More than a key—the pathological roles of SARS-CoV-2 spike protein in COVID-19 related cardiac injury

Abstract

Cardiac injury is common in hospitalized coronavirus disease 2019 (COVID-19) patients and cardiac abnormalities have been observed in a significant number of recovered COVID-19 patients, portending long-term health issues for millions of infected individuals. To better understand how Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, CoV-2 for short) damages the heart, it is critical to fully comprehend the biology of CoV-2 encoded proteins, each of which may play multiple pathological roles. For example, CoV-2 spike glycoprotein (CoV-2-S) not only engages angiotensin converting enzyme II (ACE2) to mediate virus infection but also directly activates immune responses. In this work, the goal is to review the known pathological roles of CoV-2-S in the cardiovascular system, thereby shedding lights on the pathogenesis of COVID-19 related cardiac injury.

Keywords

COVID-19 / Spike protein / Cardiovascular disease / Immune responses

References

[[1]] QH Nie, XD Luo, JZ Zhang Q. Su. Current status of severe acute respiratory syndrome in China. World J Gastroenterol, 9 (8) ( 2003), pp. 1635-1645, DOI: 10.3748/wjg.v9.i8.1635

[[2]] AM Zaki, S van Boheemen, TM Bestebroer, AD Osterhaus, RA. Fouchier. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med, 367 (19) ( 2012), pp. 1814-1820, DOI: 10.1056/NEJMoa1211721

[[3]] JF-W Chan, K-H Kok, Z Zhu, et al.. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microb Infect, 9 (1) ( 2020), pp. 221-236, DOI: 10.1080/22221751.2020.1719902

[[4]] PCY Woo, SKP Lau, C-M Chu, et al.. Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia. J Virol, 79 (2) ( 2005), pp. 884-895, DOI: 10.1128/JVI.79.2.884-895.2005

[[5]] K McIntosh, AZ Kapikian, HC Turner, JW Hartley, RH Parrott, RM. Chanock. Seroepidemiologic studies of coronavirus infection in adults and children. Am J Epidemiol, 91 (6) ( 1970), pp. 585-592, DOI: 10.1093/oxfordjournals.aje.a121171

[[6]] Y Fu, Y Cheng, Y. Wu. Understanding SARS-CoV-2-mediated inflammatory responses: from mechanisms to potential therapeutic tools. Virol Sin, 35 (3) ( 2020), pp. 266-271, DOI: 10.1007/s12250-020-00207-4

[[7]] P. Libby. The heart in COVID-19: primary target or secondary bystander. JACC Basic Transl Sci, 5 (5) ( 2020), pp. 537-542, DOI: 10.1016/j.jacbts.2020.04.001

[[8]] X. Cao. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol, 20 (5) ( 2020), pp. 269-270, DOI: 10.1038/s41577-020-0308-3

[[9]] D Atri, HK Siddiqi, JP Lang, V Nauffal, DA Morrow, EA. Bohula. COVID-19 for the cardiologist: basic virology, epidemiology, cardiac manifestations, and potential therapeutic strategies. JACC Basic Transl Sci, 5 (5) ( 2020), pp. 518-536, DOI: 10.1016/j.jacbts.2020.04.002

[[10]] JA. Siordia.Epidemiology and clinical features of COVID-19: a review of current literature. J Clin Virol, 127 ( 2020), Article 104357, DOI: 10.1016/j.jcv.2020.104357

[[11]] T Guo, Y Fan, M Chen, et al.. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol, 5 (7) ( 2020), pp. 811-818, DOI: 10.1001/jamacardio.2020.1017

[[12]] JQ Lu, JY Lu, W Wang, et al.. Clinical predictors of acute cardiac injury and normalization of troponin after hospital discharge from COVID-19. EBioMedicine, 76 ( 2022), Article 103821, DOI: 10.1016/j.ebiom.2022.103821

[[13]] S Shi, M Qin, B Shen, et al.. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in wuhan, China. JAMA Cardiol, 5 (7) ( 2020), pp. 802-810, DOI: 10.1001/jamacardio.2020.0950

[[14]] J Artico, H Shiwani, JC Moon, et al.. Myocardial involvement after hospitalization for COVID-19 complicated by troponin elevation: a prospective, multicenter, observational study. Circulation, 147 (5) ( 2023), pp. 364-374, DOI: 10.1161/CIRCULATIONAHA.122.060632

[[15]] N Dong, J Cai, Y Zhou, J Liu, F. Li. End-stage heart failure with COVID-19: strong evidence of myocardial injury by 2019-nCoV. JACC Heart Fail, 8 (6) ( 2020), pp. 515-517, DOI: 10.1016/j.jchf.2020.04.001

[[16]] I-C Kim, JY Kim,HA Kim, S. Han. COVID-19-related myocarditis in a 21-year-old female patient. Eur Heart J, 41 (19) ( 2020), p. 1859, DOI: 10.1093/eurheartj/ehaa288

[[17]] C Huang, Y Wang, X Li, et al.. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet, 395 (10223) ( 2020), pp. 497-506, DOI: 10.1016/S0140-6736(20)30183-5

[[18]] L Babuin, AS. Jaffe. Troponin: the biomarker of choice for the detection of cardiac injury. CMAJ (Can Med Assoc J), 173 (10) ( 2005), pp. 1191-1202, DOI: 10.1503/cmaj/051291

[[19]] D Pellegrini, R Kawakami, G Guagliumi, et al.. Microthrombi as a major cause of cardiac injury in COVID-19: a pathologic study. Circulation, 143 (10) ( 2021), pp. 1031-1042, DOI: 10.1161/CIRCULATIONAHA.120.051828

[[20]] G Tavazzi, C Pellegrini, M Maurelli, et al.. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail, 22 (5) ( 2020), pp. 911-915, DOI: 10.1002/ejhf.1828

[[21]] JR. Teerlink. Neurohumoral mechanisms in heart failure: a central role for the renin-angiotensin system. J Cardiovasc Pharmacol, 27 (Suppl 2) ( 1996), pp. S1-S8, DOI: 10.1097/00005344-199600002-00002

[[22]] Z Rahimi, M Moradi, H. Nasri. A systematic review of the role of renin angiotensin aldosterone system genes in diabetes mellitus, diabetic retinopathy and diabetic neuropathy. J Res Med Sci, 19 (11) ( 2014), pp. 1090-1098

