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Molecular cross-talk between integrins and cadherins leads to a loss of vascular barrier integrity during SARS-CoV-2 infection

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posted on 01.06.2022, 15:26 authored by Danielle NaderDanielle Nader, Steven KerriganSteven Kerrigan

The vascular barrier is heavily injured following SARS-CoV-2 infection and contributes enormously to life-threatening complications in COVID-19. This endothelial dysfunction is associated with the phlogistic phenomenon of cytokine storms, thrombotic complications, abnormal coagulation, hypoxemia, and multiple organ failure. The mechanisms surrounding COVID-19 associated endotheliitis have been widely attributed to ACE2-mediated pathways. However, integrins are emerging as possible receptor candidates for SARS-CoV-2, and their complex intracellular signaling events are essential for maintaining endothelial homeostasis. Here, we showed that the spike protein of SARS-CoV-2 depends on its RGD motif to drive barrier dysregulation by hijacking integrin αVβ3, expressed on human endothelial cells. This triggers the redistribution and internalization of major junction protein VE-Cadherin which leads to the barrier disruption phenotype. Both extracellular and intracellular inhibitors of integrin αVβ3 prevented these effects, similarly to the RGD-cyclic peptide compound Cilengitide, which suggests that the spike protein-through its RGD motif-binds to αVβ3 and elicits vascular leakage events. These findings support integrins as an additional receptor for SARS-CoV-2, particularly as integrin engagement can elucidate many of the adverse endothelial dysfunction events that stem from COVID-19.

Funding

RCSI StAR PhD program, Enterprise Ireland, Grant Number SI/2020/3044

3M & Global Giving grant number PT20306A01

History

Comments

The original article is available at https://www.mdpi.com/

Published Citation

Nader D, Kerrigan SW. Molecular cross-talk between integrins and cadherins leads to a loss of vascular barrier integrity during SARS-CoV-2 infection. Viruses. 2022;14(5):891.

Publication Date

25 April 2022

PubMed ID

35632633

Department/Unit

  • School of Pharmacy and Biomolecular Sciences

Publisher

MDPI

Version

  • Published Version (Version of Record)