SARS-CoV2 Spike Proteins Induce Hyperpermeability In Endothelial Cells

The spike protein of SARS-CoV2 has a strong binding affinity towards ACE2. But, the spike protein also contains an integrin-binding RGD motif on the surface of the receptor-binding domain that binds to β1 integrins on pulmonary epithelial cells and monocytes and leads to vascular inflammation and disruption of the EC barrier resulting in edema.

The direct action of SARS-CoV2 on ECs was critically studied using various in vitro assays like leukocyte adhesion assay, ELISA, vasopermeability assay, fluorescence cytochemistry, NF-κB nuclear translocation analysis, qPCR, and western blot. It was confirmed that spike proteins stimulated the adhesion of leukocytes to HUVEC (human vascular endothelial cells) in a dose-dependent manner with high potency (EC50 = 1.6 nM), and this stimulation paralleled the one induced by TNF⍺, the main inducer of EC pro-inflammatory changes. ELISA-based methods confirmed the binding of the spike to integrin α5β1 and in turn activated the NF-κB pathway in EC responsible for leukocyte infiltration.

The spike signals also bind to α5β1 to promote the formation of stress fibers, endothelial cell retraction, and inter-endothelial gap formation which results in increased vascular permeability. The spike protein upregulates RhoA which results in loss of barrier integrity and Cdc42 and downregulates Rac1 and thus reduces barrier stabilization in EC. The spike proteins also interfere with the CD31 molecules present in the EC monolayer and also activate eNOS which results in increased vasopermeability.

It was observed that inhibitors of α5β1 like volociximab and ATN-161 could successfully block leukocyte adhesion and decrease hyperpermeability of EC in response to spike, spike receptor-binding domain, and RGD tripeptide. These findings provide a better understanding of the pathophysiology of COVID-19 and will be helpful in the therapeutics development for reducing vascular inflammation in COVID-19. 

Source: BioRxiv



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