750 estudios sobre las lesiones de las inyecciones de ARNm contra COVID-19 categorizados

3 julio, 2025 Biblioteca, vacunas

Compilado por Dr. Martin Wucher, MSC Dent Sc (eq DDS), Dr Byram Bridle, PhD, Dr. Steven Hatfill, Erik Sass, et al. Extracto de CienciaySaludNatural.com

I. Compilado de investigación sobre la patogenicidad de la proteína pico o spike (n=375)

Originalmente parte de la cubierta externa del virus SARS-CoV2, donde funciona como una «llave» para “abrir” (infectar) las células, las proteínas pico o spike también son producidas en grandes cantidades por las «vacunas» de ARNm, desencadenando una respuesta inmune de corta duración en forma de anticuerpos. Sin embargo, cada vez hay más pruebas que demuestran que la proteína pico o spike es nociva por sí misma, incluidos más de 370 artículos científicos revisados por expertos.

La sección Categorías organiza la investigación en categorías amplias que incluyen tejidos y sistemas de órganos afectados, mecanismos y pruebas de patología clínica. Dado que estas áreas se solapan, muchos artículos aparecen más de una vez en la segunda sección.

II. Estudios de biodistribución de la proteína pico o spike y del ARNm de la «vacuna» (n=61)

Además de las características patógenas del antígeno de la proteína pico, más de 60 estudios revisados por pares han demostrado que tanto el ARNm de la «vacuna» que codifica para el antígeno de la proteína de la espiga como la propia proteína pico pueden penetrar en tejidos distantes, causando daños sistémicos.

Los estudios de biodistribución muestran que tanto el ARNm de la «vacuna» que codifica para el antígeno de la proteína pico como la propia proteína pico pueden penetrar en tejidos distantes, causando daños sistémicos a una variedad de órganos y sistemas de órganos, incluida la placenta. El compilado de esta sección presenta más de 60 estudios revisados por pares (n=61) que documentan la amplia distribución del ARNm de la «vacuna» y la proteína pico asociada en seres humanos y en experimentación animal.

Estos artículos confirman que el ARNm de la «vacuna» y la proteína pico o spike pueden alcanzar tejidos y órganos como el corazón, el hígado, el cerebro, los pulmones, la placenta, el cordón umbilical, la leche materna, los ganglios linfáticos, el timo, los riñones, el bazo, la vejiga, el intestino grueso, los ojos, las glándulas suprarrenales, los ovarios, los testículos, la médula ósea, la piel, las glándulas lagrimales y el apéndice.

Además, un pequeño número de estudios demuestran la capacidad de la proteína pico viral para atravesar importantes barreras fisiológicas independientemente del resto del virus, lo que sugiere que la proteína de la espiga derivada de una «vacuna» idéntica puede hacer lo mismo. Se incluye un cuadro con resumen de los resultados de docenas de estudios recogidos en esta sección II, , que muestran qué componentes y productos de la «vacuna» se examinaron (ARNm, PNL y/o proteína pico) y los principales tejidos y órganos afectados. Tomados en conjunto con las pruebas de la patogenicidad de la proteína pico, estos hallazgos sugieren que las «vacunas» de ARNm pueden distribuir la proteína píco, nociva y de larga duración, de forma incontrolable por todo el cuerpo, causando lesiones y la muerte por diversos medios.

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.III. Estudios sobre la persistencia del ARNm de la proteína pico y de la «vacuna» (n=41)

Más de 40 estudios revisados por expertos confirman que el ARNm de la «vacuna» y el antígeno proteico resultante persisten en los tejidos de los receptores humanos de la «vacuna» y de los animales de experimentación durante mucho más tiempo de lo que afirman las autoridades de salud pública; se ha demostrado que las proteínas pico virales, resultantes de la infección natural, persisten incluso durante más tiempo, lo que refuerza la preocupación de que la proteína pico idéntica de la «vacuna» también pueda durar más de lo previsto.

