Background Post-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.

Methods We 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.

Results AIS 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.

Conclusions These 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.

M.R.L.: Unrestricted educational grants from Medtronic and Stryker; consulting agreement with Aeaean Advisers, Metis Innovative, Genomadix, AIDoc, Phenox and Arsenal Medical; equity interest in Proprio, Stroke Diagnostics, Apertur, Stereotaxis, Fluid Biomed, Synchron and Hyperion Surgical; editorial board of Journal of NeuroInterventional Surgery; Data safety monitoring board of Arsenal Medical. D.M.K.: Scientific Advisory Board of Curevo. Grant support from Sanofi Pasteur. Royalty payments for institutionally-owned patents related to vaccines. J.R.Z. and M.W. declare that they have no conflict of interest.

This study did not receive any funding

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Gene expression datasets were obtained from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO). Three datasets were selected based on relevance to acute ischemic stroke, availability of whole blood or PBMC profiles, and adequate sample size for group comparisons. These included GSE58294 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE58294), GSE16561 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE16561.), and GSE37587 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE37587) GEO series matrix files and corresponding platform annotation files (GPL570, GPL6883, GPL10558) were downloaded and parsed using open-source Python libraries.

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