Engineered Wnt7a ligands rescue blood-brain barrier and cognitive deficits in a COVID-19 mouse model

Respiratory infection with SARS-CoV-2 causes systemic vascular inflammation and cognitive impairment. We sought to identify the underlying mechanisms mediating cerebrovascular dysfunction and inflammation following mild respiratory SARS-CoV-2 infection.To this end, we performed unbiased transcriptional analysis to identify brain endothelial cell signalling pathways dysregulated by mouse adapted SARS-CoV-2 MA10 in aged immunocompetent C57Bl/6 mice in vivo.This analysis revealed significant suppression of Wnt/beta-catenin signalling, a critical regulator of blood-brain barrier (BBB) 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 BBB integrity, reduced T-cell infiltration of the brain, and reduced microglial activation in SARS-CoV-2 infection. Importantly, this 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 signalling or its downstream effectors could be potential interventional strategies for restoring cognitive health following viral infections. Does blood-brain barrier (BBB) dysfunction contribute to cognitive deficits in COVID-19? Trevino et al. show that SARS-CoV-2 suppresses Wnt/beta-catenin, a critical regulator of BBB integrity. Restoring Wnt/beta-catenin improved cognition and protected the brain from leakage of blood proteins and immune cells in a COVID-19 mouse model.