SARS-CoV-2 uses major endothelial integrin αvβ3 to cause vascular dysregulation in-vitro during COVID-19.

Danielle Nader,Gerard F Curley,Steven W Kerrigan,Nicola Fletcher,Mária A Deli

doi:10.1371/journal.pone.0253347

Abstract

The unprecedented global COVID-19 pandemic has prompted a desperate international effort to accelerate the development of anti-viral candidates. For unknown reasons, COVID-19 infections are associated with adverse cardiovascular complications, implicating that vascular endothelial cells are essential in viral propagation. The etiological pathogen, SARS-CoV-2, has a higher reproductive number and infection rate than its predecessors, indicating it possesses novel characteristics that infers enhanced transmissibility. A unique K403R spike protein substitution encodes an Arg-Gly-Asp (RGD) motif, introducing a potential role for RGD-binding host integrins. Integrin αVβ3 is widely expressed across the host, particularly in the endothelium, which acts as the final barrier before microbial entry into the bloodstream. This mutagenesis creates an additional binding site, which may be sufficient to increase SARS-CoV-2 pathogenicity. Here, we investigate how SARS-CoV-2 passes from the epithelium to endothelium, the effects of αVβ3 antagonist, Cilengitide, on viral adhesion, vasculature permeability and leakage, and also report on a simulated interaction between the viral and host protein in-silico.

Highlights

The unprecedented and ongoing Coronavirus disease 2019 (COVID-19) pandemic has caused a severe shock to the entire global population
Histopathological data has confirmed SARS-CoV-2 actively targets and infects human epithelial cells, resulting in severe cytopathic effects [11]. These primary manifestations commonly experienced in the lungs of COVID-19 patients include diffuse alveolar damage, tracheobronchitis, and interestingly, vascular injury [11, 12]
High expression of Tumor Necrosis Factor (TNF) has been widely reported in patients with COVID-19, where increased levels of this pro-inflammatory cytokine promotes intestinal epithelial barrier permeability [13, 14]. This disruption of intercellular junctions encourages a paracellular mechanism for viral invasion similar to that found in other viral infections such as Dengue virus and Human Immunodeficiency Virus (HIV) [15, 16]

Summary

Introduction

The unprecedented and ongoing Coronavirus disease 2019 (COVID-19) pandemic has caused a severe shock to the entire global population. As the global death toll continues to rise, vaccine candidates and targeted, effective anti-viral and immunotherapies are desperately sought after. Compared with diseases from other coronaviruses, COVID-19 has more adverse effects on the cardiovascular system. High rates of deep vein thrombosis and pulmonary embolism have been associated with severe SARS-CoV-2 infection [1], while COVID-19 presentations with stroke, myocardial infarction and disseminated intravascular coagulopathy have been reported [2, 3]. Accumulating evidence suggests that microvascular occlusion within the lungs plays an important role in COVID-19 pathogenesis.

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Results

Conclusion