Tick-Borne Encephalitis Virus-infected human neuronal/glial cells identify antiviral drugs
Résumé
Tick-Borne Encephalitis Virus (TBEV), a member of the Flaviviridae family, is the major arbovirus of health interest in Central/Northern Europe and North-Eastern Asia. It is responsible for neurological manifestations that may cause permanent disability or death. There is currently no therapeutic treatment for the disease. Although many studies have been conducted using murine models, there is a lack of relevant in vitro human models for neuropathological studies and drug discovery. Here, we infected human neuronal/glial cells (hNGCs) with TBEV and showed that in vitro infection reproduced major hallmarks of TBEV infection in the human brain, such as preferential neuronal tropism, neuronal death and astrogliosis. We then compared the antiviral activity of 8 selected molecules in hNGCs, human neural progenitor cells (hNPCs) and A549 cell line, as 3 models of TBEV infection of different relevance. We showed that most of the molecules had an antiviral activity in A549 but only one was efficient in hNGCs, demonstrating the importance of physiologically relevant models. Next, we developed an image-based phenotypic screen using hNGCs and tested a hundred and ninety compounds for their ability to restrict viral infection. This led to the identification of new antiviral compounds amongst which two may be therapeutically repositioned as they are drugs currently used in human medicine. The antiviral activity of one of them was further confirmed in a newly developed model of human cerebral organoids infected with TBEV. Such physiologically relevant 2D/3D in vitro models of TBEV infection offer a platform that should accelerate the identification of high value antiviral molecules.