Brain endothelial cells orchestrate a neuroprotective antiviral state in the CNS in response to peripheral viral pattern sensing.

West Nile virus (WNV) and other neurotrophic arboviruses are human pathogens that can cause life-threatening encephalitis. To uncover determinants of severe disease progression, we employed a murine infection model of WNV and experimentally uncoupled peripheral pathogen sensing from active viral replication. Peripheral sensing of a viral dsRNA mimic in the footpad led to robust induction of antiviral type I interferon (IFN-I)-stimulated genes and establishment of an antiviral state within the brain. Systematic approaches combining cytokine profiling, single-nuclei transcriptomics, immune modulation, and genetic perturbations revealed critical roles for systemic IFN-I and IFN-I receptor signaling in brain microvascular endothelial cells. This inter-organ antiviral crosstalk protected against severe encephalitis caused by a range of neurotropic viruses across Orthoflaviviridae, Togaviridae, and Orthoherpesviridae. Thus, these data unravel a cross-tissue antiviral signaling network that counteracts lethal encephalitis, pointing to therapeutic avenues for encephalitic disease caused by emerging viral pathogens.