Spatial transcriptomics uncovers vasculature-centered cellular interactions driving Japanese encephalitis progression in a mouse model.

The cellular interactions that drive the neuropathology of most neuroinvasive viruses remain elusive. We used Japanese encephalitis virus (JEV) to infect female BALB/c mice and applied Stereo-seq to simultaneously capture host and viral transcriptomes in situ, thereby constructing a comprehensive spatiotemporal atlas of Japanese encephalitis (JE) pathogenesis. Our analysis pinpoints Ly6c2+ monocytes as the primary virus carrier, the most abundant infiltrating immune cell type, and a major source of IFN-γ in the infected mouse brain. Following infection, Ackr1+ endothelial cell activation is linked to blood-brain barrier disruption and immune cell chemotaxis, particularly Ly6c2+ monocytes. The crosstalk between these two cell types appears to orchestrate the pronounced inflammation and cell death, including pyroptosis and necroptosis, which radiate from the vasculature to different brain regions. Disrupting the activation and interactions of these two cell types may help mitigate JE progression. This study also provides a technical framework for investigating the pathogenesis of other neurotropic viruses.