Chandelier
Senior Member (Voting Rights)
Brain endothelial cells orchestrate a neuroprotective antiviral state in the CNS in response to peripheral viral pattern sensing
• Serum IFN-α is necessary and sufficient for the establishment of this antiviral state
• Brain endothelial cells of the CNS are the primary responders to systemic IFN-α
• IFNAR1 signaling in brain endothelial cells is necessary for neuroprotection
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.
Web | DOI | Immunity
Lewy, Tyler; Sierra, Maria A.; Pourshadi, Nastaran; Hoffmann, Hans-Heinrich; Dinnon, Kenneth H.; Gola, Anita; Wang, Wei; Chen, Hsuan-An; Quirk, Corrine; Zhang, Haotan; Doyle, Michael P.; Mason, Christopher E.; Diehl, Gretchen E.; Hohl, Tobias M.; Fuchs, Elaine; MacDonald, Margaret R.; Wu, Zhuhao; Crowe, James E.; Rice, Charles M.; Lercher, Alexander
Highlights
• Peripheral viral pattern sensing primes antiviral defenses in the CNS• Serum IFN-α is necessary and sufficient for the establishment of this antiviral state
• Brain endothelial cells of the CNS are the primary responders to systemic IFN-α
• IFNAR1 signaling in brain endothelial cells is necessary for neuroprotection
Summary
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.
Web | DOI | Immunity