[[23]] C Tikellis, MC. Thomas. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. Int J Pept, 2012 ( 2012), Article 256294, DOI: 10.1155/2012/256294

[[24]] AJ Grippo AK. Johnson. Stress, depression and cardiovascular dysregulation: a review of neurobiological mechanisms and the integration of research from preclinical disease models. Stress, 12 (1) ( 2009), pp. 1-21, DOI: 10.1080/10253890802046281

[[25]] V. Zvonarev. Takotsubo cardiomyopathy: medical and psychiatric aspects. Role of psychotropic medications in the treatment of adults with “broken heart” syndrome. Cureus, 11 (7) ( 2019), Article e5177, DOI: 10.7759/cureus.5177

[[26]] C Scally, H Abbas, T Ahearn, et al.. Myocardial and systemic inflammation in acute stress-induced (Takotsubo) cardiomyopathy. Circulation, 139 (13) ( 2019), pp. 1581-1592, DOI: 10.1161/CIRCULATIONAHA.118.037975

[[27]] P Zhou, XL Yang, XG Wang, et al.. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 579 (7798) ( 2020), pp. 270-273, DOI: 10.1038/s41586-020-2012-7

[[28]] RL Camargo, B Bombassaro, M Monfort-Pires, et al.. Plasma angiotensin II is increased in critical coronavirus disease 2019. Front Cardiovasc Med, 9 ( 2022), Article 847809, DOI: 10.3389/fcvm.2022.847809

[[29]] S Sala, G Peretto, M Gramegna, et al.. Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection. Eur Heart J, 41 (19) ( 2020), pp. 1861-1862, DOI: 10.1093/eurheartj/ehaa286

[[30]] RC Bone, RA Balk, FB Cerra, et al.. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM consensus conference committee. American college of chest physicians/society of critical care medicine. Chest, 101 (6) ( 1992), pp. 1644-1655, DOI: 10.1378/chest.101.6.1644

[[31]] WG. Land. The role of damage-associated molecular patterns (DAMPs) in human diseases: Part II: DAMPs as diagnostics, prognostics and therapeutics in clinical medicine. Sultan Qaboos Univ Med J, 15 (2) ( 2015), pp. e157-e170

[[32]] K Newton, VM. Dixit. Signaling in innate immunity and inflammation. Cold Spring Harbor Perspect Biol, 4 (3) ( 2012), Article a006049, DOI: 10.1101/cshperspect.a006049

[[33]] FG Soriano, CB Lorigados, P Pacher, C. Szabó. Effects of a potent peroxynitrite decomposition catalyst in murine models of endotoxemia and sepsis. Shock, 35 (6) ( 2011), pp. 560-566, DOI: 10.1097/SHK.0b013e31820fe5d5

[[34]] S Tian, Y Xiong, H Liu, et al.. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod Pathol, 33 (6) ( 2020), pp. 1007-1014, DOI: 10.1038/s41379-020-0536-x

[[35]] SE Fox, A Akmatbekov, JL Harbert, G Li, J Quincy Brown RS. Vander Heide. Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans. Lancet Respir Med, 8 (7) ( 2020), pp. 681-686, DOI: 10.1016/S2213-2600(20)30243-5

[[36]] SF Assimakopoulos, G Eleftheriotis, M Lagadinou, et al.. SARS CoV-2-Induced viral sepsis: the role of gut barrier dysfunction. Microorganisms, 10 (5) ( 2022), p. 1050, DOI: 10.3390/microorganisms10051050

[[37]] YR Guo, QD Cao, ZS Hong, et al.. The origin, transmission and clinical therapies on coronavirus disease 2019 ( COVID-19) outbreak - an update on the status. Mil Med Res, 7 (1) ( 2020), p. 11, DOI: 10.1186/s40779-020-00240-0

[[38]] JE Parrillo, MM Parker, C Natanson, et al.. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med, 113 (3) ( 1990), pp. 227-242, DOI: 10.7326/0003-4819-113-3-227

[[39]] Y Kakihana, T Ito, M Nakahara,K Yamaguchi, T. Yasuda. Sepsis-induced myocardial dysfunction: pathophysiology and management. J Intensive Care, 4 ( 2016), p. 22, DOI: 10.1186/s40560-016-0148-1

[[40]] F Chagnon, M Bentourkia, R Lecomte, M Lessard, O. Lesur. Endotoxin-induced heart dysfunction in rats: assessment of myocardial perfusion and permeability and the role of fluid resuscitation. Crit Care Med, 34 (1) ( 2006), pp. 127-133, DOI: 10.1097/01.ccm.0000190622.02222.df

[[41]] WS Madorin, T Rui, N Sugimoto, O Handa, G Cepinskas, PR. Kvietys. Cardiac myocytes activated by septic plasma promote neutrophil transendothelial migration: role of platelet-activating factor and the chemokines LIX and KC. Circ Res, 94 (7) ( 2004), pp. 944-951, DOI: 10.1161/01.RES.0000124395.20249.AE

[[42]] YC Liu, MM Yu, ST Shou YF. Chai. Sepsis-induced cardiomyopathy: mechanisms and treatments. Front Immunol, 8 ( 2017), p. 1021, DOI: 10.3389/fimmu.2017.01021

[[43]] AL Caforio, S Pankuweit, E Arbustini, et al.. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J, 34 (33) ( 2013), pp. 2636-2648 d, DOI: 10.1093/eurheartj/eht210

[[44]] P Jirak, R Larbig, Z Shomanova, et al.. Myocardial injury in severe COVID-19 is similar to pneumonias of other origin: results from a multicentre study. ESC Heart Fail, 8 (1) ( 2021), pp. 37-46, DOI: 10.1002/ehf2.13136

[[45]] LT Weckbach, A Curta, S Bieber, et al.. Myocardial inflammation and dysfunction in COVID-19-associated myocardial injury. Cir Cardiovasc Imag, 14 (1) ( 2021), Article e012220, DOI: 10.1016/10.1161/CIRCIMAGING.120.011713

[[46]] E Ammirati, L Lupi, M Palazzini, et al.. Prevalence, characteristics, and outcomes of COVID-19-associated acute myocarditis. Circulation, 145 (15) ( 2022), pp. 1123-1139, DOI: 10.1161/CIRCULATIONAHA.121.056817

