SARS-CoV-2 Spike Protein Induces Hemagglutination: Implications for COVID-19 Morbidities and Therapeutics and for Vaccine Adverse Effects
et al., bioRxiv, doi:10.1101/2022.11.24.517882 (Preprint) (In Vitro)
, SARS-CoV-2 Spike Protein Induces Hemagglutination: Implications for COVID-19 Morbidities and Therapeutics and.., bioRxiv, doi:10.1101/2022.11.24.517882 (Preprint) (In Vitro)
In Vitro study showing that ivermectin blocked hemagglutination (clumping of red blood cells) when added to red blood cells prior to SARS-CoV-2 spike protein, and reversed hemagglutination when added afterwards.Spike protein from four lineages of SARS-CoV-2 induced hemagglutination in human red blood cells, with omicron inducing hemagglutination at a significantly lower concentration. Authors note that the results supports other indications that spike protein-induced red blood cell clumping, as well as viral attachments to other blood cells and endothelial cells, may be a significant factor in COVID-19 morbidities.16 In Vitro studies support the efficacy of ivermectin [Boschi, Caly, Croci, De Forni, Delandre, Jeffreys, Jitobaom, Jitobaom (B), Li, Liu, Mody, Mountain Valley MD, Munson, Segatori, Surnar, Yesilbag].
1.
Boschi et al., bioRxiv, doi:10.1101/2022.11.24.517882,
SARS-CoV-2 Spike Protein Induces Hemagglutination: Implications for COVID-19 Morbidities and Therapeutics and for Vaccine Adverse Effects,
https://www.biorxiv.org/content/10.1101/2022.11.24.517882.
2.
Caly et al., Antiviral Research, doi:10.1016/j.antiviral.2020.104787,
The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro,
https://www.sciencedirect.com/science/article/pii/S0166354220302011.
3.
Croci et al., International Journal of Biomaterials, doi:10.1155/2016/8043983,
Liposomal Systems as Nanocarriers for the Antiviral Agent Ivermectin,
http://www.hindawi.com/journals/ijbm/2016/8043983/.
4.
De Forni et al., PLoS ONE, doi:10.1371/journal.pone.0276751,
Synergistic drug combinations designed to fully suppress SARS-CoV-2 in the lung of COVID-19 patients,
https://journals.plos.org/plosone/..le?id=10.1371/journal.pone.0276751.
5.
Delandre et al., Pharmaceuticals, doi:10.3390/ph15040445,
Antiviral Activity of Repurposing Ivermectin against a Panel of 30 Clinical SARS-CoV-2 Strains Belonging to 14 Variants,
https://www.mdpi.com/1424-8247/15/4/445.
6.
Jeffreys et al., International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2022.106542 (preprint 12/24/2020),
Remdesivir-ivermectin combination displays synergistic interaction with improved in vitro activity against SARS-CoV-2,
https://www.sciencedirect.com/science/article/pii/S0924857922000309.
7.
Jitobaom et al., BMC Pharmacology and Toxicology, doi:10.1186/s40360-022-00580-8 (preprint 11/30/2021),
Synergistic anti-SARS-CoV-2 activity of repurposed anti-parasitic drug combinations,
https://bmcpharmacoltoxicol.biomed..rticles/10.1186/s40360-022-00580-8.
8.
Jitobaom (B) et al., Research Square, doi:10.21203/rs.3.rs-941811/v1,
Favipiravir and Ivermectin Showed in Vitro Synergistic Antiviral Activity against SARS-CoV-2,
https://www.researchsquare.com/article/rs-941811/v1.
9.
Li et al., J. Cellular Physiology, doi:10.1002/jcp.30055,
Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment,
https://onlinelibrary.wiley.com/doi/10.1002/jcp.30055.
10.
Liu et al., bioRxiv, doi:10.1101/2022.01.20.477147,
SARS-CoV-2 Viral Genes Compromise Survival and Functions of Human Pluripotent Stem Cell-derived Cardiomyocytes via Reducing Cellular ATP Level,
https://www.biorxiv.org/content/10.1101/2022.01.20.477147.
11.
Mody et al., Communications Biology, doi:10.1038/s42003-020-01577-x,
Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents,
https://www.nature.com/articles/s42003-020-01577-x.
