Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection

  1. Troy N. Trevino
  2. Avital B. Fogel
  3. Richard Minshall
  4. Justin M. Richner
  5. Sarah E. Lutz

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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.

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  1. Rapid Reviews Infectious Diseases

    Horia Rus

    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.

  3. PREreview

    This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/10253481.

    Does the introduction explain the objective of the research presented in the preprint? Yes Explains clearly Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection
    Are the methods well-suited for this research? Somewhat appropriate
    Are the conclusions supported by the data? Somewhat supported
    Are the data presentations, including visualizations, well-suited to represent the data? Highly appropriate and clear
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Very clearly
    Is the preprint likely to advance academic knowledge? Highly likely
    Would it benefit from language editing? No
    Would you recommend this preprint to others? Yes, it's of high quality
    Is it ready for attention from an editor, publisher or broader audience? Yes, as it is

    Competing interests

    The author declares that they have no competing interests.

  4. Version published to 10.1101/2023.10.18.563024v1 on bioRxiv