Cell Fusion as a Link between the SARS-CoV-2 Spike Protein, COVID-19 Complications, and Vaccine Side Effects

Lazebnik, Yuri

doi:10.20944/preprints202106.0125.v2

Cited by 4 publications

(7 citation statements)

References 88 publications

(121 reference statements)

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“…Vaccination with the SARS-CoV-2 mRNA vaccine BNT162b2 and cell transfection with a SARS-2-S-expressing plasmid induced the production of exosomes harbouring SARS-2-S, which strongly suggests that cellular senescence induction by SARS-2-S might not be restricted to its expression site 15 . For example, even if a vaccine stays strictly in the muscle at the injection site, EVs that are produced in vaccinated patients may be able to trigger fusion in endothelial cells, neurons, or cardiomyocytes, resulting in thrombosis, neurological manifestations, or myocarditis 38 . In an exaggerated situation in which SARS-2-S expression was too high, the massive accumulation of senescent SARS-2-S syncytia exerted a tumour-promoting effect.…”

Section: Discussionmentioning

confidence: 99%

“…In an exaggerated situation in which SARS-2-S expression was too high, the massive accumulation of senescent SARS-2-S syncytia exerted a tumour-promoting effect. Based on clinical findings, vaccines that use recombinant SARS-2-S fragments or other derivatives of SARS-2-S that are not fusogenic cause fewer complications than vaccines that express fully or partially fusogenic SARS-2-S 38 . To date, no evidence of syncytia has been identified in patients with long COVID-19 syndrome or in vaccinated people, and it remains to be demonstrated whether the senescence phenotype and its pathological consequences observed in assay systems are of relevance for clinical long COVID-19 syndrome and the biology of actual vaccine effects.…”

Section: Discussionmentioning

confidence: 99%

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SARS-CoV-2 spike-induced syncytia are senescent and contribute to exacerbated heart failure

Wan¹,

Li²,

Huang³

et al. 2022

Preprint

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The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains an important health threat. Syncytial formation by infected cells mediated by the SARS-CoV-2 spike protein (SARS-2-S) is a hallmark of COVID-19-associated pathology. Although SARS-CoV-2 infection evokes cellular senescence, as in other viruses, the direct link between SARS-2-S-induced syncytia with senescence in the absence of viral infection and their senescence fate determinants remain unknown. Here, we show that syncytia formed by cells expressing exogenously delivered SARS-2-S exhibited a senescence-like phenotype in vitro and that SARS-2-S mRNA induced senescence phenotype in vivo. Extracellular vesicles (EVs) containing SARS-2-S also induced senescent syncytium formation independent of the de novo synthesis of SARS-2-S. Mechanistically, we show that the accumulation of endogenous dsRNA, partially that whose formation is induced by activation of the unfolded protein response (UPR), in SARS-2-S syncytia triggers RIG-I-MAVS signalling to drive the TNF-α-dependent survival and senescence fate of SARS-2-S syncytia. Our findings suggest that the fusogenic ability of SARS-2-S might contribute to the side effects of particular COVID-19 vaccines or perhaps long COVID-19 syndrome and provide insight into how these effects can be prevented.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 spike-induced syncytia are senescent and contribute to exacerbated heart failure

Wan¹,

Li²,

Huang³

et al. 2022

Preprint

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“…This is significant, as it could account for the reoccurrence of COVID-19 symptoms in fully vaccinated individuals [3,21,22]. In addition, this may explain the rare postvaccination events associated with cell-cell fusion, including giant cell myocarditis, giant cell arteritis, and Creutzfeldt-Jakob Disease, recorded in Vaccine Adverse Event Reporting System (VAERS) database (please see section "Vaccine core: the synthetic mRNA") [23][24][25][26][27].…”

Section: Messenger Rna Vaccines An Overviewmentioning

confidence: 99%

“…Furthermore, as pathological cellcell fusion was associated with premature cellular senescence and immunosuppression, the metalloprotease pathway may account for the dysfunctional immune responses observed in some vaccinated individuals [35,36,52]. Syncytia-related pathology may also contribute to other VAERs-documented post-vaccination events, including giant cell myocarditis, arteritis, and neurodegeneration [23,24,27,88].…”

Section: Potential Non-rbs Modalities Of Sars-cov-2 Infectionmentioning

confidence: 99%

COVID-19 mRNA vaccines and pathological cell-cell fusion: an unintended consequence

Sfera¹,

Thomas²,

Sfera³

et al. 2022

Arch Clin Trials

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“…It has been recently discovered that the SARS-CoV-2 Spike protein can cause fusion between cells and syncytia formation [17,[20][21][22][23][24][25][26][27] and that a mutation in its receptor binding site impaired cell-to-cell fusion and syncytia formation [28]. For example, multinucleated pneumocytes were found in the lung of patients deceased for COVID-19 [20,29,30].…”

Section: Introductionmentioning

confidence: 99%

Supporting Cells of the Human Olfactory Epithelium Co-Express the Lipid Scramblase TMEM16F and ACE2 and May Cause Smell Loss by SARS-CoV-2 Spike-Induced Syncytia

Hernandez-Clavijo

Gonzalez-Velandia

Rangaswamy

et al. 2022

Cell Physiol Biochem

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Background/Aims: Quantitative and qualitative alterations in the sense of smell are well established symptoms of COVID-19. Some reports have shown that non-neuronal supporting (also named sustentacular) cells of the human olfactory epithelium co-express ACE2 and TMPRSS2 necessary for SARS-CoV-2 infection. In COVID-19, syncytia were found in many tissues but were not investigated in the olfactory epithelium. Some studies have shown that syncytia in some tissues are formed when SARS-CoV-2 Spike expressed at the surface of an infected cell binds to ACE2 on another cell, followed by activation of the scramblase TMEM16F (also named ANO6) which exposes phosphatidylserine to the external side of the membrane. Furthermore, niclosamide, an approved antihelminthic drug, inhibits Spike-induced syncytia by blocking TMEM16F activity. The aim of this study was to investigate if proteins involved in Spike-induced syncytia formation, i.e., ACE2 and TMEM16F, are expressed in the human olfactory epithelium. Methods: We analysed a publicly available single-cell RNA-seq dataset from human nasal epithelium and performed immunohistochemistry in human nasal tissues from biopsies. Results: We found that ACE2 and TMEM16F are co-expressed both at RNA and protein levels in non-neuronal supporting cells of the human olfactory epithelium. Conclusion: Our results provide the first evidence that TMEM16F is expressed in human olfactory supporting cells and indicate that syncytia formation, that could be blocked by niclosamide, is one of the pathogenic mechanisms worth investigating in COVID-19 smell loss.

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Cell Fusion as a Link between the SARS-CoV-2 Spike Protein, COVID-19 Complications, and Vaccine Side Effects

Cited by 4 publications

References 88 publications

SARS-CoV-2 spike-induced syncytia are senescent and contribute to exacerbated heart failure

SARS-CoV-2 spike-induced syncytia are senescent and contribute to exacerbated heart failure

COVID-19 mRNA vaccines and pathological cell-cell fusion: an unintended consequence

Supporting Cells of the Human Olfactory Epithelium Co-Express the Lipid Scramblase TMEM16F and ACE2 and May Cause Smell Loss by SARS-CoV-2 Spike-Induced Syncytia

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