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IV. Estudios de toxicidad y alergenicidad de nanopartículas lipídicas (n=80)

80 artículos revisados por expertos muestran que las nanopartículas lipídicas ionizables (NPL) utilizadas en las inyecciones experimentales de ARNm son altamente inflamatorias por sí mismas, incluido su componente de polietilenglicol (PEG), una causa establecida de anafilaxia (una reacción alérgica extrema).

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V. Compilado de la impronta inmunitaria de la “vacuna” COVID-19 (n=140)
La impronta inmunitaria, denominada «pecado antigénico original» por Thomas Francis Jr., se produce cuando los linfocitos B de memoria producidos en respuesta a una infección vírica inicial dominan las respuestas posteriores a virus relacionados. 140 artículos revisados por expertos sugieren que las «vacunas» COVID imprimieron el sistema inmunitario de los receptores a través de la exposición a la proteína de la espiga «salvaje» de la cepa original Wuhan, moldeando su respuesta a las variantes posteriores de formas potencialmente dañinas.

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VI. Compilado de investigaciónes sobre vacunas y variantes virales del SARS-CoV2 (n=70)

Además de la patogenicidad, distribución y larga persistencia de la proteína pico de la «vacuna», esta colección de 70 artículos revisados por expertos sugiere que las “vacunas” aplicaron una fuerte presión selectiva al virus del SRAS-CoV2, que mutaba rápidamente, dando lugar rápidamente a variantes resistentes a la «vacuna».