[[47]] Y Nakamura, H Katano, N Nakajima, et al.. SARS-CoV-2 is localized in cardiomyocytes: a postmortem biopsy case. Int J Infect Dis, 111 ( 2021), pp. 43-46, DOI: 10.1016/j.ijid.2021.08.015

[[48]] G Gauchotte, V Venard, M Segondy, et al.. SARS-Cov-2 fulminant myocarditis: an autopsy and histopathological case study. Int J Leg Med, 135 (2) ( 2021), pp. 577-581, DOI: 10.1007/s00414-020-02500-z

[[49]] AL Bailey, O Dmytrenko, L Greenberg, et al.. SARS-CoV-2 infects human engineered heart tissues and models COVID-19 myocarditis. JACC Basic Transl Sci, 6 (4) ( 2021), pp. 331-345, DOI: 10.1016/j.jacbts.2021.01.002

[[50]] M Nishiga, DW Wang, Y Han, DB Lewis, JC. Wu. COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives. Nat Rev Cardiol, 17 (9) ( 2020), pp. 543-558, DOI: 10.1038/s41569-020-0413-9

[[51]] E Damiani, A Donati, M. Girardis. Oxygen in the critically ill: friend or foe. Curr Opin Anaesthesiol, 31 (2) ( 2018), pp. 129-135, DOI: 10.1097/ACO.0000000000000559

[[52]] B Huang, H Miao, Y Yuan, et al.. PEDF decreases cardiomyocyte edema during oxygen-glucose deprivation and recovery via inhibiting lactate accumulation and expression of AQP1. Int J Mol Med, 43 (5) ( 2019), pp. 1979-1990, DOI: 10.3892/ijmm.2019.4132

[[53]] C Gao, F Wang, Z Wang, J Zhang, X. Yang. Asiatic acid inhibits lactate-induced cardiomyocyte apoptosis through the regulation of the lactate signaling cascade. Int J Mol Med, 38 (6) ( 2016), pp. 1823-1830, DOI: 10.3892/ijmm.2016.2783

[[54]] G Solaini, A Baracca, G Lenaz, G. Sgarbi. Hypoxia and mitochondrial oxidative metabolism. Biochim Biophys Acta, 1797 (6-7) ( 2010), pp. 1171-1177, DOI: 10.1016/j.bbabio.2010.02.011

[[55]] AL Santos, S Sinha, AB. Lindner. The good, the bad, and the ugly of ROS: new insights on aging and aging-related diseases from eukaryotic and prokaryotic model organisms. Oxid Med Cell Longev, 2018 ( 2018), Article 1941285, DOI: 10.1155/2018/1941285

[[56]] M Choudhury, MR Boyett, GM. Morris. Biology of the sinus Node and its disease. Arrhythmia Electrophysiol Rev, 4 (1) ( 2015), pp. 28-34, DOI: 10.15420/aer.2015.4.1.28

[[57]] B Santoro, GR. Tibbs. The HCN gene family: molecular basis of the hyperpolarization-activated pacemaker channels. Ann N Y Acad Sci, 868 ( 1999), pp. 741-764, DOI: 10.1111/j.1749-6632.1999.tb11353.x

[[58]] DS Feldman, CA Carnes, WT Abraham, MR. Bristow. Mechanisms of disease: beta-adrenergic receptors--alterations in signal transduction and pharmacogenomics in heart failure. Nat Clin Pract Cardiovasc Med, 2 (9) ( 2005), pp. 475-483, DOI: 10.1038/ncpcardio0309

[[59]] ME Mangoni J. Nargeot. Properties of the hyperpolarization-activated current (I(f)) in isolated mouse sino-atrial cells. Cardiovasc Res, 52 (1) ( 2001), pp. 51-64, DOI: 10.1016/s0008-6363(01)00370-4

[[60]] A Yatani, K Okabe, J Codina, L Birnbaumer, AM. Brown. Heart rate regulation by G proteins acting on the cardiac pacemaker channel. Science, 249 (4973) ( 1990), pp. 1163-1166, DOI: 10.1126/science.1697697

[[61]] Y Gao, Y Sun, AG Ercan-Sencicek, et al.. YAP/TEAD 1 complex is a default repressor of cardiac toll-like receptor genes. Int J Mol Sci, 22 (13) ( 2021), p. 6649, DOI: 10.3390/ijms22136649

[[62]] NN Kuzmich, KV Sivak, VN Chubarev, YB Porozov,TN Savateeva-Lyubimova, F. Peri. TLR4 signaling pathway modulators as potential therapeutics in inflammation and sepsis. Vaccines (Basel), 5 (4) ( 2017), p. 34, DOI: 10.3390/vaccines5040034

[[63]] Y Wang, X Zhu, S Yuan, et al.. TLR4/NF-κB signaling induces GSDMD-related pyroptosis in tubular cells in diabetic kidney disease. Front Endocrinol, 10 ( 2019), p. 603, DOI: 10.3389/fendo.2019.00603

[[64]] T Bergsbaken, SL Fink, BT. Cookson. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol, 7 (2) ( 2009), pp. 99-109, DOI: 10.1038/nrmicro2070

[[65]] R Fallach, A Shainberg, O Avlas, et al.. Cardiomyocyte Toll-like receptor 4 is involved in heart dysfunction following septic shock or myocardial ischemia. J Mol Cell Cardiol, 48 (6) ( 2010), pp. 1236-1244, DOI: 10.1016/j.yjmcc.2010.02.020

[[66]] BL Wharram, K Fitting, SL Kunkel, DG Remick,SE Merritt, RC. Wiggins. Tissue factor expression in endothelial cell/monocyte cocultures stimulated by lipopolysaccharide and/or aggregated IgG. Mechanisms of cell:cell communication. J Immunol, 146 (5) ( 1991), pp. 1437-1445

[[67]] S Martin, K Maruta, V Burkart, S Gillis, H. Kolb. IL-1 and IFN-gamma increase vascular permeability. Immunology, 64 (2) ( 1988), pp. 301-305

[[68]] SM Schumacher SV.Naga Prasad. Tumor necrosis factor-α in heart failure: an updated review. Curr Cardiol Rep, 20 (11) ( 2018), p. 117, DOI: 10.1007/s11886-018-1067-7

[[69]] SL. Gaffen. An overview of IL-17 function and signaling. Cytokine, 43 (3) ( 2008), pp. 402-407, DOI: 10.1016/j.cyto.2008.07.017

