








key: cord-308279-gsk4qel5
authors: Suzuki, Yuichiro J.
title: The viral protein fragment theory of COVID-19 pathogenesis
date: 2020-09-11
journal: Med Hypotheses
DOI: 10.1016/j.mehy.2020.110267
sha: 
doc_id: 308279
cord_uid: gsk4qel5

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the current pandemic of coronavirus disease 2019 (COVID-19) that have killed nearly one million people so far. While this appears to be a respiratory virus, surprisingly, it has been recognized that patients with cardiovascular disease are likely to be affected severely and die of COVID-19. This phenomenon cannot be explained by the generally accepted logic that the SARS-CoV-2 infection/replication is the sole determinant of the actions of the virus to define the fate of host cells. I herein propose the viral protein fragment theory of COVID-19 pathogenesis based on my observations in cultured human vascular cells that SARS-CoV-2 spike protein can activate cell signaling events without the rest of the viral components. It is generally thought that SARS-CoV-2 and other single-stranded RNA viruses attach to the host cells through the interactions between surface proteins of the viral capsid and the host cell receptors; the fusion and the entry of the viral components, resulting in the replication of the viruses; and the host cell responses are the consequence of these events. I hypothesize that, as humans are infected with SARS-CoV-2, the virus releases a fragment of the spike protein that can target host cells for eliciting cell signaling without the rest of the viral components. Thus, COVID-19 patients are subjected to the intact virus infecting the host cells for the replication and the amplification as well as the spike protein fragment that are capable of affecting the host cells. I propose that cell signaling elicited by the spike protein fragment that occurs on cardiovascular cells would predispose infected individuals to develop complications that are seen in severe and fatal COVID-19 conditions. If this hypothesis is correct, then the strategies to treat COVID-19 should include, in addition to giving agents that inhibit the viral replication, therapeutics that inhibit the virus fragment-mediated cell signaling on cardiovascular cells.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the current pandemic of coronavirus disease 2019 (COVID-19) that have killed nearly one million people so far. While this appears to be a respiratory virus, surprisingly, it has been recognized that patients with cardiovascular disease are likely to be affected severely and die of COVID-19. This 

Viruses invade host cells, resulting in cell death. The major target cells for SARS-CoV-2 should be respiratory cells. However, surprisingly, patients with cardiovascular disease, rather than respiratory disease, are predisposed to severe COVID-19 symptoms and death. To explain this phenomenon, I herein propose the viral protein fragment theory of COVID-19 pathogenesis ( Fig. 1) . This hypothesis is based on my experimental observations in cultured human vascular cells that the recombinant full length S1 subunit of SARS-CoV-2 spike protein can activate cell signaling events without the rest of the viral components. 11 Thus, the pathology of COVID-19 may not merely depend on the spike protein serving as a fusion protein to facilitate the viral entry and the infection. I propose a scenario that, as humans are infected with SARS-CoV-2, the virus releases a fragment of the spike protein that can target host cells for eliciting cell signaling.

Thus, infected patients would have at least two entities introduced in response to the SARS-CoV-2 infection. One is the intact virus that uses its spike protein to target ACE2, resulting in the entry into the host cells for the viral replication and amplification. The other is the circulating fragment of the spike protein that independently elicits actions that ultimately results in severe pathological conditions. My experiments using cultured vascular cells also showed that, while the full length S1 subunit of SARS-CoV-2 spike protein elicits cell signaling, the shorter protein that only contains the receptor binding domain (RBD) does not. 11 These results suggest that other regions of the S1 subunit are responsible for eliciting cell signaling in host cells. Thus, if the SARS-CoV-2 spike protein fragment that has been released into our blood is responsible for the pathogenesis of severe COVID-19, therapies that target the viral replication such as inhibitors of RNA-dependent RNA polymerase alone would not work. Also, if the regions of spike protein other than the RBD are responsible for eliciting pathological cell signaling and if the fragment is released quickly after the host is exposed to SARS-CoV-2, then vaccines that target RBD would not affect the viral fragment-mediated cell signaling. Thus, therapeutic strategies to inhibit viral fragment-mediated cell signaling in cardiovascular cells, in addition to drugs that inhibits the viral replication, are necessary to reduce the COVID-19-associated death.

My specific hypothesis is that certain viruses shed fusion protein fragments that circulate in the blood that, in turn, elicit cell signal transduction that makes the infected individuals with cardiovascular diseases predisposed to severe COVID-19 conditions and death. 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 are circulated to elicit distinct processes that promote pathologic conditions. This is based on my observations that recombinant SARS-CoV-2 spike protein (without the rest of the viruses) is capable of eliciting cell signaling in cultured human vascular cells. 11 Interestingly, my experiments also showed that RBD domain-only containing protein region of SARS-CoV-2 spike protein does not activate cell signaling, suggesting the role of other regions with in the S1 subunit of the SARS-CoV-2 spike protein to activate this cell signaling event. Thus, the first experiments that are needed to test this hypothesis is to identify the regions of SARS CoV-2 spike protein that are responsible for activating cell signaling, perhaps by using cultured human cells. After identifying active protein regions of the S1 subunit of SARS-CoV-2 spike protein, the occurrence of protein fragments that possess such protein sequences should be detected in patients infected with SARS-CoV-2. Experimental animals should also be employed to determine whether the administrations of such fragments promotes cardiovascular disease conditions or worsens the existing cardiovascular pathology.

I herein propose the viral protein fragment theory of COVID-19 pathogenesis, in which a fragment or fragments of SARS-CoV-2 spike protein is/are released into the patients' blood circulation, predisposing patients with cardiovascular disease conditions to severe COVID-19 outcomes. Thus, COVID-19 deaths of patients with cardiovascular co-comorbidity are due to the death of host cells as a consequence of the viral infection and replication as well as the spike protein fragment-mediated cell signaling in human host cardiovascular cells. The current focus for developing therapeutic strategies against COVID-19 focuses on the vaccine development and searching for agents that inhibit the viral replication. If my hypothesis is correct, it is critical to also inhibit the unexpected biological events that are elicited by SARS-CoV-2 such as the release of spike protein fragments that affect cardiovascular cells in addition to inhibiting the viral replication in order to successfully reduce the mortality and morbidity associated with COVID-19 and to end the pandemic.

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The molecular biology of SARS coronavirus

A new coronavirus associated with human respiratory disease in China

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2

Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease

Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China

Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: A systematic review and meta-analysis

SARS-CoV-2 spike protein-mediated cell signaling in lung vascular cells

This work was supported in part by NIH (R21AI142649, R03AG059554, and R03AA026516) to Y.J.S. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

The author has no conflict of interest.

