BREAKING! Irish Study Shows That Integrins Could Be Receptors For SARS-CoV-2 And Integrin Signaling Upon Infection Leads To Vascular Dysregulation!

Researchers from the School of Pharmacy and Biomolecular Sciences at RCSI University of Medicine and Health Sciences-Ireland have in a new study found that integrins could be receptors for SARS-CoV-2 and that integrin signaling via a VE-Cadherin mediated pathway upon SARS-CoV-2 infection leads to vascular dysregulation!


 
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, organization of the intracellular cytoskeleton, and movement of new receptors to the cell membrane. The presence of integrins allows rapid and flexible responses to events at the cell surface (e.g. signal platelets to initiate an interaction with coagulation factors).
 
A variety of integrins exist, and one cell generally has multiple different types on its surface.
 
Integrins work alongside other proteins such as cadherins, the immunoglobulin superfamily cell adhesion molecules, selectins and syndecans, to mediate cell–cell and cell–matrix interaction. Ligands for integrins include fibronectin, vitronectin, collagen and laminin.
 
Typically, integrins have two main functions, attachment of the cells to the ECM and signal transduction from the ECM to the cells. They are also involved in a wide range of other biological activities, including extravasation, cell-to-cell adhesion, cell migration, and as receptors for certain viruses, such as adenovirus, echovirus, hantavirus, and foot-and-mouth disease, polio virus and other viruses.
 
A prominent function of the integrins is seen in the molecule GpIIb/IIIa, an integrin on the surface of blood platelets (thrombocytes) responsible for attachment to fibrin within a developing blood clot. This molecule dramatically increases its binding affinity for fibrin/fibrinogen through association of platelets with exposed collagens in the wound site. Upon association of platelets with collagen, GPIIb/IIIa changes shape, allowing it to bind to fibrin and other blood components to form the clot matrix and stop blood loss.
 
To date, we already know that the vascular barrier is heavily injured following SARS-CoV-2 infection and contributes enormously to life-threatening complications in COVID-19.
 
Importantly this endothelial dysfunction is associated with the phlogistic phenomenon of cytokine storms, thrombotic complications, abnormal coagulation, hypoxemia, and multiple organ failure.
 
So fat, the mechanisms surrounding COVID-19 associated endotheliitis have been widely attributed to ACE2-mediated pathways.
 
Now, new data show that integrins have emerged as possible receptor candidates for SARS-CoV-2, and their complex intracellular signaling events are essential for maintaining endothelial homeostasis.
 
The study team showed that the spike protein of SARS-CoV-2 depends on its RGD motif to drive barrier dysregulation through hijacking integrin αVβ3. This triggers the redistribution and internalization of major junction protein VE-Cadherin which leads to the barrier disruption phenotype.
 
Interestingly 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, thr ough its RGD motif – binds to αVβ3 and elicits vascular leakage events.
 
The study 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.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.03.15.484274v1
 
The study findings demonstrated the role of integrin signaling in vascular dysfunction associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
 
Typically following SARS-CoV-2 infection, the vascular barrier is severely damaged. This endothelial malfunctioning by SARS-CoV-2 contributes significantly to life-threatening consequences in coronavirus disease 2019 (COVID-19).
 
Importantly, the phlogistic phenomena of multiple organ failure, hypoxemia, abnormal coagulation, cytokine storms, and thrombotic complications are linked to endothelial dysfunction caused by SARS-CoV-2 infection.
 
To date, angiotensin-converting enzyme 2 (ACE2)-mediated routes have been generally linked to the processes of COVID-19-associated endothelitis.
 
However, integrins, on the other hand, have recently surfaced as potential SARS-CoV-2 receptor candidates, and their intricate intracellular signaling processes are critical for preserving endothelial homeostasis.
 
It was noted that the study team were the first to identify a trend of vascular dysfunction after SARS-CoV-2 infection.
 
The team also hypothesized that vascular endothelial cadherin (VE-cadherin), a key endothelial adherens junction protein, was implicated in the SARS-CoV-2-related endothelial dysregulation.
 
The study findings determined the direct mechanism connecting integrins with vascular dysregulation in SARS-CoV-2 infection.
 