[[70]] B. Bozkurt. Activation of cytokines as a mechanism of disease progression in heart failure. Ann Rheum Dis, 59 (suppl 1) ( 2000), pp. i90-i93. 10.1136/ard.59.suppl_1.i90

[[71]] JE Sims DE. Smith. The IL-1 family: regulators of immunity. Nat Rev Immunol, 10 (2) ( 2010), pp. 89-102, DOI: 10.1038/nri2691

[[72]] Z Liu, N Zhao, H Zhu, et al.. Circulating interleukin-1β promotes endoplasmic reticulum stress-induced myocytes apoptosis in diabetic cardiomyopathy via interleukin-1 receptor-associated kinase-2. Cardiovasc Diabetol, 14 ( 2015), p. 125, DOI: 10.1186/s12933-015-0288-y

[[73]] N El Khoury, S Mathieu, C. Fiset. Interleukin-1β reduces L-type Ca2+ current through protein kinase Cε activation in mouse heart. J Biol Chem, 289 (32) ( 2014), pp. 21896-21908, DOI: 10.1074/jbc.M114.549642

[[74]] G Monnerat, ML Alarcón, LR Vasconcellos, et al.. Macrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice. Nat Commun, 7 ( 2016), Article 13344, DOI: 10.1038/ncomms13344

[[75]] M Buoncervello, S Maccari, B Ascione, et al.. Inflammatory cytokines associated with cancer growth induce mitochondria and cytoskeleton alterations in cardiomyocytes. J Cell Physiol, 234 (11) ( 2019), pp. 20453-20468, DOI: 10.1002/jcp.28647

[[76]] TL. Vincent.IL-1 in osteoarthritis: time for a critical review of the literature. F1000Res. 2019;8:F1000 Faculty Rev-934. DOI: 10.12688/f1000research.18831.1

[[77]] CA Hunter SA. Jones. IL-6 as a keystone cytokine in health and disease. Nat Immunol, 16 (5) ( 2015), pp. 448-457, DOI: 10.1038/ni.3153

[[78]] H Zhang, HY Wang, R Bassel-Duby, et al.. Role of interleukin-6 in cardiac inflammation and dysfunction after burn complicated by sepsis. Am J Physiol Heart Circ Physiol, 292 (5) ( 2007), pp. H2408-H2416, DOI: 10.1152/ajpheart.01150.2006

[[79]] F Chen, D Chen, Y Zhang, et al.. Interleukin-6 deficiency attenuates angiotensin II-induced cardiac pathogenesis with increased myocyte hypertrophy. Biochem Biophys Res Commun, 494 (3-4) ( 2017), pp. 534-541, DOI: 10.1016/j.bbrc.2017.10.119

[[80]] N Smart, MH Mojet, DS Latchman, MS Marber, MR Duchen, RJ. Heads. IL-6 induces PI 3-kinase and nitric oxide-dependent protection and preserves mitochondrial function in cardiomyocytes. Cardiovasc Res, 69 (1) ( 2006), pp. 164-177, DOI: 10.1016/j.cardiores.2005.08.017

[[81]] X Yu, RH Kennedy, SJ. Liu. JAK2/STAT3, not ERK1/2, mediates interleukin-6-induced activation of inducible nitric-oxide synthase and decrease in contractility of adult ventricular myocytes. J Biol Chem, 278 (18) ( 2003), pp. 16304-16309, DOI: 10.1074/jbc.M212321200

[[82]] S Kang, T Tanaka, M Narazaki, T. Kishimoto. Targeting interleukin-6 signaling in clinic. Immunity, 50 (4) ( 2019), pp. 1007-1023, DOI: 10.1016/j.immuni.2019.03.026

[[83]] M. Bickel. The role of interleukin-8 in inflammation and mechanisms of regulation. J Periodontol, 64 (5 Suppl) ( 1993), pp. 456-460

[[84]] RC Russo, CC Garcia, MM Teixeira, FA. Amaral. The CXCL8/IL-8 chemokine family and its receptors in inflammatory diseases. Expet Rev Clin Immunol, 10 (5) ( 2014), pp. 593-619, DOI: 10.1586/1744666X.2014.894886

[[85]] GL Kukielka, CW Smith, GJ LaRosa, et al.. Interleukin-8 gene induction in the myocardium after ischemia and reperfusion in vivo. J Clin Invest, 95 (1) ( 1995), pp. 89-103, DOI: 10.1172/JCI117680

[[86]] M Bilusic, CR Heery, JM Collins, et al.. Phase I trial of HuMax-IL 8 (BMS-986253), an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors. J Immunother Cancer, 7 (1) ( 2019), p. 240, DOI: 10.1186/s40425-019-0706-x

[[87]] SA Su, D Yang, W Zhu, et al.. Interleukin-17A mediates cardiomyocyte apoptosis through Stat3-iNOS pathway. Biochim Biophys Acta, 1863 (11) ( 2016), pp. 2784-2794, DOI: 10.1016/j.bbamcr.2016.08.013

[[88]] RG Langley, BE Elewski, M Lebwohl, et al.. Secukinumab in plaque psoriasis--results of two phase 3 trials. N Engl J Med, 371 (4) ( 2014), pp. 326-338, DOI: 10.1056/NEJMoa1314258

[[89]] P Bhattacharya, M Thiruppathi, HA Elshabrawy, K Alharshawi, P Kumar, BS. Prabhakar. GM-CSF: an immune modulatory cytokine that can suppress autoimmunity. Cytokine, 75 (2) ( 2015), pp. 261-271, DOI: 10.1016/j.cyto.2015.05.030

[[90]] L Forechi, MP Baldo, D Meyerfreund, JG. Mill. Granulocyte colony-stimulating factor improves early remodeling in isoproterenol-induced cardiac injury in rats. Pharmacol Rep, 64 (3) ( 2012), pp. 643-649, DOI: 10.1016/s1734-1140(12)70860-5

[[91]] H Okada, G Takemura, Y Li, et al.. Effect of a long-term treatment with a low-dose granulocyte colony-stimulating factor on post-infarction process in the heart. J Cell Mol Med, 12 (4) ( 2008), pp. 1272-1283, DOI: 10.1111/j.1582-4934.2008.00294.x