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Acevedo-Whitehouse K and R Bruno, “Potential health risks of mRNA-based vaccine
therapy: A hypothesis,” Med. Hypotheses 2023, 171: 111015. doi:
https://doi.org/10.1016/j.mehy.2023.111015 – https://cienciaysaludnatural.com/riesgos-potenciales-para-la-salud-de-la-terapia-con-vacunas-basadas-en-arnm/
Almehdi AM et al., “SARS-CoV-2 Spike Protein: Pathogenesis, Vaccines, and
Potential Therapies,” Infection 2021, 49, 5: 855–876. doi:
https://doi.org/10.1007/s15010-021-01677-8
Baldari CT et al., “Emerging Roles of SARS-CoV-2 Spike-ACE2 in Immune Evasion
and Pathogenesis,” Trends Immunol. 2023, 44, 6. doi: 10.1016/j.it.2023.04.001
Bansal S et al., “Cutting Edge: Circulating Exosomes with COVID Spike Protein Are
Induced by BNT162b2 (Pfizer-BioNTech) Vaccination prior to Development of
Antibodies: A Novel Mechanism for Immune Activation by mRNA Vaccines,” J.
Immunol. 2021, 207, 10: 2405–2410. doi: 10.4049/jimmunol.2100637
Bellucci M et al., “Post-SARS-CoV-2 infection and post-vaccine-related neurological
complications share clinical features and the same positivity to anti-ACE2
antibodies,” Front. Immunol. 2024, 15 (Sec. Multiple Sclerosis and
Neuroimmunology). doi: https://doi.org/10.3389/fimmu.2024.1398028
Boros LG et al., “Long-lasting, biochemically modified mRNA, and its frameshifted
recombinant spike proteins in human tissues and circulation after COVID-19
vaccination,” Pharmacol Res Perspect 2024, 12, 3: e1218. doi: 10.1002/prp2.1218
Brady M et al., “Spike protein multiorgan tropism suppressed by antibodies targeting
SARS-CoV-2,” Comm. Biol. 2021, 4, 1318. doi: 10.1038/s42003-021-02856-x
Cari L et al., “Di]erences in the expression levels of SARS-CoV-2 spike protein in
cells treated with mRNA-based COVID-19 vaccines: a study on vaccines from the
real world,” Vaccines 2023, 11, 4: 879. doi: 10.3390/vaccines11040879
Cosentino M and Franca Marino, “Understanding the Pharmacology of COVID- 19
mRNA Vaccines: Playing Dice with the Spike?” Int. J. Mol. Sci. 2022, 23, 18: 10881.
doi: https://doi.org/10.3390/ijms231810881
Fertig TE et al., “Beyond the injection site: identifying the cellular targets of mRNA
vaccines,” J Cell Ident 2024, 3, 1. doi: 10.47570/joci.2024.004
Fertig TE et al., “Vaccine mRNA Can Be Detected in Blood at 15 Days Post
Vaccination,” Biomedicines 2022, 10, 7: 1538. doi: 10.3390/biomedicines10071538
Giannotta G et al., “COVID-19 mRNA Vaccines: The Molecular Basis of Some
Adverse Events,” Vaccines 2023, 11, 4: 747. doi: 10.3390/vaccines11040747
Gussow AB et al., “Genomic Determinants of Pathogenicity in SARS-CoV-2 and
Other Human Coronaviruses,” PNAS 117, 2020, 26: 15193–15199. doi:
https://doi.org/10.1073/pnas.2008176117
Halma MTJ et al., “Strategies for the Management of Spike Protein-Related
Pathology,” Microorganisms 2023, 11, 5: 1308, doi:
https://doi.org/10.3390/microorganisms11051308
Kent SJ et al., “Blood Distribution of SARS-CoV-2 Lipid Nanoparticle mRNA Vaccine
in Humans,” ACS Nano 2024, 18, 39: 27077-27089. doi: 10.1021/acsnano.4c11652
Kowarz E et al., “Vaccine-induced COVID-19 mimicry syndrome,” eLife 2022, 11:
e74974. doi: https://doi.org/10.7554/eLife.74974
Lamprinou M et al., “COVID-19 vaccines adverse events: potential molecular
mechanisms,” Immunol. Res. 2023, 71: 356-372. doi: 10.1007/s12026-023-09357-5
Lehmann KJ, “Impact of SARS-CoV-2 Spikes on Safety of Spike-Based COVID-19
Vaccinations,” Immunome Res. 2024, 20, 2: 1000267. doi: 10.35248/1745-
7580.24.20.267