12.
Mountain Valley MD,
Mountain Valley MD Receives Successful Results From BSL-4 COVID-19 Clearance Trial on Three Variants Tested With Ivectosol™,
https://www.globenewswire.com/en/n..ariants-Tested-With-Ivectosol.html.
13.
Munson et al., British Society For Nanomedicine Early Career Researcher Summer Meeting, 2021,
Niclosamide and ivermectin modulate caspase-1 activity and proinflammatory cytokine secretion in a monocytic cell line,
https://michealmunson.github.io/COVID.pdf.
14.
Segatori et al., Viruses, doi:10.3390/v13102084,
Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients,
https://www.mdpi.com/1999-4915/13/10/2084.
Boschi et al., 28 Nov 2022, France, preprint, 8 authors.
Contact:
dscheim@alum.mit.edu (corresponding author), bernard.la-scola@univamu.fr.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
SARS-CoV-2 Spike Protein Induces Hemagglutination: Implications for COVID-19 Morbidities and Therapeutics and for Vaccine Adverse Effects
doi:10.1101/2022.11.24.517882
Experimental findings for SARS-CoV-2 related to the glycan biochemistry of coronaviruses indicate that attachments from spike protein to glycoconjugates on the surfaces of red blood cells (RBCs), other blood cells and endothelial cells are key to the infectivity and morbidity of COVID-19. To provide further insight into these glycan attachments and their potential clinical relevance, the classic hemagglutination (HA) assay was applied using spike protein from the Wuhan, Alpha, Delta and Omicron B.1.1.529 lineages of SARS-CoV-2 mixed with human RBCs. The electrostatic potential of the central region of spike protein from these four lineages was studied through molecular modeling simulations. Inhibition of spike protein-induced HA was tested using the macrocyclic lactone ivermectin (IVM), which is indicated to bind strongly to SARS-CoV-2 spike protein glycan sites. The results of these experiments were, first, that spike protein from these four lineages of SARS-CoV-2 induced HA. Omicron induced HA at a significantly lower threshold concentration of spike protein than for the three prior lineages and was much more electropositive on its central spike protein region. IVM blocked HA when added to RBCs prior to spike protein and reversed HA when added afterwards. These results validate and extend prior findings on the role of glycan bindings of viral spike protein in COVID-19. They furthermore suggest therapeutic options using competitive glycan-binding agents such as IVM and may help elucidate rare serious adverse effects (AEs) associated with COVID-19 mRNA vaccines which use spike protein as the generated antigen.
References
Ahmetaj-Shala, Vaja, Atanur, George, Kirkby et al., Cardiorenal Tissues Express SARS-CoV-2 Entry Genes and Basigin (BSG/CD147) Increases With Age in Endothelial Cells, JACC: Basic to Translational Science
Aminpour, Cannariato, Safaeeardebili, Preto, Moracchiato et al., Silico Analysis of the Multi-Targeted Mode of Action of Ivermectin and Related Compounds, Computation
Aoki, A Comprehensive Review of Our Current Understanding of Red Blood Cell (RBC) Glycoproteins, Membranes
Au Sam, Storey Brian, Moore John, Tang, Chen et al., Clusters of circulating tumor cells traverse capillary-sized vessels, Proceedings of the National Academy of Sciences
Back, Kostova, Klei, Beuger, Van Zwieten et al., RBC Adhesive Capacity Is Essential for Efficient 'Immune Adherence Clearance' and Provide a Generic Target to Deplete Pathogens from Septic Patients, Blood
Baker, Richards, Guy, Congdon, Hasan et al., The SARS-COV-2 Spike Protein Binds Sialic Acids and Enables Rapid Detection in a Lateral Flow Point of Care Diagnostic Device, ACS Central Science
