COVID-19 mRNA Vaccines: The Molecular Basis of Some Adverse Events
Abstract
:1. Introduction
2. Human Heart
3. Systemic Symptoms
4. Inflammatory Cardiac Channelopathies and Arrhythmias
5. The Cardiac Action Potential (AP)
6. The Ionic Basis of AP
7. Pro-Inflammatory Cytokines
8. Myo-Pericarditis
8.1. Probable Pathogenesis of Myocarditis
8.1.1. One or Two Shots?
8.1.2. Inflammatory Infiltration of Myocardium
8.1.3. Who Opens the Gate
8.1.4. Exosomes
8.1.5. Spike Protein Induces Endothelial Cells (ECs) Dysfunction
Spike Protein and Cardiomyocytes (CM)
8.1.6. Young Males: The Favorite Target
8.1.7. Other Pathological Mechanisms Triggered by the Spike Protein
Renin–Angiotensin–Aldosterone System (RAAS)
Toxicity of Lipid Nanoparticles (LNPs)
8.1.8. TCD8, TCD3/CD45R0,and Macrophages CD68 in Myo-Pericarditis
8.2. Diagnostic Items
8.3. Trans-Endothelial Migration towards Heart Tissue
8.4. Immune Black Hole
8.5. Experimental Myocarditis
9. Multisystem Inflammatory Syndromes (MIS)
10. Discussion
Potential Effects after COVID-19 mRNA Vaccination. | Ref. |
---|---|
Endothelial dysfunctions produced by the Spike protein. | [103] |
After vaccination, angiotensin II accumulates. | [131] |
The binding of Spike protein to ACE2 receptors promotes their downregulation. | [131,146] |
Decreased ACE2 levels may lead to Ang II upregulation and over-activity of the classical RAAS axis (ACE, angiotensin II, and AT1R) resulting in the production of all the effects already described in this study [127,128,129,130,132,133,134,135,136,137,138,139,140,141,142,143,144,145]. | [147] |
Excessive Th1-type immune responses. | [197] |
Persistence of the Spike protein in circulation for a prolonged period of time. | [198] |
Prolonged immune and inflammatory response against the Spike protein. | [198,199] |
Strong pro-inflammatory activity of LNPs. | [149,150,151,152,153,154,155,156] |
Spike protein alone can easily reach the myocardium. | [104,106] |
Spike protein was found in cardiomyocytes (CMs). | [106] |
Different levels of expression of pro-inflammatory cytokines over time. | [199,200] |
Circulating CoV-2-S1 is a TLR4-recognizable alarmin that may harm the CMs by triggering their innate immune responses. | [104] |
TLR4 initiates the expression of several pro-inflammatory genes, cell surface molecules, and chemokines through the MyD88-dependent pathway, which exacerbates the damage to myocardium. | [22] |
Activation of TLR4 and the TLR4/NFκB axis in cardiomyocytes by the Spike protein. | [24] |
Unmitigated TLR4 activation may lead to increased risk for cardiac inflammation. | [105] |
CoV-2-S1 activates TLR4 signaling to induce pro-inflammatory responses in murine and human macrophages. | [107] |
Diffuse myocardial macrophages infiltration in the patient biopsy sample suggest an increased level of IL-18 produced by monocytes and macrophages in the heart with COVID-19 vaccine-related myo-pericarditis. | [91] |
In an inflammatory microenvironment, caspase-1 is regulated by NF-κB, and this enzyme facilitates the conversion of pro-IL-18 in IL-18. | [90] |
Lymphocytic infiltration with predominant immunostaining for CD8 and CD68-positive cells (macrophages) is present in myocarditis following COVID-19 mRNA vaccines. | [83] |