[[92]] B Hibbert, B Hayley, RS Beanlands, et al.. Granulocyte colony-stimulating factor therapy for stem cell mobilization following anterior wall myocardial infarction: the CAPITAL STEM MI randomized trial. CMAJ (Can Med Assoc J), 186 (11) ( 2014), pp. E427-E434, DOI: 10.1503/cmaj.140133

[[93]] A Anzai, JL Choi, S He, et al.. The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes. J Exp Med, 214 (11) ( 2017), pp. 3293-3310, DOI: 10.1084/jem.20170689

[[94]] AT Stock, JA Hansen, MA Sleeman, BS McKenzie, IP. Wicks. GM-CSF primes cardiac inflammation in a mouse model of Kawasaki disease. J Exp Med, 213 (10) ( 2016), pp. 1983-1998, DOI: 10.1084/jem.20151853

[[95]] B Mathias, BE Szpila, FA Moore, PA Efron, LL. Moldawer.A review of GM-CSF therapy in sepsis. Medicine (Baltim), 94 (50) ( 2015), Article e2044, DOI: 10.1097/MD.0000000000002044

[[96]] M Liu, S Guo, JM Hibbert, et al.. CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications. Cytokine Growth Factor Rev, 22 (3) ( 2011), pp. 121-130, DOI: 10.1016/j.cytogfr.2011.06.001

[[97]] J Yuan, Z Liu, T Lim, et al.. CXCL 10 inhibits viral replication through recruitment of natural killer cells in coxsackievirus B3-induced myocarditis. Circ Res, 104 (5) ( 2009), pp. 628-638, DOI: 10.1161/CIRCRESAHA.108.192179

[[98]] L Mayer, WJ Sandborn, Y Stepanov, et al.. Anti-IP-10 antibody (BMS-936557) for ulcerative colitis: a phase II randomised study. Gut, 63 (3) ( 2014), pp. 442-450, DOI: 10.1136/gutjnl-2012-303424

[[99]] WJ Sandborn, JF Colombel, S Ghosh, et al.. Eldelumab [Anti-IP-10] induction therapy for ulcerative colitis: a randomised, placebo-controlled, phase 2b study. J Crohns Colitis, 10 (4) ( 2016), pp. 418-428, DOI: 10.1093/ecco-jcc/jjv224

[[100]] SL Deshmane, S Kremlev, S Amini, BE. Sawaya. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res, 29 (6) ( 2009), pp. 313-326, DOI: 10.1089/jir.2008.0027

[[101]] K Kaikita, T Hayasaki, T Okuma, WA Kuziel, H Ogawa, M. Takeya. Targeted deletion of CC chemokine receptor 2 attenuates left ventricular remodeling after experimental myocardial infarction. Am J Pathol, 165 (2) ( 2004), pp. 439-447, DOI: 10.1016/S0002-9440(10)63309-3

[[102]] O Dewald, P Zymek, K Winkelmann, et al.. CCL2/Monocyte Chemoattractant Protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res, 96 (8) ( 2005), pp. 881-889, DOI: 10.1161/01.RES.0000163017.13772.3a

[[103]] S Yokochi, H Hashimoto, Y Ishiwata, et al.. An anti-inflammatory drug, propagermanium, may target GPI-anchored proteins associated with an MCP-1 receptor, CCR2. J Interferon Cytokine Res, 21 (6) ( 2001), pp. 389-398, DOI: 10.1089/107999001750277862

[[104]] MJ Trifilo, CC Bergmann, WA Kuziel, TE. Lane. CC chemokine ligand 3 (CCL3) regulates CD8(+)-T-cell effector function and migration following viral infection. J Virol, 77 (7) ( 2003), pp. 4004-4014, DOI: 10.1128/jvi.77.7.4004-4014.2003

[[105]] PJ Price, B Luckow, LE Torres-Domínguez, et al.. Chemokine (C-C Motif) receptor 1 is required for efficient recruitment of neutrophils during respiratory infection with modified vaccinia virus Ankara. J Virol, 88 (18) ( 2014), pp. 10840-10850, DOI: 10.1128/JVI.01524-14

[[106]] D Gibaldi, G Vilar-Pereira, IR Pereira, AA Silva, et al.. CCL3/Macrophage inflammatory protein-1α is dually involved in parasite persistence and induction of a TNF- and IFNγ-enriched inflammatory milieu in trypanosoma cruzi-induced chronic cardiomyopathy. Front Immunol, 11 ( 2020), p. 306, DOI: 10.3389/fimmu.2020.00306

[[107]] C Ye, D Brand, SG. Zheng.Targeting IL-2: an unexpected effect in treating immunological diseases. Signal Transduct Targeted Ther, 3 ( 2018), p. 2, DOI: 10.1038/s41392-017-0002-5

[[108]] PA Sobotka, J McMannis, RI Fisher, DG Stein, JX. Thomas. Effects of interleukin 2 on cardiac function in the isolated rat heart. J Clin Invest, 86 (3) ( 1990), pp. 845-850, DOI: 10.1172/JCI114783

[[109]] C Conceicao, N Thakur, S Human, et al.. The SARS-CoV-2 Spike protein has a broad tropism for mammalian ACE2 proteins. PLoS Biol, 18 (12) ( 2020), Article e3001016, DOI: 10.1371/journal.pbio.3001016

[[110]] CB Jackson, M Farzan, B Chen, H. Choe. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol, 23 (1) ( 2022), pp. 3-20, DOI: 10.1038/s41580-021-00418-x

[[111]] CL Albert, AE Carmona-Rubio, AJ Weiss, GG Procop,RC Starling, ER. Rodriguez. The enemy within: sudden-onset reversible cardiogenic shock with biopsy-proven cardiac myocyte infection by severe acute respiratory syndrome coronavirus 2. Circulation, 142 (19) ( 2020), pp. 1865-1870, DOI: 10.1161/CIRCULATIONAHA.120.050097

[[112]] GP Bulfamante, GL Perrucci, M Falleni, et al.. Evidence of SARS-CoV-2 transcriptional activity in cardiomyocytes of COVID-19 patients without clinical signs of cardiac involvement. Biomedicines, 8 (12) ( 2020), p. 626, DOI: 10.3390/biomedicines8120626

