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.
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.”
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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