COVID-19 News: U.S. NIH Funded Study Discovers That SARS-CoV-2 Spike Protein Binds And Modulates Estrogen Receptors, Increasing Risk Of Thrombosis!

COVID-19 News: A new study funded by the U.S. NIH has found that the spike proteins of the SARS-CoV-2 virus also binds to estrogen receptors (Erα and Erβ) and modulates them. The study findings suggest that, given the role of ERα in the coagulation cascade, S-protein could increase the pro-coagulation activity of endothelial cells leading to an enhanced risk of thrombosis.


 
The SARS-CoV-2 spike (S) protein typically binds with angiotensin-converting enzyme 2 as its primary infection mechanism. However, interactions between S and endogenous proteins occur after infection but are not well understood.
 
The study team profiled binding of S against >9000 human proteins and found an interaction between S and human estrogen receptor α (ERα).
 
Utilizing bioinformatics, supercomputing, and experimental assays, the study team identified a highly conserved and functional nuclear receptor coregulator (NRC) LXD-like motif on the S2 subunit.
 
Interestingly, in cultured cells, S DNA transfection increased ERα cytoplasmic accumulation, and S treatment induced ER-dependent biological effects.
 
Non-invasive imaging in SARS-CoV-2–infected hamsters localized lung pathology with increased ERα lung levels. Postmortem lung experiments from infected hamsters and humans confirmed an increase in cytoplasmic ERα and its colocalization with S in alveolar macrophages.
 
The study findings describe the discovery of a S-ERα interaction, implying a role for S as a nuclear receptor coregulator or NRC.
 
The study findings were published in the peer reviewed journal: Science Advances
https://www.science.org/doi/10.1126/sciadv.add4150
 
This is the first study to date that has detailed the novel function of the SARS-CoV-2 spike (S) protein interaction with the human Estrogen Receptor Alpha (ERα) that may lead to the severe coagulopathy observed in patients with COVID-19 and a minority of subjects receiving the SARS-CoV-2 vaccine.
 
The study team included researchers from the U.S. National Institute on Drug Abuse, part of the U.S. National Institutes of Health, Johns Hopkins University, The Scripps Institute, Stanford School of Medicine, University of L'Aquila, in Italy and EXSCALATE, Dompé farmaceutici S.p.A, Napoli, Italy.
 
To date, it is already known that the SARS-CoV-2 virus can cause severe vasculopathy, which may, in turn, result in fatal thrombosis.
 
The study team's findings are consistent with the sex-specific differences in thrombosis observed in hospitalized patients with COVID-19, and in a minority of subjects receiving the SARS-CoV-2 vaccine.
 
The key data leading to the study emerged from the results of the Exscalate4CoV (E4C) project, a group composed of 30 public and private institutions from seven countries aimed at fighting Coronavirus with the latest European supercomputing resources and experimental facilities.
 
The ambitious project leveraged the computational power of Exscalate, Dompé's supercomputing platform expl oiting a database of 500 billion molecules to find those capable of targeting clinically relevant coronavirus variants.
 
As a result of its processing capacity of more than 3 million molecules per second, Exscalate is currently the most powerful intelligent supercomputing drug design platform running on Leonardo, the 4th most powerful supercomputer in the world. This processing power allowed the E4C researchers to rapidly select and repurpose a generic molecule (raloxifene) with known efficacy and tolerability as an estrogen modulator for treating osteoporosis.
 
Utilizing the Exscalate platform to identify spike protein binding partners beyond the canonical ACE2 receptor, the study team identified prominent interactions between two human estrogen receptors (ERα, ERβ) and SARS-CoV-2 spike protein.
 
Importantly, after an unbiased primary screen to profile the binding of full-length spike protein against more than 9,000 human proteins, the study team found a consistent interaction with the human estrogen receptor alpha (ERα).
 
High ERα levels were also found in the damaged lungs of infected hamsters, as well as in human postmortem lung samples.
 
The study team suggests that, given the role of ERα in the coagulation cascade, S-protein could increase the pro-coagulation activity of endothelial cells leading to an enhanced risk of thrombosis.
 
Although circulating estrogens play a protective role by regulating the immune response to infection, it may be possible that the modulation of ER signaling in SARS-CoV-2-infected lung tissue can stimulate proinflammatory signals leading to hypertrophy, vasoconstriction, and vessel obstruction.
 
This hypothesis has been validated by a further set of experimental findings, demonstrating that the interaction between the spike protein and ERα leads to an increase in tissue factor (TF) and overall pro-coagulation activity in a human endothelial cell line, a result further confirmed by overexpressing S-protein in mice.
 
The study findings are consistent with the researchers' demonstration that deletion of the appropriate point mutations in the spike sequence abolished the binding of ERα and its effects without compromising its immunogenicity and pointing at a way to mitigate the rare side effects observed with the currently available vaccines.
 
Roberto Viola, Director-General of the European Commission's Directorate-General for Communications Networks, Content and Technology (DG CONNECT) who last week inaugurated Leonardo supercomputer in Bologna, Italy told COVID-19 News reporters, "Supercomputing has already demonstrated its capacity to find answers to questions we could not answer only a few years ago. And it will increasingly help us find solutions in all kinds of areas: from climate change with extreme weather forecasts and urban planning to understanding human brain and body. Medicine is the field where supercomputing is already giving concrete fruits. I am very proud of the support which the European Commission gave to the Exscalate4Cov consortium to discover promising leads for fighting COVID-19 more effectively."
 
Dompé farmaceutici's Chief Scientific Officer, Dr Marcello Allegretti further added, "Eventually, the overall evidence provides a solid rationale for some previously published results obtained by our team. namely, the beneficial role of estrogen receptor modulators, especially raloxifene, in preventing some of the infection side-effects and support raloxifene use for both therapy and vaccine side-effects mitigation."
 
Meanwhile the study team also added, “As compared to female patients, hyperactivation of ER signaling in pulmonary tissue in males has been associated with lower frequency but more severe progression of vascular obliteration in pulmonary arterial hypertension. This model could also potentially explain the widely discussed effect of ER modulation in SARS-CoV-2 infection and the reported protective effect of antiestrogenic treatment on COVID-19 prevalence in women with ovarian and breast cancer.
 
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