[[113]] M Dolhnikoff, et al..J Ferreira Ferranti, RA de Almeida Monteiro, SARS-CoV-2 in cardiac tissue of a child with COVID-19-related multisystem inflammatory syndrome. Lancet Child Adolesc Health, 4 (10) ( 2020), pp. 790-794, DOI: 10.1016/S2352-4642(20)30257-1

[[114]] PJ Hanson, F Liu-Fei, C Ng, et al.. Characterization of COVID-19-associated cardiac injury: evidence for a multifactorial disease in an autopsy cohort. Lab Invest, 102 (8) ( 2022), pp. 814-825, DOI: 10.1038/s41374-022-00783-x

[[115]] ME Francis, U Goncin, A Kroeker, et al.. SARS-CoV-2 infection in the Syrian hamster model causes inflammation as well as type I interferon dysregulation in both respiratory and non-respiratory tissues including the heart and kidney. PLoS Pathog, 17 (7) ( 2021), Article e1009705, DOI: 10.1371/journal.ppat.1009705

[[116]] L Yang, BE Nilsson-Payant, Y Han, et al.. Cardiomyocytes recruit monocytes upon SARS-CoV-2 infection by secreting CCL2. Stem Cell Rep, 16 (9) ( 2021), pp. 2274-2288, DOI: 10.1016/j.stemcr.2021.07.012

[[117]] Y Han, J Zhu, L Yang, et al.. SARS-CoV-2 infection induces ferroptosis of sinoatrial Node pacemaker cells. Circ Res, 130 (7) ( 2022), pp. 963-977, DOI: 10.1161/CIRCRESAHA.121.320518

[[118]] JA Perez-Bermejo, S Kang, SJ Rockwood, et al.. SARS-CoV-2 infection of human iPSC-derived cardiac cells reflects cytopathic features in hearts of patients with COVID-19. Sci Transl Med, 13 (590) ( 2021), Article eabf7872, DOI: 10.1126/scitranslmed.abf7872

[[119]] S Marchiano, T-Y Hsiang, A Khanna, et al.. SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical function. Stem Cell Rep, 16 (3) ( 2021), pp. 478-492, DOI: 10.1016/j.stemcr.2021.02.008

[[120]] D Bojkova, JUG Wagner, M Shumliakivska, et al.. SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes. Cardiovasc Res, 116 (14) ( 2020), pp. 2207-2215, DOI: 10.1093/cvr/cvaa267

[[121]] E Avolio, M Carrabba, R Milligan, et al.. The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD147 receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease. Clin Sci (Lond), 135 (24) ( 2021), pp. 2667-2689, DOI: 10.1042/CS20210735

[[122]] Z Ma, X Li, RLY Fan, et al.. A human pluripotent stem cell-based model of SARS-CoV-2 infection reveals an ACE2-independent inflammatory activation of vascular endothelial cells through TLR4. Stem Cell Rep, 17 (3) ( 2022), pp. 538-555, DOI: 10.1016/j.stemcr.2022.01.015

[[123]] CK Navaratnarajah, DR Pease, PJ Halfmann, et al.. Highly efficient SARS-CoV-2 infection of human cardiomyocytes: spike protein-mediated cell fusion and its inhibition. J Virol, 95 (24) ( 2021), Article e0136821, DOI: 10.1128/JVI.01368-21

[[124]] A Sharma, G Garcia Jr., Y Wang, et al.. Human iPSC-derived cardiomyocytes are susceptible to SARS-CoV-2 infection. Cell Rep Med, 1 (4) ( 2020), Article 100052, DOI: 10.1016/j.xcrm.2020.100052

[[125]] Y Yang, Z Wei,C Xiong, H. Qian. Direct mechanisms of SARS-CoV-2-induced cardiomyocyte damage: an update. J Virol, 19 (1) ( 2022), p. 108, DOI: 10.1186/s12985-022-01833-y

[[126]] I Jungreis, R Sealfon, M. Kellis.SARS-CoV-2 gene content and COVID-19 mutation impact by comparing 44 Sarbecovirus genomes. Nat Commun, 12 (1) ( 2021), p. 2642, DOI: 10.1038/s41467-021-22905-7

[[127]] N Redondo, S Zaldívar-López, JJ Garrido, M. Montoya. SARS-CoV-2 accessory proteins in viral pathogenesis: knowns and unknowns. Front Immunol, 12 ( 2021), Article 708264, DOI: 10.3389/fimmu.2021.708264

[[128]] AC Walls, YJ Park, MA Tortorici, A Wall, AT McGuire, D. Veesler. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell, 181 (2) ( 2020), pp. 281-292, DOI: 10.1016/j.cell.2020.02.058. e6

[[129]] Y Cai, J Zhang, T Xiao, et al.. Distinct conformational states of SARS-CoV-2 spike protein. Science, 369 (6511) ( 2020), pp. 1586-1592, DOI: 10.1126/science.abd4251

[[130]] A Bayati, R Kumar,V Francis, PS. McPherson. SARS-CoV-2 infects cells after viral entry via clathrin-mediated endocytosis. J Biol Chem, 296 ( 2021), Article 100306, DOI: 10.1016/j.jbc.2021.100306

[[131]] G Simmons, DN Gosalia, AJ Rennekamp, JD Reeves, SL Diamond, P. Bates. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc Natl Acad Sci U S A, 102 (33) ( 2005), pp. 11876-11881, DOI: 10.1073/pnas.0505577102

[[132]] MM Zhao, WL Yang, FY Yang, et al.. Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development. Signal Transduct Targeted Ther, 6 (1) ( 2021), p. 134, DOI: 10.1038/s41392-021-00558-8

[[133]] J Buchrieser, J Dufloo, M Hubert, et al.. Syncytia formation by SARS-CoV-2-infected cells. EMBO J, 39 (23) ( 2020), Article e106267, DOI: 10.15252/embj.2020107405

[[134]] L Braga, H Ali, I Secco, et al.. Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia. Nature, 594 (7861) ( 2021), pp. 88-93, DOI: 10.1038/s41586-021-03491-6

[[135]] PS Aguilar, MK Baylies, A Fleissner, et al.. Genetic basis of cell-cell fusion mechanisms. Trends Genet, 29 (7) ( 2013), pp. 427-437, DOI: 10.1016/j.tig.2013.01.011

[[136]] JM Whitlock LV. Chernomordik. Flagging fusion: phosphatidylserine signaling in cell-cell fusion. J Biol Chem, 296 ( 2021), Article 100411, DOI: 10.1016/j.jbc.2021.100411