Barshtein, Wajnblum, Yedgar, Kinetics of linear rouleaux formation studied by visual monitoring of red cell dynamic organization, Biophys J
Baum, Ward, Conway, Natural selection on the erythrocyte surface, Mol Biol Evol
Becker, COVID-19 update: Covid-19-associated coagulopathy, J Thromb Thrombolysis
Berzuini, Bianco, Migliorini, Maggioni, Valenti et al., Red blood cell morphology in patients with COVID-19-related anaemia, Blood Transfus
Biancatelli, Solopov, Sharlow, Lazo, Marik et al., The SARS-CoV-2 spike protein subunit S1 induces COVID-19-like acute lung injury in Κ18-hACE2 transgenic mice and barrier dysfunction in human endothelial cells, Am J Physiol Lung Cell Mol Physiol
Boschi, Colson, Bancod, Moal, La Scola, Omicron Variant Escapes Therapeutic Monoclonal Antibodies (mAbs) Including Recently Released Evusheld®, Contrary to 8 Prior Main Variant of Concern (VOC), Clinical Infectious Diseases
Boulant, Stanifer, Lozach, Dynamics of virus-receptor interactions in virus binding, signaling, and endocytosis, Viruses
Callebaut, Pensaert, Characterization and isolation of structural polypeptides in haemagglutinating encephalomyelitis virus, J Gen Virol
Chen, Hui, Ren, Luo, Shu et al., The N-glycosylation sites and Glycan-binding ability of S-protein in SARS-CoV-2 Coronavirus, bioRxiv, doi:10.1101/2020.12.01.406025
Choi, Cao, Frank, Woo, Park et al., Structure, Dynamics, Receptor Binding, and Antibody Binding of the Fully Glycosylated Full-Length SARS-CoV-2 Spike Protein in a Viral Membrane, Journal of Chemical Theory and Computation
Cognetti, Miller, Monitoring Serum Spike Protein with Disposable Photonic Biosensors Following SARS-CoV-2 Vaccination, Sensors
Colson, Levasseur, Delerce, Pinault, Dudouet et al., Spreading of a new SARS-CoV-2 N501Y spike variant in a new lineage, Clin Microbiol Infect
Cosentino, Marino, The spike hypothesis in vaccine-induced adverse effects: questions and answers, Trends in Molecular Medicine
Doria, Santin, Tuszynski, Scheim, Aminpour, Omicron SARS-CoV-2 Spike-1 Protein's Decreased Binding Affinity to α7nAChr: Implications for Autonomic Dysregulation of the Parasympathetic Nervous System and the Cholinergic Anti-Inflammatory Pathway-An In Silico Analysis, BioMedInformatics
Fantini, Di Scala, Chahinian, Yahi, Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection, International Journal of Antimicrobial Agents
Fantini, Yahi, Azzaz, Chahinian, Structural dynamics of SARS-CoV-2 variants: A health monitoring strategy for anticipating Covid-19 outbreaks, J Infect
Fantini, Yahi, Colson, Chahinian, La Scola et al., The puzzling mutational landscape of the SARS-2-variant Omicron, Journal of Medical Virology
Gao, Zeng, Jia, Stavenhagen, Matsumoto et al., SARS-CoV-2 Spike Protein Interacts with Multiple Innate Immune Receptors, bioRxiv, doi:10.1101/2020.07.29.227462
Gattinoni, Coppola, Cressoni, Busana, Rossi et al., COVID-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome, Am J Respir Crit Care Med
Giovannini, Dark Field Microscopic Analysis on the Blood of 1,006 Symptomatic Persons After Anti-COVID mRNA Injections from Pfizer/BioNTech or Moderna, International Journal of Vaccine Theory, Practice, and Research
Grobbelaar, Venter, Vlok, Ngoepe, Laubscher et al., SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19, Bioscience Reports
Guex, Peitsch, SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling, Electrophoresis
Guo, Lakshminarayanan, Rodriguez-Palacios, Salata, Xu et al., Glycan Nanostructures of Human Coronaviruses, Int J Nanomedicine
Gupta, Maciorowski, Zak, Kulkarni, Herbert et al., Heparin: A simplistic repurposing to prevent SARS-CoV-2 transmission in light of its in-vitro nanomolar efficacy, Int J Biol Macromol
Hao, Ma, Li, Wang, Gao et al., Binding of the SARS-CoV-2 spike protein to glycans, Sci Bull
