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Review 1: "Caveolin-1 Mediates Neuroinflammation and Cognitive Impairment in SARS-CoV-2 Infection"

While acknowledging some limitations in neurobehavioral testing and the need for further research, the reviewer emphasized the study's potential relevance to long COVID and its identification of a new target for improving outcomes in patients with neurological sequelae.

Published onJul 02, 2024
Review 1: "Caveolin-1 Mediates Neuroinflammation and Cognitive Impairment in SARS-CoV-2 Infection"
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key-enterThis Pub is a Review of
Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection
Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection
Description

Abstract Leukocyte infiltration of the CNS can contribute to neuroinflammation and cognitive impairment. Brain endothelial cells regulate adhesion, activation, and diapedesis of T cells across the blood-brain barrier (BBB) in inflammatory diseases. The integral membrane protein Caveolin-1 (Cav-1) critically regulates BBB permeability, but its influence on T cell CNS infiltration in respiratory viral infections is unknown. In this study, we sought to determine the role of Cav-1 at the BBB in neuroinflammation in a COVID-19 mouse model. We used mice genetically deficient in Cav-1 to test the role of this protein in T cell infiltration and cognitive impairment. We found that SARS-CoV-2 infection upregulated brain endothelial Cav-1. Moreover, SARS-CoV-2 infection increased brain endothelial cell vascular cell adhesion molecule-1 (VCAM-1) and CD3+ T cell infiltration of the hippocampus, a region important for short term learning and memory. Concordantly, we observed learning and memory deficits. Importantly, genetic deficiency in Cav-1 attenuated brain endothelial VCAM-1 expression and T cell infiltration in the hippocampus of mice with SARS-CoV-2 infection. Moreover, Cav-1 KO mice were protected from the learning and memory deficits caused by SARS-CoV-2 infection. These results indicate the importance of BBB permeability in COVID-19 neuroinflammation and suggest potential therapeutic value of targeting Cav-1 to improve disease outcomes.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review: The study investigates the role of Caveolin-1 (Cav 1) in mediation of neuroinflammation and cognitive impairment (brain fog) in SARS-CoV-2 infection. Caveolin is an integral membrane protein which plays a role in the regulation of brain blood barrier (BBB) permeability. The role of this protein in T-cell central nervous system infiltration and respiratory viral infections is unknown. The authors investigate its role in BBB in neuroinflammation in a COVID-19 mouse model. Using genetically deficient mice in Cav-1 to test its role in T-cell infiltration and cognitive impairment. Importantly they found that SARS-CoV-2 infection induced vascular cells adhesion molecule-1 (VECAM-1) expression and T-cell infiltration in the hippocampus are diminished significantly in Cav-1 deficient mice. In addition, Cav-1 mice were protected from the learning and memory deficits caused by SARS-CoV-2 infection. Their results identify an actionable target at the level of BBB which can lead to improved outcome in patients with long COVID and memory deficits.

In fact, the results show very strong differences between WT and Cav-1 mice and the immunohistochemical staining’s document very well the differences. The neurobehavioral tests were conducted in a limited manner due to the limitations of the use of a biosafety cabinet in the BSL 3 suite. In addition, another caveat mentioned by the authors is that is unknow at this point if Cav-1 protection from neuroinflammation might be due to the pulmonary of cerebrovascular effects.

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