Age exacerbates SARS-CoV-2-induced blood-brain barrier leakage and neuropsychiatric dysfunction

Niladhuri, S. B.; Clare, G. O.; Robinson, K. F.; Class, J.; Almousawi, A. A.; Trevino, T. N.; Marottoli, F.; Tai, L. M.; Richner, J. M.; Lutz, S. E.

doi:10.1101/2022.06.02.494552

bioRxiv · 10.1101/2022.06.02.494552

Age exacerbates SARS-CoV-2-induced blood-brain barrier leakage and neuropsychiatric dysfunction

Niladhuri, S. B.·Clare, G. O.·Robinson, K. F.·Class, J.·Almousawi, A. A.·Trevino, T. N.·Marottoli, F.·Tai, L. M.·Richner, J. M.·Lutz, S. E.

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Abstract

Respiratory infection with SARS-CoV-2 causes systemic vascular inflammation and cognitive impairment. We sought to identify the underlying mechanisms mediating vascular dysfunction and inflammation following mild respiratory SARS-CoV-2 infection. To this end, we conduced unbiased transcriptional analysis to identify brain endothelial cell signaling pathways dysregulated by SARS-CoV-2 in vivo. This analysis revealed significant suppression of Wnt/{beta}-catenin signaling, a critical regulator of blood brain barrier integrity. We therefore hypothesized that enhancing cerebrovascular Wnt/{beta}-catenin activity would offer protection against BBB permeability, neuroinflammation, and neurological signs in acute infection. Indeed, we found that delivery of cerebrovascular-targeted, engineered Wnt7a ligands protected blood brain barrier integrity, reduced T cell infiltration of the brain, and reduced microglial activation in SARS-CoV-2 infection. Importantly, this therapeutic strategy also mitigated SARS-CoV-2 induced deficits in the novel object recognition assay for learning and memory and the pole descent task for bradykinesia. These observations suggest that enhancement of Wnt/{beta}-catenin signaling or its downstream effectors could be potential interventional strategies for restoring cognitive health following acute viral infections.

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Niladhuri, S. B., Clare, G. O., Robinson, K. F., Class, J., Almousawi, A. A., Trevino, T. N., Marottoli, F., Tai, L. M., Richner, J. M., Lutz, S. E.. 2022-06-03. Age exacerbates SARS-CoV-2-induced blood-brain barrier leakage and neuropsychiatric dysfunction. https://doi.org/10.1101/2022.06.02.494552

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