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

Abstract

Persistent cognitive impairment and neuropsychiatric disorders are prevalent sequelae of SARS-CoV-2-induced COVID-19 in middle-aged adults. To model age-related neurological vulnerability to COVID-19, we induced respiratory SARS-CoV-2 MA10 infections by nasal inoculation in young (2 months) and middle-aged (12 months) mice. We hypothesized that aging and SARS-CoV-2 synergistically damage the blood-brain barrier (BBB) to worsen disease. Indeed, the combined action of aging and SARS-CoV-2 infection caused more fibrinogen leakage, T cell infiltration, and neuroinflammation in middle-aged SARS-CoV-2-infected mice than in similarly inoculated young adults. Mechanistically, SARS-CoV-2 exacerbated age-related increases in Caveolin-1 BBB transcellular permeability and loss of Wnt/β-catenin ligands, with no apparent changes in tight junction proteins. Finally, SARS-CoV-2 infection induced age-dependent neuropsychiatric abnormalities including bradykinesia and repetitive behavior. These observations indicate that cerebrovascular aging, including loss of Wnt suppression of Caveolin-1, heightens vulnerability to SARS-CoV-2-induced neuroinflammation and neuropsychiatric sequalae. Our work suggests that modulation of Wnt signaling or its downstream effectors at the BBB could be potential interventional strategies for Long COVID.

MMCCI: multimodal integrative analysis of single-cell and spatial cell-type communications to uncover overarching and condition-specific ligand-receptor interaction pathways

“…The second pair, Gnαi2-Cav1, interacted only within oligodendrocytes in the young brain, but in the aged, interactions occurred between vascular cells, neurons, astrocytes, and oligodendrocytes. Cav1 is a ligand known to be involved with neuroinflammation at the blood brain barrier, (BBB), and Gαi2 regulates tight junction integrity of BBB [33,34].…”