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SARS-CoV-2 disrupts respiratory vascular barriers by suppressing Claudin-5 expression

Rina Hashimoto1, Junya Takahashi2, Keisuke Shirakura2

  • 1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

Science Advances
|September 21, 2022
PubMed

Insights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disrupts the respiratory endothelial barrier by reducing Claudin-5 (CLDN5). Restoring CLDN5 levels offers a potential therapeutic strategy for COVID-19 patients.

Area of Science:

  • * Virology
  • * Cell Biology
  • * Respiratory Medicine

Background:

  • * Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection initially targets respiratory epithelial cells.
  • * SARS-CoV-2 is hypothesized to breach vascular barriers via an unknown mechanism affecting endothelial cells.
  • * Understanding SARS-CoV-2's impact on endothelial barriers is crucial for COVID-19 pathogenesis.

Purpose of the Study:

  • * To investigate the effect of SARS-CoV-2 on the respiratory endothelial barrier.
  • * To identify the molecular mechanisms underlying SARS-CoV-2-induced endothelial barrier disruption.
  • * To explore potential therapeutic strategies targeting endothelial barrier integrity in COVID-19.

Main Methods:

  • * Utilized an airway-on-a-chip model to mimic respiratory organ function and SARS-CoV-2 infection.
  • * Assessed the impact of SARS-CoV-2 on tight junction proteins, specifically Claudin-5 (CLDN5).
  • * Analyzed CLDN5 gene and protein expression in lung tissue from a COVID-19 patient.

Main Results:

  • * SARS-CoV-2 infection disrupted the endothelial barrier by decreasing Claudin-5 (CLDN5) expression.
  • * Vascular endothelial cadherin-mediated adherens junctions were also disrupted by SARS-CoV-2.
  • * Reduced CLDN5 levels were observed in the lungs of a COVID-19 patient.
  • * Overexpression of CLDN5 or treatment with Fluvastatin ameliorated SARS-CoV-2-induced barrier disruption.

Conclusions:

  • * Down-regulation of CLDN5 is a key mechanism in SARS-CoV-2-induced endothelial barrier dysfunction in respiratory organs.
  • * Enhancing CLDN5 expression presents a promising therapeutic avenue for treating COVID-19.
  • * Targeting endothelial barrier integrity could be a novel strategy against SARS-CoV-2 infection.

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