The Viral Fragment Theory of Covid-19 Vascular Complications

meryana (35) in news • 4 years ago

SARS-CoV-2 replication alone may not explain Covid-19.

One perplexing feature of Covid-19 is that it targets multiple organ systems despite being one type of virus. One answer to this oddity is that the coronavirus, SARS-CoV-2, exploits multiple receptors. The recent discovery of neuropilin-1 and CD147 (basigin) receptors — in addition to the previously known ACE2 receptor — explains why SARS-CoV-2 can invade the olfactory, pulmonary, vascular, and immune systems.

Another reason may be the virus’s capacity to inflame the blood vessels and cause clotting. As the blood vessels transverse all organs, vascular problems may have widespread health consequences. In line with this, a new theory has cast light on how SARS-CoV-2 might disturb the vascular system.
New findings

In a study published last month in Vascular Pharmacology, Yuichiro J. Suzuki, a professor at the Department of Pharmacology and Physiology at Georgetown University, and co-workers discovered that the spike protein of SARS-CoV-2 is enough to trigger a response in lab-cultured human endothelial and smooth muscle cells from the lungs’ blood vessels. Yes, just the spike protein, without the whole virion or its genome.

Specifically, the MEK/ERK cell signaling was activated in response to the spike protein. The MEK/ERK pathway is responsible for initiating cell growth, which may explain the thickening of blood vessels’ walls seen in autopsies of deceased patients from Covid-19.

This study also noticed that such vascular thickening did not happen during the autopsy of influenza cases. In those who died of influenza, the vascular thickness was about 6.7μm; in Covid-19 cases, the number reached 15.4 μm. Interestingly, looking back at published autopsy reports of SARS-1, the study authors also did not find evidence of vascular thickening. So, this disease feature is unique to SARS-CoV-2 or Covid-19.

…SARS-CoV-2 may not need to complete viral infection and replication to cause disease. Just the spike protein lingering around may be enough to trigger biological problems, such as vascular thickening.

“The present study shows that cell growth signaling may be triggered by this virus in both cultured cells and in Covid-19 patient samples,” the study authors concluded. “We propose that SARS-CoV-2 spike protein-mediated cell signaling promotes the hyperplasia and/or hypertrophy of vascular smooth muscle and endothelial cells, contributing to the complex cardiovascular outcomes in Covid-19.”

New hypothesis

In another paper by Prof. Suzuki published in Medical Hypotheses, he further discussed the study’s implications, where he proposed a new hypothesis, “The viral protein fragment theory of COVID-19 pathogenesis.”

Based on the study, it appears that SARS-CoV-2 may not need to complete viral infection and replication to cause disease. Just the spike protein lingering around may be enough to trigger biological problems, such as vascular thickening.

Prof. Suzuki hypothesized that, upon SARS-CoV-2 infection, some of its spike proteins might get released elsewhere. These viral fragments may then activate growth signals in blood vessels. Infected people now face two types of attacks— SARS-CoV-2 replication inside cells to produce new virions and lingering spike protein fragments targeting other cells. As he stated:

Thus, infected patients would have at least two entities that may cause complications when they are infected with SARS-CoV-2: (i) virus itself that gets incorporated into the host cells where the viral replication and amplification occur; and (ii) components of viral fusion proteins (i.e. spike protein for SARS-CoV-2) that get circulated to elicit distinct processes promoting pathologic conditions.

If the theory is correct, then treatments stopping SARS-CoV-2 replication only will be ineffective. Remdesivir is one prime example, where it only stops the viral enzyme needed for its replication. The released spike protein fragments of SARS-CoV-2 may still cause health problems. Indeed, remdesivir failed to produce any clinical benefit in the W.H.O Solidarity trial and other trials. (But remdesivir is still approved for use due to other trials' positive results, so it may be better than nothing.) Thus, a successful antiviral may need to halt both viral replication and released spike protein fragments.

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It’s a theory

Still, it’s a theory or hypothesis that requires more research to verify. Presently, the viral spike protein fragment theory of Covid-19 vascular complications is only supported by in vitro (cultured cells outside a living organism) work, which may or may not translate to animals or humans. So, the next step might be to expose lab animals to SARS-CoV-2 spike proteins and see if vascular problems develop, and what might stop them.

Infected people now face two types of attacks — SARS-CoV-2 replication inside cells to produce new virions and lingering spike protein fragments targeting other cells.

Plus, whether SARS-CoV-2 actually releases its spike protein before, during, or after cell infection remains unconfirmed. But it’s plausible that not all spike proteins on the SARS-CoV-2 surface are needed to bind to receptors on human cells. So, some unused spike proteins may run elsewhere.

The theory also concerns mRNA vaccines. “Covid-19 mRNA vaccines give instructions for our cells to make a harmless piece of what is called the “spike protein,” the CDC stated. It’s harmless as the virus can’t replicate without its genome. But if the theory is correct, then the spike protein of SARS-CoV-2 may not be 100% safe. However, judging from the safety data of the mRNA vaccines clinical trials, we can be assured that the vaccine-induced spike protein production will not cause any major health issues. Perhaps the spike proteins are being made in the right quantity to trigger useful immune responses, and not too much to affect the blood vessels.

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Short abstract

A study offers new insights into what might cause blood vessel dysfunction in Covid-19. The study found that the spike protein of SARS-CoV-2 is sufficient to induce growth signaling in blood vessels in the lungs. This is consistent with the blood vessel wall thickening observed in autopsies of Covid-19, and not in other respiratory viral diseases. Thus, SARS-CoV-2 may attack the host via two ways: virus replication inside cells and release of spike protein fragments. If this theory is true, then drugs halting SARS-CoV-2 replication alone like remdesivir will not work.

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4 years ago by meryana (35)

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