SARS-CoV-2 From Infected Epithelial Cells Disrupts The Endothelial Barrier By Downregulating Claudin-5

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A new study by researchers from Kyoto University-Japan and Osaka University-Japan has found the detailed mechanism by which SARS-CoV-2 invades into the blood vessels.

The study findings were published in the peer reviewed journal: Science Advances.
https://www.science.org/doi/10.1126/sciadv.abo6783

Airways and alveoli are the main organs infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infects ciliated cells and type II alveolar epithelial cells using angiotensin-converting enzyme 2 (ACE2) (1). Because vascular endothelial cells (ECs) hardly express ACE2, SARS-CoV-2 rarely infects these cells (2). However, vasculitis and vascular barrier disruption are often observed in patients with severe coronavirus disease 2019 (COVID-19) (3).

This barrier disruption promotes the transfer of SARS-CoV-2 from the respiratory organs to other organs through blood vessels. Vascular hyperpermeability in the lung induces the infiltration of immune cells and blood components there and respiratory failure, including pneumonia and acute respiratory distress syndrome (ARDS) (4). In this respect, elucidation of the mechanism for SARS-CoV-2–induced vascular permeability is an urgent issue, but the mechanism is poorly understood.

ECs cover the inner layer of blood vessels. In respiratory organs, ECs control the passage of substances and cells from epithelial cells to blood by regulating vascular permeability. The loss or impairment of this control can lead to severe and sometimes fatal organ dysfunction in pathological conditions, including inflammation and sepsis (5). Endothelial permeability is mainly regulated by cell-cell junctions, including adherens and tight junctions. Adherence junctions are regulated by cadherins and nectins, whereas tight junctions are composed of occludin, claudins, and junctional adhesion molecules (5, 6).

Among these transmembrane proteins, vascular endothelial cadherin (VE-cadherin) and Claudin-5 (CLDN5), which are specifically expressed in ECs, are well studied as regulators of endothelial permeability. VE-cadherin binds to several proteins, including β-catenin, via its cytoplasmic domain. Pivotal roles of VE-cadherin for vascular integrity and permeability have been shown by antibody-mediated loss-of-function studies (7). On the other hand, CLDN5 has been shown to control the tight sealing of ECs in the blood-brain barrier (BBB). CLDN5 size-selectively inhibits the transfer of small molecules across the vasculature in the brain (8). However, little is known about the physiological function of CLDN5 in other organs.

A large number of patients with severe COVID-19 die from ARDS, pneumonia, and pulmonary edema, which are induced by vascular hyperpermeability in the lung (9). In patients with severe COVID-19, activated ECs produce inflammatory cytokines and adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), which induce cytokine storm, the infiltration of inflammatory cells, and vascular leakage (10, 11).

This information suggests that SARS-CoV-2 also affects the inflammation and permeability of ECs in the lung. However, it has been reported that SARS-CoV-2 hardly infects ECs (2). In addition, there is limited information about how ECs are activated in patients with COVID-19. These studies would benefit from clarifying the effect of SARS-CoV-2 infection on EC functions in the lung, especially regarding the junction-mediated endothelial barrier function.

In patients with COVID-19, SARS-CoV-2 is found in the blood, and SARS-CoV-2 protein is expressed in many organs including respiratory organs (12). On the other hand, in the hamsters and ferrets widely used in COVID-19 studies, SARS-CoV-2 protein is hardly detected in organs other than respiratory organs (13). This difference is thought to be due to species differences of the SARS-CoV-2 distribution in the body.

Therefore, a human model to investigate the respiratory-to-vascular transfer of SARS-CoV-2 and the SARS-CoV-2 infection–mediated disruption of the endothelial barrier is preferred. To examine the effects of SARS-CoV-2 replicated in airway epithelial cells on vascular ECs, in the present study, we used airway-on-a-chip technology (14, 15).

An airway-on-a-chip is a coculture system of airway epithelial cells and ECs and mimics the in vivo dynamic microenvironment by flowing air and medium. In general, organ-on-a-chip technology makes it possible to generate a three-dimensional and dynamic in vitro model and to study interactions between multiple organs (e.g., respiratory organs and blood vessels).

In this study, a comprehensive gene expression analysis was performed of human lung microvascular ECs (HMVEC-L) in an airway-on-a-chip infected with SARS-CoV-2. We found that SARS-CoV-2 disrupts the respiratory endothelial barrier by decreasing CLDN5 expression and disorganizing the VE-cadherin–mediated junction. A loss of CLDN5 function by anti-CLDN5 antibody induced severe vascular leakage and edema specifically in the lungs of mice.

Furthermore, we demonstrated that the respiratory endothelial barrier disruption caused by SARS-CoV-2 is suppressed by CLDN5 overexpression and Fluvastatin treatment. In conclusion, we successfully identified CLDN5 as a SARS-CoV-2–responsive gene in HMVEC-L and revealed the mechanism of SARS-CoV-2–mediated disruption of the respiratory vascular barrier in respiratory organs.

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