different cell types of the CNS to different USUV lineages and the susceptibility of murine models. Europe 2 lineage seems to be the more virulent and its effect on the BBB has been compared to the WNV lineage 2 effect, these two lineages being associated to neuronal symptom appearance during human infection. The BBB model used allows the replication of both arbovirus with passage in the CNS, WNV also leads to integrity perturbations of the barrier, and the two viruses are able to induce strong antiviral response with secretion of inflammatory molecules as cytokines (interleukins, interferons), chemokines and cell adhesion molecules. This inflammation induces immune cell recruitment and increases neuroinflammation. Unlike WNV, USUV is able to infect dendritic cells that can be recruited by the BBB and that can be Trojan horses during CNS infection. WNV infected patient sera have been analyzed to highlight the neuroinflammation and to search potential biomarkers of neurological impairments. Infected patients with neurological disorders show high serological concentrations of pro-inflammatory molecules, persisting more than 20 days before infection starting date, and of molecules associated to neurodegenerative or neuroinflammatory diseases. The concentration of TDP-43 could be followed after WNV infection in order to anticipate the consequences of its aggregation that can promote neurodegenerative disease development, for example. In a “One Health” approach, this work also studies circulation of these viruses in the south of France. Seroprevalence assays have been done to determine USUV and WNV exposition in vectors, reservoirs and other hosts. Finally, to investigate emerging virus that cause neuronal disorders, a study of the BBB infection by SARS-CoV-2 has been accomplished. Indeed, this virus can cause neuronal symptoms with possible sequels. Results suggest a poor direct infection of the barrier. Taken together, this work allow a better understanding of BBB viral infections and neuroinflammation, in a context of emergence associated to public health concerns that highlights importance of these studies.