Lehmann KJ, “Suspected Causes of the Specific Intolerance Profile of Spike-Based
Covid-19 Vaccines,” Med. Res. Arch 2024, 12, 9. doi: 10.18103/mra.v12i9.5704
Lesgard JF et al., “Toxicity of SARS-CoV-2 Spike Protein from the Virus and Produced
from COVID-19 mRNA or Adenoviral DNA Vaccines,” Arch Microbiol Immun 2023, 7,
3: 121- 138. doi: 10.26502/ami.936500110
Letarov AV et al., “Free SARS-CoV-2 Spike Protein S1 Particles May Play a Role in the
Pathogenesis of COVID-19 Infection,” Biochemistry (Moscow) 2021, 86, 257–261.
doi: https://doi.org/10.1134/S0006297921030032
Nuovo JG 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,” Ann.
Diagn. Pathol. 2021, 51, 151682. doi: 10.1016/j.anndiagpath.2020.151682
Pallas RM, “Innate and adaptative immune mechanisms of COVID-19 vaccines.
Serious adverse events associated with SARS-CoV-2 vaccination: A systematic
review,” Vacunas (English ed.) 2024, 25, 2: 285.e1-285.e94. doi:
https://doi.org/10.1016/j.vacune.2024.05.002
Parry PL et al., “‘Spikeopathy’: COVID-19 Spike Protein Is Pathogenic, from Both
Virus and Vaccine mRNA,” Biomedicine 2023, 11, 8: 2287. doi:
https://doi.org/10.3390/biomedicines11082287
Pateev I et al., “Biodistribution of RNA Vaccines and of Their Products: Evidence
from Human and Animal Studies,” Biomedicines 2024, 12, 1: 59.
doi: https://doi.org/10.3390/biomedicines12010059
Peluso MJ et al., “Plasma-based antigen persistence in the post-acute phase of
COVID-19,” Lancet 2024, 24, 6: E345-E347. doi: 10.1016/S1473-3099(24)00211-1
Rzymski P and Andrzej Fal, “To aspirate or not to aspirate? Considerations for the
COVID-19 vaccines,” Pharmacol. Rep 2022, 74: 1223–1227. doi:
https://doi.org/10.1007/s43440-022-00361-4
Saadi F et al., “Spike glycoprotein is central to coronavirus pathogenesis-parallel
between m-CoV and SARS-CoV-2,” Ann Neurosci. 2021, 28 (3-4): 201–218. doi:
https://doi.org/10.1177/09727531211023755
Sacco K et al., “Immunopathological signatures in multisystem inflammatory
syndrome in children and pediatric COVID-19,” Nat. Med. 2022, 28: 1050-1062. doi:
https://doi.org/10.1038/s41591-022-01724-3
Scholkmann F and CA May, “COVID-19, post-acute COVID-19 syndrome (PACS,
‘long COVID’) and post-COVID-19 vaccination syndrome (PCVS, ‘post-COVIDvacsyndrome’): Similarities and di]erences,” Pathol Res Pract. 2023, 246: 154497. doi:
https://doi.org/10.1016/j.prp.2023.154497
Schwartz L et al., “Toxicity of the spike protein of COVID-19 is a redox shift
phenomenon: A novel therapeutic approach,” Free Rad. Biol. Med. 2023, 206: 106–
doi: https://doi.org/10.1016/j.freeradbiomed.2023.05.034
Swank Z, et al. “Persistent Circulating Severe Acute Respiratory Syndrome
Coronavirus 2 Spike Is Associated With Post-acute Coronavirus Disease 2019
Sequelae,” Clin. Infect. Dis 2023, 76, 3: e487–e490. doi: 10.1093/cid/ciac722
Theoharides TC, “Could SARS-CoV-2 Spike Protein Be Responsible for Long-COVID
Syndrome?” Mol. Neurobiol. 2022, 59, 3: 1850–1861. doi: 10.1007/s12035-021-
02696-0
Theoharides TC and P. Conti, “Be Aware of SARS-CoV-2 Spike Protein: There Is More
Than Meets the Eye,” J Biol Reg Homeostat Agents 2021, 35, 3: 833–838. doi:
10.23812/THEO_EDIT_3_21
Trougakos IP et al., “Adverse E]ects of COVID-19 mRNA Vaccines: The Spike
Hypothesis,” Trends Mol Med. 2022, 28, 7: 542–554. doi:
10.1016/j.molmed.2022.04.007
Tyrkalska SD et al., “Di]erential proinflammatory activities of spike proteins of
SARS-CoV-2 variants of concern,” Sci. Adv. 2022, 8, 37: eabo0732. doi:
10.1126/sciadv.abo0732