Hassanzadeh, Perez Pena, Dragotto, Buccarello, Iorio et al., Considerations around the SARS-CoV-2 Spike Protein with Particular Attention to COVID-19 Brain Infection and Neurological Symptoms, ACS Chem Neurosci
Huertas, Montani, Savale, Pichon, Tu et al., Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)?, Eur Respir J
Jaafar, Boschi, Aherfi, Bancod, Le Bideau et al., High Individual Heterogeneity of Neutralizing Activities against the Original Strain and Nine Different Variants of SARS-CoV-2, Viruses, doi:10.3390/v13112177
Karim, Devnarain, Time to Stop Using Ineffective Covid-19 Drugs, N Engl J Med
Kim, Chivian, Baker, Protein structure prediction and analysis using the Robetta server, Nucleic Acids Res
Klotz, Ogbuokiri, Okonkwo, Ivermectin binds avidly to plasma proteins, Eur J Clin Pharmacol
Koehler, Delguste, Sieben, Gillet, Alsteens, Initial Step of Virus Entry: Virion Binding to Cell-Surface Glycans, Annual Review of Virology
Kumar, Karuppanan, Subramaniam, Omicron, BA.1) and sub-variants (BA.1.1, BA.2, and BA.3) of SARS-CoV-2 spike infectivity and pathogenicity: A comparative sequence and structural-based computational assessment, Journal of Medical Virology
Lakhdari, Tabet, Boudraham, Laoussati, Aissanou et al., Red blood cells injuries and hypersegmented neutrophils in COVID-19 peripheral blood film, medRxiv, doi:10.1101/2020.07.24.20160101
Lam, Murphy, Kuri-Cervantes, Weisman, Ittner et al., Erythrocytes Reveal Complement Activation in Patients with COVID-19, medRxiv, doi:10.1101/2020.05.20.20104398
Lam, Waman, Orengo, Lees, Insertions in the SARS-CoV-2 Spike N-Terminal Domain May Aid COVID-19 Transmission, bioRxiv, doi:10.1101/2021.12.06.471394
Lang, Li, Li, Koerhuis, Van Den Burg et al., Coronavirus hemagglutinin-esterase and spike proteins coevolve for functional balance and optimal virion avidity, Proc Natl Acad Sci
Li, Chen, Zhao, Lung, Ye et al., Intravenous Injection of Coronavirus Disease 2019 (COVID-19) mRNA Vaccine Can Induce Acute Myopericarditis in Mouse Model, Clinical Infectious Diseases
Maeda, Seike, Kon, Shiga, Erythrocyte Aggregation as a Determinant of Blood Flow: Effect of pH, Temperature and Osmotic Pressure, doi:10.1007/978-1-4615-9510-6_68pp.563-570
Magro, Mulvey, Berlin, Nuovo, Salvatore et al., Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases, Transl Res
Mansanguan, Charunwatthana, Piyaphanee, Dechkhajorn, Poolcharoen et al., Cardiovascular Manifestation of the BNT162b2 mRNA COVID-19 Vaccine in Adolescents, Tropical Medicine and Infectious Disease
Marini, Gattinoni, Management of COVID-19 Respiratory Distress, JAMA
Maslo, Friedland, Toubkin, Laubscher, Akaloo et al., Characteristics and Outcomes of Hospitalized Patients in South Africa During the COVID-19 Omicron Wave Compared With Previous Waves, JAMA
Melkumyants, Buryachkovskaya, Lomakin, Antonova, Serebruany, Mild COVID-19 and Impaired Blood Cell-Endothelial Crosstalk: Considering Long-Term Use of Antithrombotics?, Thromb Haemost
Menter, Haslbauer, Nienhold, Savic, Hopfer et al., Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction, Histopathology
Morniroli, Giannì, Consales, Pietrasanta, Mosca, Human Sialome and Coronavirus Disease-2019 (COVID-19) Pandemic: An Understated Correlation?, Frontiers in Immunology
Neu, Bauer, Stehle, Viruses and sialic acids: rules of engagement, Curr Opin Struct Biol
Nguyen, Mccord, Bui, Bouwman, Kitova et al., Sialic acid-containing glycolipids mediate binding and viral entry of SARS-CoV-2, Nature Chemical Biology
Nuovo, Magro, Shaffer, Awad, Suster et al., Endothelial cell damage is the central part of COVID-19 and a mouse model induced by injection of the S1 subunit of the spike protein, Annals of Diagnostic Pathology
