Immunity 2026
More than a wall
The same finding written twice: once for the journal, once for everyone else.
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.
Abstract as published in Immunity, retrieved from PubMed.
West Nile virus (WNV), a pathogen carried by mosquitos in the US, causes encephalitis in roughly one case per 150. When it does, the illness can be fatal or result in life-long deficits like paralysis.
In this study, the team explored the relationship between the brain and the other organs during infection using a mouse model. They made the striking finding that the brain begins responding to viral infection mere hours after the virus enters the foot.
Typical WNV experiments trying to separate peripheral and brain infection are difficult due to the virus's ability to breach the blood-brain barrier. To solve this issue, the team simulated a viral infection in the foot using a sterile viral mimic.
Through this approach, the team was able to uncover a multi-organ signaling network wherein cells in the foot rapidly alerted the brain through alarm molecules called interferons, allowing it to transition to an antiviral state and fend off direct intracranial WNV challenge.
Specialized cells in the blood-brain barrier were critical for this communication network. When the group silenced those cells' ability to respond to interferon, the protection disappeared and the virus went back to 100% lethality.
This finding highlighted that the blood-brain barrier is not a static wall, but rather a rich immune signaling hub, relaying information from the periphery into the central nervous system.
Coverage
The work was written up by Rockefeller University (opens in a new tab), and picked up by Medical Xpress (opens in a new tab) and ThePrint (opens in a new tab).
Full paper: Lewy T, Sierra MA, Pourshadi N, et al. Brain endothelial cells orchestrate a neuroprotective antiviral state in the central nervous system in response to peripheral viral pattern sensing. Immunity 2026;59(7):1825–1842.e11. doi:10.1016/j.immuni.2026.06.009 (opens in a new tab)