Israeli Scientist Identify NSP2, NSP5_C145A And NSP7 As Key SARS-CoV-2 Proteins That Damage Human Host Endothelial Cells Of Blood Vessels
Israeli researchers from Tel Aviv University have successfully identified 3 key proteins out of the total of 29 proteins found in the SAR-CoV-2 genome that can damage the blood vessels of the human host. These three key proteins were nsp2, nsp5_c145a (catalytic dead mutant of nsp5), and nsp7.
The SARS-CoV-2 infection can lead to severe disease associated with cytokine storm, vascular dysfunction, coagulation, and progressive lung damage. It affects several vital organs, seemingly through a pathological effect on endothelial cells.
To date it is known that the SARS-CoV-2 genome encodes 29 proteins, whose contribution to the disease manifestations, and especially endothelial complications, is unknown.
The study team cloned and expressed 26 of these proteins in human cells and characterized the endothelial response to overexpression of each, individually.
The study findings showed that whereas most SARS-CoV-2 proteins induced significant changes in endothelial permeability, nsp2, nsp5_c145a (catalytic dead mutant of nsp5), and nsp7 also reduced CD31, and increased von Willebrand factor expression and IL-6, suggesting endothelial dysfunction.
Utilizing propagation-based analysis of a protein–protein interaction (PPI) network, the study team predicted the endothelial proteins affected by the viral proteins that potentially mediate these effects.
The team further applied the PPI model to identify the role of each SARS-CoV-2 protein in other tissues affected by coronavirus disease (COVID-19). While validating the PPI network model, the study team found that the tight junction (TJ) proteins cadherin-5, ZO-1, and β-catenin are affected by nsp2, nsp5_c145a, and nsp7 consistent with the model prediction.
The study findings identify the SARS-CoV-2 proteins that might be most detrimental in terms of endothelial dysfunction, thereby shedding light on vascular aspects of COVID-19.
The study findings were published in the peer reviewed journal: eLIfe
To date, almost 23 months since the SARS-CoV-2 coronavirus made its debut in Wuhan-China and has infected more than 248 million people globally and caused more than 5.02 million COVID-19 deaths, the mystery of which proteins in the SARS-CoV-2 virus are responsible for severe vascular damage that could even lead to heart attack or stroke has not yet been solved.
For the first time, a team of medical experts led by Tel Aviv University has been able to identify 3 of the 29 proteins that make up the virus that are responsible for damaging blood vessels.
Although the team originally identified 5 proteins ie nsp5_c145a, nsp13, nsp7, orf7a, and nsp2, the three proteins nsp2, nsp5_c145a and nsp7 were the three key agents involved in damaging the blood vessels.
The study team hopes that the identification of these proteins will help develop targeted drugs for COVID-19 that reduce vascular damage.
The research was led by Dr Ben Maoz of the Department of Biomedical Engineering and Sagol School of Neuroscience, Professor Dr Uri Ashery of the Wise Faculty of Life Sciences and Sagol School of Neuroscience, and Professor Dr Roded Sharan of the Blavatnik School of Computer Science-all Tel Aviv University researchers.
Also participating in the study were Dr Rossana Rauti, Dr Yael Bardoogo, and doctoral student Meishar Shahoah of Tel Aviv University and Professor Yaakov Nahmias of the Institute of Life Sciences at the Hebrew University.
Dr Ben Maoz told Thailand Medical News
, "We see a very high incidence of vascular disease and blood clotting, for example stroke and heart attack, among COVID patients. We tend to think of COVID as primarily a respiratory disease, but the truth is that coronavirus patients are up to three times more likely to have a stroke or heart attack. All the evidence shows that the virus severely damages the blood vessels or the endothelial cells that line the blood vessels. However, to this day the virus has been treated as one entity. We wanted to find out which proteins in the virus are responsible for this type of damage."
It should be noted that the SARS-CoV-2 coronavirus is a relatively simple virus in that it only comprises a total of 29 different proteins (compared to the tens of thousands of proteins produced by the human body!).
The Israeli study team used the RNA of each of the COVID-19 proteins and examined the reaction that occurred when the various RNA sequences were inserted into human blood vessel cells in the lab; they were thereby able to identify five coronavirus proteins that damage the blood vessels.
Dr Maoz explained, "When the SARS-CoV-2 coronavirus enters the human body, it begins to produce 29 proteins, a new virus is formed, that virus produces 29 new proteins, and so on. In this process, our blood vessels turn from opaque tubes into kind of permeable nets or pieces of cloth, and in parallel there is an increase in blood clotting. We thoroughly examined the effect of each of the 29 proteins expressed by the virus, and were successful in identifying the five specific proteins that cause the greatest damage to endothelial cells and hence to vascular stability and function. In addition, we used a computational model developed by Professor Sharan which allowed us to assess and identify which coronavirus proteins have the greatest effect on other tissues, without having seen them 'in action' in the lab."
The study team concluded that the identification of these proteins may have significant consequences in the fight against the virus.
They commented, "Our research could help find targets for a drug that will be used to stop the virus's activity, or at least minimize damage to blood vessels."
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