Cardiovascular Infection Research Group, School of Pharmacy and Biomolecular Sciences (PBS), RCSI University of Medicine and Health Sciences, 123 St. Stephen's Green, D02 YN77 Dublin, Ireland.
Viruses. 2022 Apr 25;14(5):891. doi: 10.3390/v14050891.
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.
血管屏障在 SARS-CoV-2 感染后受到严重损伤，并极大地促成了 COVID-19 中的危及生命的并发症。这种血管内皮功能障碍与细胞因子风暴的炎症现象、血栓并发症、异常凝血、低氧血症和多器官衰竭有关。与 COVID-19 相关的血管内皮炎的机制被广泛归因于 ACE2 介导的途径。然而，整合素作为 SARS-CoV-2 的可能受体候选物正在出现，它们复杂的细胞内信号事件对于维持血管内皮细胞的稳态至关重要。在这里，我们表明，SARS-CoV-2 的刺突蛋白依赖其 RGD 基序通过劫持人血管内皮细胞上表达的整合素 αVβ3 来驱动屏障失调。这会触发主要连接蛋白 VE-Cadherin 的重分布和内化，从而导致屏障破坏表型。整合素 αVβ3 的细胞外和细胞内抑制剂均可阻止这些效应，类似于 RGD 环肽化合物 Cilengitide，这表明刺突蛋白通过其 RGD 基序与 αVβ3 结合，并引发血管渗漏事件。这些发现支持整合素作为 SARS-CoV-2 的另一种受体，特别是因为整合素的参与可以阐明源自 COVID-19 的许多不良血管内皮功能障碍事件。