The study also evaluated whether the SARS-CoV-2 spike (S) protein's arginyl-glycyl-aspartic acid (RGD) motif suppression was enough to alleviate the endothelial dysregulation phenotype in COVID-19.
 
For the study, primary-derived Human Aortic Endothelial Cells (HAoEC; Promocell C-12271) were used.
 
Also, enzyme-linked immunoassay (ELISA)-based tests were conducted to evaluate contacts between integrins and recombinant SARS-CoV-2 S proteins of wild-type (WT) virus and the Delta and Omicron variants.
 
The studies were performed with and without neutralizing antibodies targeting αVβ3 integrin's active site or its β3 subunit and cyclic RGD peptide molecule, cilengitide. VE-cadherin expression and endothelial barrier damage were quantified using immunofluorescence and transwell permeability tests. Further, Western blot analysis was conducted to detect VE-cadherins.

The study findings showed that the SARS-CoV-2 S protein uses its RGD motif to cause the endothelial barrier dysfunction via integrin αVβ3 hijacking. This causes the main junction protein VE-Cadherin to redistribute and internalize, resulting in the barrier disruption phenotype.
 
It was also found that besides cilengitide, both intracellular and extracellular integrin αVβ3 inhibitors blocked the barrier dysregulation effects induced by SARS-CoV-2.
 
Thailand Medical News would separately like to add that based on our studies, the phytochemicals Amentoflavone, Arctigenin, Kumatakenin and Oridonin can also act as integrin αVβ3 inhibitors and also block the barrier dysregulation effects caused by the SARS-CoV-2 coronavirus.
 
Basically, the integrin αVβ3 recognizes the SARS-CoV-2 Delta and Omicron variants of concern (VOC)s' S proteins because they both maintain the RGD site. Both integrin neutralizing antibodies and cilengitide inhibited S binding to integrins in the same way, indicating that this interaction was probably RGD-dependent.
 
However, although integrin antagonists like GLPG-0187 efficiently minimized SARS-CoV-2 infection at high doses, they failed to inhibit S interaction with integrins at comparable concentrations with cilengitide. This might be because of the wide range of GLPG-0187 activity relative to the highly selective binding of cilengitide with αVβ3.
 
It was found that the binding of SARS-CoV-2 S protein with integrin αVβ3 had no discernible influence on VE-cadherin levels.
 
Nonetheless, SARS-CoV-2 infection caused a significant change in VE-cadherin structure by inducing its internalization, which resulted in the malfunctioning endothelial barrier phenotype.
 
Past studies have demonstrated that the SARS-CoV-2 S protein stimulates Ras homolog family member A (RhoA) in infected venous endothelial cells via Ras-related C3 botulinum toxin substrate 1 (Rac1) downregulation, which enhances endothelial leakage and permeability.
https://pubmed.ncbi.nlm.nih.gov/35143839/
 
https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.118.314560
 
After integrin ligation, VE-cadherin collaborates with Rac1 to suppress RhoA and control cell spreading. https://pubmed.ncbi.nlm.nih.gov/15075376/
 
Based on both past and current findings, the study team suggest the prevention of primary interaction between host proteins and SARS-CoV-2 using integrin antagonists might be efficient in precluding vascular damage in COVID-19.
 
Importantly, the research findings have revealed the downstream signaling transduction route that connects integrins to vasculopathy observed during COVID-19.
 
The SARS-CoV-2 S protein via its RGD motif interacts with αVβ3 and causes events of vascular leakage. The findings also suggest integrins as an alternative SARS-CoV-2 receptor, especially because integrin interaction can explain several COVID-19-induced endothelial dysfunction events.
 
The drug, Cilengitide, an αVβ3 integrin inhibitor, has shown potential in preventing the SARS-CoV-2-associated endothelial dysregulation.
 
The study findings imply that by decreasing the initial signal that activates integrins, the downstream signaling pathways that govern cellular hyperpermeability in COVID-19 can be reduced.
 
On the whole, the findings suggest that the endothelial cells are important participants in viral infection, and delineation of the processes governing vascular integrity is necessary for the generation of therapeutics to combat SARS-CoV-2 pathogenesis.

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