B. ACE2

Aboudounya MM and RJ Heads, “COVID-19 and Toll-Like Receptor 4 (TLR4): SARSCoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, Facilitating Entry
and Causing Hyperinflammation,” Mediators Inflamm. 2021, 8874339. doi:
https://doi.org/10.1155/2021/8874339
Aksenova AY et al., “The increased amyloidogenicity of Spike RBD and pHdependent binding to ACE2 may contribute to the transmissibility and pathogenic
properties of SARS-CoV-2 omicron as suggested by in silico study,” Int J Mol Sci.
2022, 23, 21: 13502. doi: https://doi.org/10.3390/ijms232113502
Angeli F et al., “COVID-19, vaccines and deficiency of ACE2 and other
angiotensinases. Closing the loop on the ‘Spike e]ect’,” Eur J. Intern. Med. 2022,
103: 23–28. doi: 10.1016/j.ejim.2022.06.015
Baldari CT et al., “Emerging Roles of SARS-CoV-2 Spike-ACE2 in Immune Evasion
and Pathogenesis,” Trends Immunol. 2023, 44, 6. doi: 10.1016/j.it.2023.04.001
Bellucci M et al., “Post-SARS-CoV-2 infection and post-vaccine-related neurological
complications share clinical features and the same positivity to anti-ACE2
antibodies,” Front. Immunol. 2024, 15 (Sec. Multiple Sclerosis and
Neuroimmunology). doi: https://doi.org/10.3389/fimmu.2024.1398028
Devaux CA and L. Camoin-Jau, “Molecular mimicry of the viral spike in the SARSCoV-2 vaccine possibly triggers transient dysregulation of ACE2, leading to vascular
and coagulation dysfunction similar to SARS-CoV-2 infection,” Viruses 2023, 15, 5:
doi: https://doi.org/10.3390/v15051045
Foster K et al., “Abstract 111: Cerebrovascular E]ects Of Pre/post-losartan
Treatment In Humanized ACE2 Knock-in Mice After SARS-CoV-2 Spike Protein
Injection,” Stroke 2023, 54. doi: https://doi.org/10.1161/str.54.suppl_1.11
Gao X et al., “Spike-Mediated ACE2 Down-Regulation Was Involved in the
Pathogenesis of SARS-CoV-2 Infection,” J. Infect. 2022, 85, 4: 418–427. doi:
10.1016/j.jinf.2022.06.030
Jabi MSA et al., “Abstract 53: Covid-19 Spike-protein Causes Cerebrovascular
Rarefaction And Deteriorates Cognitive Functions In A Mouse Model Of Humanized
ACE2,” Stroke 2022, 53. doi: https://doi.org/10.1161/str.53.suppl_1.53
Kato Y et al., “TRPC3-Nox2 Protein Complex Formation Increases the Risk of SARSCoV-2 Spike Protein-Induced Cardiomyocyte Dysfunction through ACE2
Upregulation,” Int. J. Mol. Sci. 2023, 24, 1: 102. doi: 10.3390/ijms24010102
Ken W et al., “Low dose radiation therapy attenuates ACE2 depression and
inflammatory cytokines induction by COVID-19 viral spike protein in human
bronchial epithelial cells,” Int J Radiat Biol. 2022, 98, 10: 1532-1541. doi:
https://doi.org/10.1080/09553002.2022.2055806
Lei Y et al., “SARS-CoV-2 Spike Protein Impairs Endothelial Function via
Downregulation of ACE 2,” Circulation Research 2021, 128, 9: 1323–1326. doi:
https://doi.org/10.1161/CIRCRESAHA.121.318902
Lu J and PD Sun, “High a]inity binding of SARS-CoV-2 spike protein enhances ACE2
carboxypeptidase activity,” J. Biol. Chem 2020, 295, 52: p18579-18588. doi:
10.1074/jbc.RA120.015303
Maeda Y et al., “Di]erential Ability of Spike Protein of SARS-CoV-2 Variants to
Downregulate ACE2,” Int. J. Mol. Sci. 2024, 25, 2: 1353. doi: 10.3390/ijms25021353
Magro N et al., “Disruption of the blood-brain barrier is correlated with spike
endocytosis by ACE2 + endothelia in the CNS microvasculature in fatal COVID-19.
Scientific commentary on ‘Detection of blood-brain barrier disruption in brains of
patients with COVID-19, but no evidence of brain penetration by SARS-CoV-2’,” Acta
Neuropathol. 2024, 147, 1: 47. doi: https://doi.org/10.1007/s00401-023-02681-y
Montezano AC et al., “SARS-CoV-2 spike protein induces endothelial inflammation
via ACE2 independently of viral replication,” Sci Rep. 2023, 13, 1: 14086. doi:
https://doi.org/10.1038/s41598-023-41115-3
Satta S et al., “An engineered nano-liposome-human ACE2 decoy neutralizes SARSCoV-2 Spike protein-induced inflammation in both murine and human
macrophages,” Theranostics 2022, 12, 6: 2639–2657. doi: 10.7150/thno.66831
Solopov et al., “Alcohol increases lung angiotensin-converting enzyme 2 expression
and exacerbates severe acute respiratory syndrome coronavirus 2 spike protein
subunit 1-induced acute lung injury in K18-hACE2 transgenic mice,” Am J Pathol
2022, 192, 7: 990-1000. doi: 10.1016/j.ajpath.2022.03.012
Sui Y et al., “SARS-CoV-2 Spike Protein Suppresses ACE2 and Type I Interferon
Expression in Primary Cells From Macaque Lung Bronchoalveolar Lavage,” Front.
Immunol. 2021, 12. doi: https://doi.org/10.3389/fimmu.2021.658428
Tetz G and Victor Tetz, “Prion-Like Domains in Spike Protein of SARS-CoV-2 Di]er
across Its Variants and Enable Changes in A]inity to ACE2,” Microorganisms 2025,
10, 2: 280. doi: https://doi.org/10.3390/microorganisms10020280
Vargas-Castro R et al., “Calcitriol prevents SARS-CoV spike-induced inflammation
in human trophoblasts through downregulating ACE2 and TMPRSS2 expression,” J
Steroid Biochem Mol Biol 2025, 245: 106625. doi: 10.1016/j.jsbmb.2024.106625
Youn JY et al., “Therapeutic application of estrogen for COVID-19: Attenuation of
SARS-CoV-2 spike protein and IL-6 stimulated, ACE2-dependent NOX2 activation,
ROS production and MCP-1 upregulation in endothelial cells,” Redox Biol. 2021, 46:
doi: https://doi.org/10.1016/j.redox.2021.102099
Zhang S et al., “SARS-CoV-2 Binds Platelet ACE2 to Enhance Thrombosis in COVID19,” J. Hematol. Oncol. 2020, 13, 120: 120. doi: 10.1186/s13045-020-00954-7