Ogata, Cheng, Desjardins, Senussi, Sherman et al., Circulating Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine Antigen Detected in the Plasma of mRNA-1273 Vaccine Recipients, Clin Infect Dis
Pascarella, Ciccozzi, Bianchi, Benvenuto, Cauda et al., The value of electrostatic potentials of the spike receptor binding and N-terminal domains in addressing transmissibility and infectivity of SARS-CoV-2 variants of concern, J Infect
Pawłowski, Additional Positive Electric Residues in the Crucial Spike Glycoprotein S Regions of the New SARS-CoV-2 Variants, Infect Drug Resist
Perico, Morigi, Galbusera, Pezzotta, Gastoldi et al., SARS-CoV-2 Spike Protein 1 Activates Microvascular Endothelial Cells and Complement System Leading to Platelet Aggregation, Front Immunol
Price, Mccabe, Garfield, Wort, Thrombosis and COVID-19 pneumonia: the clot thickens!, European Respiratory Journal
Rambaut, Holmes, O'toole, Hill, Mccrone et al., A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology, Nature Microbiology
Röltgen, Nielsen, Silva, Younes, Zaslavsky et al., Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination, Cell
Santin, Scheim, Mccullough, Yagisawa, Borody, Ivermectin: a multifaceted drug of Nobel prize-honored distinction with indicated efficacy against a new global scourge, COVID-19, New Microbes and New Infections
Scheim, A Deadly Embrace: Hemagglutination Mediated by SARS-CoV-2 Spike Protein at its 22 N-Glycosylation Sites, Red Blood Cell Surface Sialoglycoproteins, and Antibody, Int. J. Mol. Sci
Scheim, From cold to killer: How SARS-CoV-2 evolved without hemagglutinin esterase to agglutinate, then clot blood cells in pulmonary and systemic microvasculature
Schultze, Gross, Brossmer, Herrler, The S protein of bovine coronavirus is a hemagglutinin recognizing 9-O-acetylated sialic acid as a receptor determinant, J Virol
Seaman, Electrochemical features of platelet interactions, Thrombosis Research
Shafiee, Teymouri Athar, Kohandel Gargari, Jafarabady, Siahvoshi et al., Ivermectin under scrutiny: a systematic review and meta-analysis of efficacy and possible sources of controversies in COVID-19 patients, Virology Journal
Shajahan, Supekar, Gleinich, Azadi, Deducing the N-and O-glycosylation profile of the spike protein of novel coronavirus SARS-CoV-2, Glycobiology
Shilts, Wright, No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor, bioRxiv, doi:10.1101/2020.07.25.221036
Sikora, Von Bülow, Blanc, Gecht, Covino et al., Computational epitope map of SARS-CoV-2 spike protein, PLOS Computational Biology
Stone, Ndarukwa, Scheim, Dancis, Dancis et al., Changes in SpO2 on Room Air for 34 Severe COVID-19 Patients after Ivermectin-Based Combination Treatment: 62% Normalization within 24 Hours, Biologics
Strilić, Eglinger, Krieg, Zeeb, Axnick et al., Electrostatic Cell-Surface Repulsion Initiates Lumen Formation in Developing Blood Vessels, Current Biology
Ströh, Stehle, Glycan Engagement by Viruses: Receptor Switches and Specificity, Annual Review of Virology
Townsend, Rijal, Xiao, Tan, Huang et al., A haemagglutination test for rapid detection of antibodies to SARS-CoV-2, Nat Commun
Trougakos, Terpos, Alexopoulos, Politou, Paraskevis et al., Adverse effects of COVID-19 mRNA vaccines: the spike hypothesis, Trends in Molecular Medicine
Varki, Gagneux, Multifarious roles of sialic acids in immunity, Ann N Y Acad Sci
Yagisawa, Omura, None
Yamakawa, Vanbeselaere, Chang, Yu, Ducrocq et al., Systems glycomics of adult zebrafish identifies organ-specific sialylation and glycosylation patterns, Nature Communications
Zheng, Zhao, Li, Guo, Sheng et al., SARS-CoV-2 spike protein causes blood coagulation and thrombosis by competitive binding to heparan sulfate, Int J Biol Macromol
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