Role of Innate Immune and Inflammatory Signaling in West Nile Virus Tropism and Neuronal and Glial Cell Death

West Nile virus (WNV) is a mosquito-borne virus that causes severe neurological disease in humans. Despite substantial advances, our knowledge of the mechanisms involved in damaging the human brain is still limited. To address this gap, we developed a physiologically relevant in vitro model using human neuronal/glial cells and aimed to determine WNV tropism, assess whether the virus induces innate immune and inflammatory responses, and elucidate the resulting pathophysiological consequences. We found that WNV productively infected glial cells, whereas neurons exhibited a remarkable and unexpected resistance to infection. Despite the induction of a robust innate immune response mediated by IFN signalling and a rapid control of WNV replication in glial cells, we observed substantial death of astrocytes, oligodendrocytes, and neurons. Analysis of cytokine and chemokine expression further revealed that infection triggered an inflammatory response, potentially contributing to bystander cell death. We also showed that IFN signaling did not contribute to the resistance of neurons and identified IFI6 as an effector of the antiviral response in human glial cells. Together, our results underscore the importance of human neural models for confirming previous findings obtained in less physiologically relevant models and for unravelling novel cellular and molecular mechanisms.