C. Amyloid, prion-like properties

Aksenova AY et al., “The increased amyloidogenicity of Spike RBD and pHdependent binding to ACE2 may contribute to the transmissibility and pathogenic
properties of SARS-CoV-2 omicron as suggested by in silico study,” Int. J. Mol. Sci.
2022, 23, 21: 13502. doi: https://doi.org/10.3390/ijms232113502
Cao S et al., “Spike Protein Fragments Promote Alzheimer’s Amyloidogenesis,” ACS
Appl. Mater. Interfaces 2023, 15, 34: 40317-40329. doi: 10.1021/acsami.3c09815
Chakrabarti SS et al., “Rapidly Progressive Dementia with Asymmetric Rigidity
Following ChAdOx1 nCoV-19 Vaccination,” Aging Dis. 2022, 13, 3: 633-636. doi:
10.14336/AD.2021.1102
Freeborn J, “Misfolded Spike Protein Could Explain Complicated COVID-19
Symptoms,” Medical News Today, May 26, 2022,
https://www.medicalnewstoday.com/articles/misfolded-spike-protein-couldexplain-complicated-covid-19-symptoms
Idrees D and Vijay Kumar, “SARS-CoV-2 Spike Protein Interactions with
Amyloidogenic Proteins: Potential Clues to Neurodegeneration,” Biochemical and
Biophysical Research Communications 2021, 554 : 94–98. doi:
https://doi.org/10.1016/j.bbrc.2021.03.100
Hillard P et al., “Abstract WP400: SARS-CoV-2 Spike Protein Accelerates Alzheimer’s
Disease-Related Dementia Through Increased Cerebrovascular Inflammation in
hACE2 Mice,” Stroke 2025, 56. doi: https://doi.org/10.1161/str.56.suppl_1.WP400
Ma G et al., “SARS-CoV-2 Spike protein S2 subunit modulates γ-secretase and
enhances amyloid-β production in COVID-19 neuropathy,” Cell Discov 2022, 8, 99.
doi: https://doi.org/10.1038/s41421-022-00458-3
Nahalka J, “1-L Transcription of SARS-CoV-2 Spike Protein S1 Subunit,” Int. J. Mol.
Sci. 2024, 25, 8: 4440. doi: https://doi.org/10.3390/ijms25084440
Nyström S, “Amyloidogenesis of SARS-CoV-2 Spike Protein,” J. Am. Chem.
Soc. 2022, 144, 8945–8950. doi: https://doi.org/10.1021/jacs.2c03925
Petrlova J et al., “SARS-CoV-2 spike protein aggregation is triggered by bacterial
lipopolysaccharide,” FEBS Lett. 2022, 596:2566–2575. doi:
https://doi.org/10.1002/1873-3468.14490
Petruk G et al., “SARS-CoV-2 spike protein binds to bacterial lipopolysaccharide and
boosts proinflammatory activity,” J. Mol. Cell Biol. 2020, 12: 916-932. doi:
https://doi.org/10.1093/jmcb/mjaa067
Rong Z et al., “Persistence of spike protein at the skull-meninges-brain axis may
contribute to the neurological sequelae of COVID-19,” Cell Host Microbe 2024, 26:
S1931-3128(24)00438-4. doi: 10.1016/j.chom.2024.11.007
Tetz G and Victor Tetz, “Prion-Like Domains in Spike Protein of SARS-CoV-2 Di]er
across Its Variants and Enable Changes in A]inity to ACE2,” Microorganisms 2022,
10, 2: 280, doi: https://doi.org/10.3390/microorganisms10020280
Wang J et al., “SARS-CoV-2 Spike Protein S1 Domain Accelerates α-Synuclein
Phosphorylation and Aggregation in Cellular Models of Synucleinopathy,” Mol
Neurobiol. 2024, 61, 4: 2446-2458. doi: 10.1007/s12035-023-03726-9

