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Viral Reactivation After Stroke: A Novel Model for Post-Stroke Depression

Walker, M.; Zunt, J. R.; Levitt, M.; Koelle, D. M.

2025-04-04 neurology
10.1101/2025.04.02.25325132 medRxiv
Show abstract

BackgroundPost-stroke depression (PSD) is a common and debilitating complication of acute ischemic stroke (AIS), yet its biological basis remains unclear. AIS induces immune dysregulation and blood-brain barrier (BBB) disruption, which may allow reactivation of latent viruses such as JC virus (JCV), a neurotropic polyomavirus that uses the serotonin receptor 5-HT2A to enter neurons involved in mood regulation. MethodsWe evaluated peripheral expression of host genes required for JCV entry, replication, and trafficking in three AIS transcriptomic datasets and assessed endothelial compromise using a complementary panel of BBB-associated genes. We then examined the anatomical relevance of viral entry receptors using publicly available brain expression datasets. ResultsAIS samples showed upregulation of host chaperone and trafficking genes, with concurrent downregulation of 5-HT2A. BBB-related profiles revealed reduced expression of structural junction proteins and increased expression of endothelial activation markers. Brain mapping localized high 5-HT2A expression to regions implicated in mood regulation. ConclusionsThese findings support a biologically plausible model in which AIS transiently enables JCV reactivation and CNS entry, particularly in serotonin-rich brain regions that may contribute to PSD pathogenesis.

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