[[137]] J Suzuki, M Umeda, PJ Sims, S. Nagata. Calcium-dependent phospholipid scrambling by TMEM16F. Nature, 468 (7325) ( 2010), pp. 834-838, DOI: 10.1038/nature09583

[[138]] B Alberts, A Johnson, J Lewis, M Raff, K Roberts, P Walter.The compartmentalization of cells. Molecular Biology of the Cell (4^th edition), Garland Science ( 2002)

[[139]] C Kho, A Lee, RJ. Hajjar. Altered sarcoplasmic reticulum calcium cycling—targets for heart failure therapy. Nat Rev Cardiol, 9 (12) ( 2012), pp. 717-733, DOI: 10.1038/nrcardio.2012.145

[[140]] M Tada, T. Toyofuku. SR Ca(2+)-ATPase/phospholamban in cardiomyocyte function. J Card Fail, 2 (4 Suppl) ( 1996), pp. S77-S85, DOI: 10.1016/s1071-9164(96)80062-5

[[141]] J Shang, Y Wan, C Luo, et al.. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A, 117 (21) ( 2020), pp. 11727-11734, DOI: 10.1073/pnas.2003138117

[[142]] S George, AC Pal, J Gagnon, et al.. Evidence for SARS-CoV-2 spike protein in the urine of COVID-19 patients. Kidney, 2 (6) ( 2021), pp. 924-936, DOI: 10.34067/KID.0002172021

[[143]] Y Zhao, M Kuang, J Li, et al.. SARS-CoV-2 spike protein interacts with and activates TLR41. Cell Res, 31 (7) ( 2021), pp. 818-820, DOI: 10.1038/s41422-021-00495-9

[[144]] K Shirato, T. Kizaki. SARS-CoV-2 spike protein S1 subunit induces pro-inflammatory responses via Toll-like receptor 4 signaling in murine and human macrophages. Heliyon, 7 (2) ( 2021), Article e06187, DOI: 10.1016/j.heliyon.2021.e06187

[[145]] S Khan, MS Shafiei, C Longoria, JW Schoggins, RC Savani, H. Zaki. SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway. Elife, 10 ( 2021), Article e68563, DOI: 10.7554/eLife.68563

[[146]] YC Lu, WC Yeh, PS. Ohashi. LPS/TLR4 signal transduction pathway. Cytokine, 42 (2) ( 2008), pp. 145-151, DOI: 10.1016/j.cyto.2008.01.006

[[147]] 147 Negron SG, Kessinger CW, Xu B, Pu WT, Lin Z. Selectively expressing SARS-CoV-2 Spike protein S1 subunit in cardiomyocytes induces cardiac hypertrophy in mice. 2021.

[[148]] Q Lu, J Liu, S Zhao, et al.. SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2. Immunity, 54 (6) ( 2021), pp. 1304-1319, DOI: 10.1016/j.immuni.2021.05.006. e9

[[149]] Jeong D-E, McCoy M, Artiles K, et al. Assemblies-of-putative-SARS-CoV2-spike-encoding-mRNA-sequences-for-vaccines-BNT-162b2-and-mRNA-1273. 2021.

[[150]] B Pulendran, P S Arunachalam, DT. O’Hagan. Emerging concepts in the science of vaccine adjuvants. Nat Rev Drug Discov, 20 (6) ( 2021), pp. 454-475, DOI: 10.1038/s41573-021-00163-y

[[151]] PS Arunachalam, MKD Scott, T Hagan, et al.. Systems vaccinology of the BNT162b 2 mRNA vaccine in humans. Nature, 596 (7872) ( 2021), pp. 410-416, DOI: 10.1038/s41586-021-03791-x

[[152]] M Saresella, F Piancone, I Marventano, et al.. Innate immune responses to three doses of the BNT162b 2 mRNA SARS-CoV-2 vaccine. Front Immunol ( 2022), Article 13947320, DOI: 10.3389/fimmu.2022.947320

[[153]] C Li, Y Chen, Y Zhao, et al.. Intravenous injection of COVID-19 mRNA vaccine can induce acute myopericarditis in mouse model. Clin Infect Dis, 74 (11) ( 2022), pp. 1933-1950, DOI: 10.1093/cid/ciab707

[[154]] AF Ogata, CA Cheng, M Desjardins, 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, 74 (4) ( 2022), pp. 715-718, DOI: 10.1093/cid/ciab465

[[155]] SJ Theobald, A Simonis, JM Mudler, et al.. Spleen tyrosine kinase mediates innate and adaptive immune crosstalk in SARS-CoV-2 mRNA vaccination. EMBO Mol Med, 14 (8) ( 2022), Article e15888, DOI: 10.15252/emmm.202215888

[[156]] SR Paludan TH. Mogensen. Innate immunological pathways in COVID-19 pathogenesis. Sci Immunol, 7 (67) ( 2022), Article eabm5505, DOI: 10.1126/sciimmunol.abm5505.

[[157]] Ricklin, G Hajishengallis, K Yang, JD. Lambris. Complement: a key system for immune surveillance and homeostasis. Nat Immunol, 11 (9) ( 2010), pp. 785-797, DOI: 10.1038/ni.1923

[[158]] VW. van Hinsbergh. Endothelium--role in regulation of coagulation and inflammation. Semin Immunopathol, 34 (1) ( 2012), pp. 93-106, DOI: 10.1007/s00281-011-0285-5

[[159]] E Rawish, M Sauter, R Sauter, H Nording, HF. Langer. Complement, inflammation and thrombosis. Br J Pharmacol, 178 (14) ( 2021), pp. 2892-2904, DOI: 10.1111/bph.15476

[[160]] U Amara, MA Flierl, D Rittirsch, et al.. Molecular intercommunication between the complement and coagulation systems. J Immunol, 185 (9) ( 2010), pp. 5628-5636, DOI: 10.4049/jimmunol.0903678

[[161]] H Kerr, A. Richards. Complement-mediated injury and protection of endothelium: lessons from atypical haemolytic uraemic syndrome. Immunobiology, 217 (2) ( 2012), pp. 195-203, DOI: 10.1016/j.imbio.2011.07.028

