Transcriptomic profiling of brain microvascular endothelial cells (BMECs) and matching whole brain tissue isolated at 6 hours post footpad treament with PBS (control) or polyIC (50µg).

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. This approach revealed an antiviral signaling network that counteracts lethal encephalitis.

Peripheral sensing of a viral dsRNA mimic in the footpad led to robust induction of antiviral interferon stimulated genes (ISGs) and establishment of an antiviral state within the brain. Mechanistically, this depended on production of systemic type I interferon (IFN-I) and IFN-I receptor (IFNAR) signaling in brain microvascular endothelial cells (BMECs). Strikingly, this inter-organ antiviral crosstalk potently protected against severe encephalitis caused by a range of neurotropic viruses across Orthoflaviviridae, Togaviridae and Orthoherpesviridae.