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

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.