[[162]] Ackermann, SE Verleden, M Kuehnel, et al.. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid-19. N Engl J Med, 383 (2) ( 2020), pp. 120-128, DOI: 10.1056/NEJMoa2015432

[[163]] LE Gralinski, TP Sheahan, TE Morrison, et al.. Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis. mBio, 9 (5) ( 2018), pp. e01753-18, DOI: 10.1128/mBio.01753-18

[[164]] L Liu, P Chopra, X Li, et al.. Heparan sulfate proteoglycans as attachment factor for SARS-CoV-2. ACS Cent Sci, 7 (6) ( 2021), pp. 1009-1018, DOI: 10.1021/acscentsci.1c00010

[[165]] Yu, X Yuan, H Chen, S Chaturvedi, EM Braunstein, RA. Brodsky. Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition. Blood, 136 (18) ( 2020), pp. 2080-2089, DOI: 10.1182/blood.2020008248

[[166]] S Panigrahi, T Goswami, B Ferrari, et al.. SARS-CoV-2 spike protein destabilizes microvascular homeostasis. Microbiol Spectr, 9 (3) ( 2021), Article e0073521, DOI: 10.1128/Spectrum.00735-21

[[167]] L Perico, M Morigi, M Galbusera, et al.. SARS-CoV-2 spike protein 1 activates microvascular endothelial cells and complement system leading to platelet aggregation. Front Immunol, 13 ( 2022), Article 827146, DOI: 10.3389/fimmu.2022.827146

[[168]] Y Lei, J Zhang, CR Schiavon, et al.. SARS-CoV-2 spike protein impairs endothelial function via downregulation of ACE 2. Circ Res, 128 (9) ( 2021), pp. 1323-1326, DOI: 10.1161/CIRCRESAHA.121.318902

[[169]] CJ Lowenstein SD. Solomon. Severe COVID-19 is a microvascular disease. Circulation, 142 (17) ( 2020), pp. 1609-1611, DOI: 10.1161/CIRCULATIONAHA.120.050354

[[170]] Q Li, Y Wang, Q Sun, et al.. Immune response in COVID-19: what is next. Cell Death Differ, 29 (6) ( 2022), pp. 1107-1122, DOI: 10.1038/s41418-022-01015-x

[[171]] CA Janeway Jr, P Travers, M Walport, MJ Shlomchik. Principles of innate and adaptive immunity. The Immune System in Health and Disease (5th edition), Garland Science ( 2001)

[[172]] BL Kotzin, DY Leung, J Kappler, P. Marrack. Superantigens and their potential role in human disease. Adv Immunol, 54 ( 1993), pp. 99-166, DOI: 10.1016/s0065-2776(08)60534-9

[[173]] AI Roberts, RS Blumberg, AD Christ, RE Brolin, EC. Ebert. Staphylococcal enterotoxin B induces potent cytotoxic activity by intraepithelial lymphocytes. Immunology, 101 (2) ( 2000), pp. 185-190, DOI: 10.1046/j.1365-2567.2000.00088.x

[[174]] CR Consiglio, N Cotugno, F Sardh, et al.. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell, 183 (4) ( 2020), pp. 968-981, DOI: 10.1016/j.cell.2020.09.016. e7

[[175]] MH Cheng, S Zhang, RA Porritt, et al.. Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation. Proc Natl Acad Sci U S A, 117 (41) ( 2020), pp. 25254-25262, DOI: 10.1073/pnas.2010722117

[[176]] L Hoste, L Roels, L Naesens, et al.. TIM3+ TRBV11- 2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C. J Exp Med, 219 (2) ( 2022), Article e20211381, DOI: 10.1084/jem.20211381

[[177]] RA Porritt, L Paschold, MN Rivas, et al.. HLA class I-associated expansion of TRBV11- 2 T cells in multisystem inflammatory syndrome in children. J Clin Invest, 131 (10) ( 2021), Article e146614, DOI: 10.1172/JCI146614

[[178]] C Amormino, V Tedeschi, G Paldino, et al.. SARS-CoV-2 spike does not possess intrinsic superantigen-like inflammatory activity. Cells, 11 (16) ( 2022), p. 2526, DOI: 10.3390/cells11162526

[[179]] G Petruk, M Puthia, J Petrlova, et al.. SARS-CoV-2 spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity. J Mol Cell Biol, 12 (12) ( 2020), pp. 916-932, DOI: 10.1093/jmcb/mjaa067

[[180]] M Puthia, L Tanner, G Petruk, A. Schmidtchen. Experimental model of pulmonary inflammation induced by SARS-CoV-2 spike protein and endotoxin. ACS Pharmacol Transl Sci, 5 (3) ( 2022), pp. 141-148, DOI: 10.1021/acsptsci.1c00219

[[181]] A Hamdy, A. Leonardi.Superantigens and SARS-CoV-2. Pathogens, 11 (4) ( 2022), p. 390, DOI: 10.3390/pathogens11040390

[[182]] LB Giron, H Dweep, X Yin, et al.. Plasma markers of disrupted gut permeability in severe COVID-19 patients. Front Immunol, 12 ( 2021), Article 686240, DOI: 10.3389/fimmu.2021.686240

[[183]] SM Hirabara, TDA Serdan, R Gorjao, et al.. SARS-COV-2 variants: differences and potential of immune evasion. Front Cell Infect Microbiol, 11 ( 2021), Article 781429, DOI: 10.3389/fcimb.2021.781429

[[184]] H Shuai, JF Chan, B Hu, et al.. Attenuated replication and pathogenicity of SARS-CoV-2 B.1.1.529 Omicron. Nature, 603 (7902) ( 2022), pp. 693-699, DOI: 10.1038/s41586-022-04442-5

[[185]] R Suzuki, D Yamasoba, I Kimura, et al.. Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant. Nature, 603 (7902) ( 2022), pp. 700-705, DOI: 10.1038/s41586-022-04462-1.

[[186]] B Meng, A Abdullahi, IATM Ferreira, et al.. Altered TMPRSS 2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity. Nature, 603 (7902) ( 2022), pp. 706-714, DOI: 10.1038/s41586-022-04474-x

[[187]] LM Yonker, Z Swank, YC Bartsch, et al.. Circulating spike protein detected in post-COVID-19 mRNA vaccine myocarditis. Circulation, 147 (11) ( 2023), pp. 867-876, DOI: 10.1161/CIRCULATIONAHA.122.061025