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

ABSTRACT: In the initial process of COVID-19, SARS-CoV-2 infects respiratory epithelial cells and then transfers to other organs via the blood vessels. It is believed that SARS-CoV-2 can pass the vascular wall by altering the endothelial barrier using an unknown mechanism. In this study, we investigated the effect of SARS-CoV-2 on the endothelial barrier using an airway-on-a-chip that mimics respiratory organs and found that SARS-CoV-2 produced from infected epithelial cells disrupts the barrier by decreasing Claudin-5 (CLDN5), a tight junction protein, and disrupting vascular endothelial cadherin (VE-cadherin)-mediated adherens junctions. Consistently, the gene and protein expression levels of CLDN5 in a COVID-19 patient’s lungs were decreased. CLDN5 overexpression or Fluvastatin treatment could rescue the SARS-CoV-2-induced respiratory endothelial barrier disruption. We therefore concluded that the downregulation of CLDN5 expression is a pivotal mechanism for SARS-CoV-2-induced endothelial barrier disruption in respiratory organs and that inducing CLDN5 expression is a novel therapeutic strategy against COVID-19.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196113 | GEO | 2022/09/22

REPOSITORIES: GEO

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Project description:SARS-CoV-2 primarily affects the respiratory system but extra-pulmonary manifestations in individuals with COVID-19 are commonly seen. All major organ systems have been reported to be affected by SARS-CoV-2 and complications arising from ensuing organ dysfunction significantly increase the mortality rate of COVID-19. Yet, despite the clinical importance of systemic involvement of SARS-CoV-2, little is known about the pathogenesis of extra-pulmonary complications of COVID-19. Here, we create a murine model of SARS-CoV-2 induced severe systemic toxicity and multi- organ involvement by expressing the human ACE2 transgene in multiple tissues using an adeno associated virus (serotype 9) followed by administration of the SARS-CoV-2 virus intra-peritoneally. The animals develop a profound phenotype within 7 days of SARS-CoV-2 infection with severe weight loss, morbidity and failure to thrive, that necessitated euthanasia. We demonstrate that following a robust anti-viral immune response, there is metabolic suppression of oxidative phosphorylation and the tri- carboxylic acid (TCA) cycle in multiple organs with neutrophilia, lymphopenia and splenic atrophy mirroring human COVID-19 phenotypes with adverse prognosis. Animals had a significantly lower heart rate and electron microscopy demonstrated myofibrillar disarray and myocardial edema, a common pathogenic cardiac phenotype in human COVID-19. An organ wide metabolic reprogramming consistent with depression of oxidative phosphorylation led to utilization of peripheral fat stores and gross accumulation of fat in the heart and other vital organs. We perform metabolomic profiling of peripheral blood and identify a panel of TCA cycle metabolites that serve as biomarkers of depressed oxidative phosphorylation, several of these markers been noted in human clinical studies to be associated with adverse prognosis. Finally, we observed that SARS-CoV-2 induces epigenetic changes with a significant number of differentially methylated sites in vital organs, across the whole host cell genome, that affects expression of immune response genes and could in part contribute to dysregulated gene expression in affected tissues. Our model suggests that SARS-CoV- 2 induced metabolic reprogramming and epigenetic changes in internal organs could contribute to systemic toxicity and lethality in COVID-19.

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

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