D. Autoimmune

Anft M et al., “E]ect of immunoadsorption on clinical presentation and immune
alterations in COVID-19–induced and/or aggravated ME/CFS,” Mol. Ther. 2025, 33, 6:
2886-2899. doi: 10.1016/j.ymthe.2025.01.007
Chen Y et al., “New-onset autoimmune phenomena post-COVID-19 vaccination,”
Immunology 2022, 165, 4: 386-401. doi: https://doi.org/10.1111/imm.13443
Cheng MY et al., “Clinical Research into Central Nervous System Inflammatory
Demyelinating Diseases Related to COVID-19 Vaccines,” Diseases 2024, 12, 3: 60.
doi: https://doi.org/10.3390/diseases12030060
Diaz M et al., “SARS-CoV-2 spike peptide analysis reveals a highly conserved region
that elicits potentially pathogenic autoantibodies: implications to pan-coronavirus
vaccine development,” Front. Immunol. 2025, 16 (Sec. B Cell Biology). doi:
https://doi.org/10.3389/fimmu.2025.1488388
Elrashdy F et al., “Autoimmunity roots of the thrombotic events after COVID-19
vaccination,” Autoimmun. Rev. 2021, 20, 11: 102941. doi:
10.1016/j.autrev.2021.102941
Heil M, “Self-DNA driven inflammation in COVID-19 and after mRNA-based
vaccination: lessons for non-COVID-19 pathologies,” Front. Immunol., 2023, 14. doi:
https://doi.org/10.3389/fimmu.2023.1259879
Kanduc D, “From Anti-SARS-CoV-2 Immune Responses to COVID-19 via Molecular
Mimicry,” Antibodies 2020, 9, 3: 33. doi: https://doi.org/10.3390/antib9030033
Kanduc D and Y Shoenfeld, “Molecular mimicry between SARS-CoV-2 spike
glycoprotein and mammalian proteomes: implications for the vaccine,” Immunol
Res 2020, 68: 310-313. doi: https://doi.org/10.1007/s12026-020-09152-6
Lee AR et al., “SARS-CoV-2 spike protein promotes inflammatory cytokine activation
and aggravates rheumatoid arthritis,” Cell Commun Signal. 2023, 21, 1: 44. doi:
https://doi.org/10.1186/s12964-023-01044-0
Nunez-Castilla J et al., “Potential autoimmunity resulting from molecular mimicry
between SARS-CoV-2 spike and human proteins,” Viruses 2022, 14, 7: 1415. doi:
https://doi.org/10.3390/v14071415
Polykretis P et al., “Autoimmune Inflammatory Reactions Triggered by the COVID-19
Genetic Vaccines in Terminally Di]erentiated Tissues,” Autoimmunity 2023, 56:
doi: https://doi.org/10.1080/08916934.2023.2259123
Rodriguez Y et al., “Autoinflammatory and autoimmune conditions at the crossroad
of COVID-19,” J. Autoimmun. 2020, 114: 102506. doi: 10.1016/j.jaut.2020.102506
Vojdani A and D Kharrazian, “Potential antigenic cross-reactivity between SARSCoV-2 and human tissue with a possible link to an increase in autoimmune
diseases,” Clin Immunol. 2020, 217: 108480. doi: 10.1016/j.clim.2020.108480
Vojdani A et al., “Reaction of Human Monoclonal Antibodies to SARS-CoV-2
Proteins With Tissue Antigens: Implications for Autoimmune Diseases,” Front.
Immunol. 2021, 11 (Sec. Autoimmune and Autoinflammatory Disorders). doi:
https://doi.org/10.3389/fimmu.2020.617089

