Engineered Wnt7a ligands rescue blood–brain barrier and cognitive deficits in a COVID-19 mouse model
Troy N. Trevino, A Fogel, Guliz Otkiran, Seshadri B. Niladhuri, Mark A. Sanborn, Jacob Class, Ali A. Almousawi, Benoît Vanhollebeke, Leon M. Tai, Jalees Rehman, Justin M. Richner, Sarah E. Lutz
Abstract
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/β-catenin signalling, a critical regulator of blood-brain barrier (BBB) integrity. We therefore hypothesized that enhancing cerebrovascular Wnt/β-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/β-catenin signalling or its downstream effectors could be potential interventional strategies for restoring cognitive health following viral infections.