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Brain : a journal of neurology
05 03, 2024;147 (5): 1636-1643.

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

Troy N Trevino, Avital B Fogel, Guliz Otkiran, Seshadri B Niladhuri, Mark A Sanborn, Jacob Class, Ali A Almousawi, Benoit Vanhollebeke, Leon M Tai, Jalees Rehman, Justin M Richner, Sarah E Lutz
Author Information
  1. Troy N Trevino: Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. ORCID
  2. Avital B Fogel: Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
  3. Guliz Otkiran: Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
  4. Seshadri B Niladhuri: Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
  5. Mark A Sanborn: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
  6. Jacob Class: Department of Microbiology and Immunology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
  7. Ali A Almousawi: Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
  8. Benoit Vanhollebeke: Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles (ULB), Gosselies B-6041, Belgium.
  9. Leon M Tai: Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
  10. Jalees Rehman: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
  11. Justin M Richner: Department of Microbiology and Immunology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
  12. Sarah E Lutz: Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. ORCID
PMID: 38306655 DOI: 10.1093/brain/awae031

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.

Keywords

COVID-19 SARS-CoV-2 Wnt7a blood–brain barrier endothelial cell neuroinflammation

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Grants

  1. R25 GM121212/NIGMS NIH HHS
  2. /University of Illinois
  3. R01 HL162308/NHLBI NIH HHS
  4. R01 HL163978/NHLBI NIH HHS
  5. R01 HL152515/NHLBI NIH HHS
  6. /DOD MS200290
  7. R01 AI150672/NIAID NIH HHS

MeSH Term

Animals
Blood-Brain Barrier
COVID-19
Mice
Wnt Proteins
Disease Models, Animal
Mice, Inbred C57BL
Cognitive Dysfunction
Wnt Signaling Pathway
Ligands
SARS-CoV-2
Male
Brain

Chemicals

Wnt Proteins
Wnt7a protein, mouse
Ligands
Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

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