Differentiated LUHMES Cells as a Model to Investigate Neurotropic Arboviruses and Evaluate Host-Directed Therapeutics

Abstract

Arthropod-borne viruses such as Alphaviruses and Flaviviruses are the causative agents of severe human disease, highlighted by fatal encephalitis and neurological sequelae in survivors. The lack of FDA-approved vaccines and therapeutics that can prevent or treat these infections results in a significant global disease burden. An important unmet need to address this capability gap is the need for affordable, scalable, clinically relevant human-based neuronal models to study neuroinvasive viruses and evaluate therapeutic options. Here, we described the application of a human neuronal precursor cell model, LUHMES (Lund human mesencephalic) cells, that can be differentiated into dopaminergic midbrain neurons and used to study virus infections. In this study, we demonstrated the susceptibility of LUHMES cells to infection by three arthropod-borne neurotropic viruses: Venezuelan equine encephalitis virus, dengue virus serotype 2, and West Nile virus. We also demonstrated how the model may be applied to evaluate potential therapeutic options using an FDA-approved small molecule, Omaveloxolone. Finally, we analyzed host cell responses to infection and treatment using gene expression and phospho-signaling analyses. These findings highlight the value of this model to interpret the pathogenic mechanisms of neurotropic viral infections and evaluate potential therapeutic intervention strategies in a clinically relevant in vitro human neuronal model.