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. 2021 Dec 7;12(25):2476-2488.
doi: 10.18632/oncotarget.28088.

Cell fusion as a link between the SARS-CoV-2 spike protein, COVID-19 complications, and vaccine side effects

Yuri Lazebnik  1
Affiliations

Cell fusion as a link between the SARS-CoV-2 spike protein, COVID-19 complications, and vaccine side effects

Yuri Lazebnik. Oncotarget. .

Abstract

A distinctive feature of the SARS-CoV-2 spike protein is its ability to efficiently fuse cells, thus producing syncytia found in COVID-19 patients. This commentary proposes how this ability enables spike to cause COVID-19 complications as well as side effects of COVID-19 vaccines, and suggests how these effects can be prevented.

Keywords: cancer; cell fusion; neuropathy; thrombosis; vaccines.

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Conflict of interest statement

CONFLICTS OF INTEREST Author have no conflicts of interest to declare.

Figures

Figure 1
Figure 1. An outline of the blood coagulation cascade.
Blood coagulation cascade is a network of proteases, their precursors, cofactors, cells, enzymes, feedbacks, and feedforwards whose complexity and still unresolved questions make this outline by necessity rudimentary, with the primary goal to illustrate where the proteins that require binding to externalized PS (phosphatidylserine) for activation are in the network. Most proteins involved in coagulation are called factors and are labeled by Roman numerals, such as Factor X or FX (hence enzymes that process FX are tenases). For simplicity, in this cartoon the letter F is omitted. Activated factors are labeled with an a, as in FXa. Orange arrows represent proteolytic activity, grey arrows show a transition between forms. Blue horizontal lines represent a cellular membrane with the cell surface facing down. Accordingly, the pinheads of externalized PS also face down. Note that most PS is actively relocated to face the cytoplasm unless the cell dies or the distribution is randomized by lipid scramblases. As discussed in the text, the primary trigger of coagulation induced by viral infections is the extrinsic tenase (top left), which is a complex of TF (Tissue Factor) and FVIIa assembled on externalized PS in the presence of calcium ions. This tenase produces FXa to activate enough thrombin to generate the components of the intrinsic tenase, which increases the production of FXa, and, consequently, of thrombin, which generates enough fibrin to make a thrombus, a meshwork of polymerized and cross-linked fibrin with entrapped blood cells, primarily platelets, which is large and stiff enough to obstruct a blood vessel. Note that TF is encrypted and so is unable to activate FVIIa, until it is de-encrypted by externalized PS [10].
Figure 2
Figure 2. Syncytia induced by SARS-CoV-2 spike as a platform for triggering blood coagulation cascade.
SARS-CoV-2 is covered by an envelope, which is fused to the cell membrane by spike once this protein is activated by binding to one of its receptors and processed by a membrane protease (both are not shown for simplicity). The infected cell produces viral components, including spike. Now, spike can fuse the membrane of the host cell with the membrane of an adjacent cell if that cell also has a spike receptor. Braga and colleagues [3] found that spike-induced cell fusion is associated with activation of TMEM16F, a scramblase that externalizes PS. This commentary proposes that PS externalized by spike enables the formation of the extrinsic tenase (Figure 1), the key trigger of blood coagulation cascade during viral infections. SARS-CoV-2 spike can also fuse cells if the virus is not infectious, or even if spike is incorporated into membrane vesicles, [22] like extracellular vesicles released by infected cells. This mechanism is known as fusion from without [21], as the viral particle or a vesicle provides a bridge between the membranes. Because syncytia produced by this mechanisms are not infected with SARS-CoV-2 in this case, their origin may be difficult to trace. Note that TF is encrypted, meaning that it is unable to activate FVIIa, until it is de-encrypted by externalized PS [10].
Figure 3
Figure 3. The incidence of suspected vaccine complications recorded in the European database of suspected adverse drug reactions reports (EudraVigilance) [109] as of August 6, 2021.
The numbers of doses administered by that date, and shown next to the bars. were taken from: https://vaccinetracker.ecdc.europa.eu/public/extensions/COVID-19/vaccine-tracker.html#distribution-tab.
See this image and copyright information in PMC

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