Vaccinated mice showed signs of myocarditis 2 days after injection of the second dose of BNT162b2 vaccine. | [81] |
Free Spike antigen was detected in the blood of adolescents and young adults who developed myocarditis following COVID-19 mRNA vaccine. | [201] |
SARS-CoV-2 Spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway. | [202] |
Immune Cells in the Myocardium | EMB in Vaccinated | EMB in SARS-CoV-2 Infection | Autopsy in SARS-CoV-2 Infection |
---|---|---|---|
CD68 macrophages | Yes | Yes [226,227,228] | Not reported |
CD3 lymphocytes | Yes | Yes [226,227,228] | Not reported |
CD4 lymphocytes | No | Not reported | Yes [229,230] |
CD8 lymphocytes | No | Not reported | Yes [231] |
NET | No | Not reported | Yes [231] |
11. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ACE | Angiotensin-Converting Enzyme |
ACE2 | Angiotensin-Converting Enzyme 2 |
AEs | Adverse Events |
ANS | Autonomic Nervous System |
AP | Action Potential |
AT1R axis | Angiotensin II/ AT1R axis |
AT2R axis | Angiotensin II /AT2R axis |
CECs | Cardiac Endothelial Cells |
CD | Cluster of Differentiation Molecules |
CFs | Cardiac Fibroblasts |
CMR | Cardiac Magnetic Resonance |
CMs | Cardiomyocytes |
CoV-2-S1 | S1 Subunit of CoV-2 Spike Protein |
DCs | Dendritic Cells |
ECM | Extracellular Matrix |
ECs | Endothelial cells |
EMB | Endomyocardial Biopsy |
HPA axis | Hypothalamic–Pituitary–Adrenal axis |
ICAM-1 | Intercellular Adhesion Molecule 1 |
IL-1β | Interleukin-1β |
IL-6 | Interleukin-6 |
IP | Inflammatory Pyramid |
LGE | Late Gadolinium Enhancement |
LNPs | Lipid Nanoparticles |
LQT1 | Long QT syndrome type 1 |
MIS-A | Multisystem Inflammatory Syndrome in adult |
MIS-C | Multisystem Inflammatory Syndrome in children |
MIS-V | Multisystem Inflammatory Syndrome following COVID-19 mRNA vaccines |
MHC | Major Histocompatibility Complex |
MSCs | Mesenchymal Stem Cells |
NF-κB | Nuclear Factor- κB |
RAAS | Renin–Angiotensin–Aldosterone System |
SAM axis | Sympathetic–Adreno–Medullar axis |
SRS | Stress Response System |
TLR4 | Toll-Like Receptor 4 |
TNF-α | Tumor Necrosis Factor-α |
VCAM-1 | Vascular Cell Adhesion Protein 1 |
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Channel | Current | Current Type | Ion | AP Phase | Interference |
---|---|---|---|---|---|
Kv 4.3 | Ito | Outward | K+ | 1 | IL-1β, TNF-α |
L-type | ICaL | Inward | Ca2+ | 2 | IL-1β, IL-6 |
Kv 11.1 hERG | IKr | Outward | K+ | 3 | IL-6, TNF-α |
Kv 7.1 | IKs | Outward | K+ | 3 | TNF-α |
Kir 2.1/2.3 | IK1 | Inward | K+ | 4 |
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Giannotta, G.; Murrone, A.; Giannotta, N. COVID-19 mRNA Vaccines: The Molecular Basis of Some Adverse Events. Vaccines 2023, 11, 747. https://doi.org/10.3390/vaccines11040747
Giannotta G, Murrone A, Giannotta N. COVID-19 mRNA Vaccines: The Molecular Basis of Some Adverse Events. Vaccines. 2023; 11(4):747. https://doi.org/10.3390/vaccines11040747
Chicago/Turabian StyleGiannotta, Girolamo, Antonio Murrone, and Nicola Giannotta. 2023. "COVID-19 mRNA Vaccines: The Molecular Basis of Some Adverse Events" Vaccines 11, no. 4: 747. https://doi.org/10.3390/vaccines11040747