BREAKING! U.S. NIH Study Finds That SARS-CoV-2 Spike Proteins Interacts With Platelet Integrins To Cause Deformities That Results In Coagulopathies!
: SARS-CoV-2 Infections are typically associated with abnormalities in blood coagulation in severe cases and even in those with mild infections, clotting issues that causes strokes seems to be a lingering issue in Long COVID.
The SARS-CoV-2 virus has been detected in the blood samples collected from COVID-19 patients.
Though detected viral load is generally low, the amount of virus present in the plasma typically correlates with the severity of COVID-19.
In a past study observing the clinical aspects of COVID-19, 59.6% of the COVID-19 patients had viral loads in their blood. Particularly, in critical patients, a constant high amount of viral load (176 copies/ml) was observed, in contrast to the patients with mild cases (81.7 copies/ml).
It should be noted that most COVID-19 News
coverages by mainstream media have never questioned as to why nasal or saliva swab tests are still being used to determine COVID-19 recovery when viremia (virus in the blood) is a common occurrence!
Interestingly, a low count of platelets (thrombocytopenia) together with the development of disseminated intravascular coagulation, myocardial infarction and non-vessel thrombotic complications are commonly observed in COVID-19 patients.
Platelets isolated from COVID-19 patients have also shown abnormalities such as hyperactivity and an increase in their spreading behavior.
The causes of these abnormalities have been hypothesized as cytokines, antiphospholipid antibodies, interactions with other immune cells, and direct interaction between SARS-CoV-2 and platelets.
Interestingly, isolated platelets from healthy donors mixed with SARS-CoV-2 or the SARS-CoV-2 spike (S) protein show a faster thrombin-dependent clot retraction and activate platelets independent of thrombin with upregulation of signaling factors.
Another recent study further suggests the involvement of thrombin and tissue factor (TF) in the hyperactivation of platelets.
However, a new study by researchers from the U.S. NIH, Bethesda-Maryland has found via direct Cryo-ET
observation of platelet deformation induced by SARS-CoV-2 Spike 2 protein.
In the study, scientists from the Laboratory of Structural Cell Biology, National Heart, Lung, and Blood Institute, US-NIH found that SARS-CoV-2 Spike Proteins interacts with Platelet Integrins to cause deformities that results in severe coagulopathies!
The study team reported the direct observation of the interactions between S protein and platelets. Live imaging showed that the S protein triggers platelets to deform dynamically, in some cases, leading to their irreversible activation.
Strikingly, cellular cryo-electron tomography revealed dense decorations of S protein on the platelet surface, inducing filopodia formation.
The study team hypothesizing that S protein binds to filopodia-inducing integrin receptors, tested the binding to RGD motif-recognizing platelet integrins and found that S protein recognizes integrin αvβ3.
The study findings infer that the stochastic activation of platelets is due to weak interactions of S protein with integrin, which can attribute to the pathogenesis of COVID-19 and the occurrence of coagulopathies.
The study findings were published on a preprint server and are currently being peer reviewed.
The study team also comprised of scientists from Campus Llamaquique, University of Oviedo - Spain, Osaka University Institute for Protein Research - Japan, National Institute of Arthritis and Musculoskeletal and Skin Diseases - USA the Health Research Institute of Asturias (ISPA), Avenida Hospital Universitario - Spain.
The SARS-CoV-2 infections have shown unique pathological symptoms that can lead to a wide range of coagulopathic events in severe cases and also in mild cases in post-COVID.
The study team probed the direct effect of S protein to the change in morphology of platelets at a molecular level, and for the first time, the researchers directly visualized the binding of S protein to the platelet surface.
The study team hypothesized that the binding of the SARS-CoV-2 is mediated by integrin receptors based on the following reasons:
-the activation of platelets is governed by filopodia formation,
-filopodia formation is initiated by integrin receptors,
-the major receptors on the platelets are integrin receptors and
-SARS-CoV-2 S protein contains a “RGD” sequence in the RBD, which is recognized by a subtype of integrin, and therefore the study team tested the interaction of platelet-expressed integrins with S protein.
Importantly, the integrin inhibition experiment using utilizing Cilengitide and in vitro solid-phase binding assays support this hypothesis, particularly with the possibility that S protein recognizes integrin αvβ3.
It was noted that the binding of S protein to integrin was much lower compared to the interaction of integrins with their physiological ligands, and interestingly, the study team did not detect the binding to the major platelet integrin αIIbβ3.
Past studies showed an increased binding of the activated integrin αIIbβ3 antibody PAC-1 to platelets in the presence of S protein.
The study team says that this may be due to an inside-out effect, in which the outside-in signaling is activated by the direct binding of S protein to integrin αvβ3 and in turn, αIIbβ3 would get activated through the intracellular signaling (inside-out).
The study team surmises that the weak affinity of S protein to platelet integrin receptors and the reversible binding, may reflect the fact that blood clotting defects observed in patients are rare complications and occur in severe cases of COVID-19.
The study team however warns that other receptors on platelets that may also be accountable for the interaction with S protein and combinatory effects of the binding of S protein to multiple receptors may also occur.
The SARS-CoV-2 virus has already been found in the blood stream of COVID-19 patients, and an open question is how it can lead to rare but severe coagulation defects.
The study findings showed that the deformation of platelets itself does not always alter their intracellular signaling), or induces activation.
Rather appears that platelets exposed to S protein are primed for the activation upon further stimuli, such as the attachment to an adhesion surface.
Hence, based on this observation, the study team speculates that the combination of the direct binding of S protein to platelets and other identified coagulation factors may induce a synergistic and irreversible activation of platelets, leading to coagulation.
It has been found that during SARS-CoV-2 infection, several other procoagulant players are active, for example the formation of neutrophil extracellular traps, the release of TF23, elevated fibrinogen levels and dysregulated release of cytokines, creating a hypercoagulative environment in the context of COVID-19.
The study team are the first to have visualized the adaptable attachment of S protein to the platelet plasma membrane with a high degree of flexibility for the engagement to continuously curved membrane surfaces.
It has been reported that the stalk domain of S protein proximal to the viral membrane surface contains three hinges, presumably allowing the flexible motion of individual S protein on the viral surface to adapt to curved host cell surfaces.
The study team says that this dual flexibility likely increases the probability for S protein to attach to a host cell receptor, thus, allowing an efficient action of S protein to the membrane surface.
This new study findings can also pave the way for new therapeutics to deal with SARS-CoV-2 induced coagulopathies.
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