Molecular Cross-Talk between Integrins and Cadherins Leads to a Loss of Vascular Barrier Integrity during SARS-CoV-2 Infection

Abstract

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.

Intracellular peptides in SARS-CoV-2-infected patients

“… 28 , 65 , 69 The S-SARS-CoV-2 was shown to depend on its integrin RGD motif to elicit vascular leakage events, which can be prevented by the RGD-cyclic peptide compound cilengitide. 70 , 71 Herein, the relative ratio of InPeps containing RGD or LDS motifs were reported to be increased in patients infected by SARS-CoV-2. Moreover, peptides presenting LDS motif were increased in M/C and S/C groups, but not in D/C group, which may help patients to survive the SARS-CoV-2 infection.…”

Murine alveolar macrophages rapidly accumulate intranasally administered SARS-CoV-2 Spike protein leading to neutrophil recruitment and damage

“…Also arguing against a role for ACE2 in our model, the responses to intranasal Spike protein in hACE2 transgenic mice resembled those of wild-type mice. The Spike protein RGD (arginine-glycine-aspartic acid) motif can also bind α V β 3 integrins present on endothelial cells ( Nader and Kerrigan, 2022 ). This affects VE-cadherin function and vascular integrity.…”

Murine Alveolar Macrophages Rapidly Accumulate Intranasally Administered SARS-CoV-2 Spike Protein leading to Neutrophil Recruitment and Damage

“…Also arguing against a role for ACE2 in our model, the responses to intranasal Spike protein in human ACE2 transgenic mice resembled those of wild type mice. The Spike protein RGD (Arginine-Glycine-Aspartic Acid) motif can also bind α V β 3 integrins present on endothelial cells (46). This affects VE-cadherin function and vascular integrity.…”