Engineered Wnt7a ligands rescue blood–brain barrier and cognitive deficits in a COVID-19 mouse model
Year: 2024
Type: article
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.
Source: Brain
Institutions: University of Illinois Chicago, Université Libre de Bruxelles
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,831
Funders: U.S. Department of Defense, National Institutes of Health, University of Illinois at Urbana-Champaign, University of Illinois at Chicago, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Congressionally Directed Medical Research Programs, H2020 European Research Council
Awards: Dengue virus mRNA lipid nanoparticle vaccine, G1290260593, UIC Portal to Biomedical Research Careers PREP (UIC PBRC-PREP), Mechanisms of Immune Dysfunction in Oral Post-Acute Sequelae of Covid-19, G2227305194, G6329837513, G7348409733, G7506495297, Blood-brain barrier: from molecular mechanisms to intervention strategies, G8730804632, G9000132187, G9000135281, G9000271994, Mechanisms and Treatment of SARS-CoV-2 induced Lung Endothelial Injury, iPSC-Derived Vascularized Human Lung Organoids and Interaction Between Lung Endothelial Cells and Alveolar Epithelial Cells
OpenAlex ID: W4391465552