E. Blood pressure/hypertension

Angeli F et al., “The spike e]ect of acute respiratory syndrome coronavirus 2 and
coronavirus disease 2019 vaccines on blood pressure,” Eur J Intern Med. 2023, 109:
12-21. doi: 10.1016/j.ejim.2022.12.004
Sun Q et al., “SARS-coV-2 spike protein S1 exposure increases susceptibility to
angiotensin II-induced hypertension in rats by promoting central neuroinflammation
and oxidative stress,” Neurochem. Res. 2023, 48, 3016–3026.
doi: https://doi.org/10.1007/s11064-023-03949-1

F. CD147

Avolio E 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. 2021, 135, 24: 2667–
doi: https://doi.org/10.1042/CS20210735
Loh D, “The potential of melatonin in the prevention and attenuation of oxidative
hemolysis and myocardial injury from cd147 SARS-CoV-2 spike protein receptor
binding,” Melatonin Research 2020, 3, 3: 380-416. doi: 10.32794/mr11250069
Maugeri N et al., “Unconventional CD147-Dependent Platelet Activation Elicited by
SARS-CoV-2 in COVID-19,” J. Thromb. Haemost. 2021, 20, 2: 434–448.
doi: 10.1111/jth.15575

G. Cell membrane permeability, barrier dysfunction

Asandei A et al., “Non-Receptor-Mediated Lipid Membrane Permeabilization by the
SARS-CoV-2 Spike Protein S1 Subunit,” ACS Appl. Mater. Interfaces 2020, 12, 50:
55649–55658. doi: https://doi.org/10.1021/acsami.0c17044
Biancatelli RMLC, et al. “The SARS-CoV-2 spike protein subunit S1 induces COVID19-like acute lung injury in Kappa18-hACE2 transgenic mice and barrier dysfunction
in human endothelial cells,” Am. J. Physiol. Lung Cell. Mol. Physiol. 2021, 321: L477–
L484. doi: https://doi.org/10.1152/ajplung.00223.2021
Biering SB et al., “SARS-CoV-2 Spike Triggers Barrier Dysfunction and Vascular Leak
via Integrins and TGF-β Signaling,” Nat. Commun. 2022, 13: 7630. doi:
https://doi.org/10.1038/s41467-022-34910-5
Buzhdygan TP et al., “The SARS-CoV-2 Spike Protein Alters Barrier Function in 2D
Static and 3D Microfluidic in-Vitro Models of the Human Blood-Brain
Barrier,” Neurobiol. Dis. 2020, 146: 105131. doi: 10.1016/j.nbd.2020.105131
Cappalletti G et al., “iPSC-derived human cortical organoids display profound
alterations of cellular homeostasis following SARS-CoV-2 infection and Spike
protein exposure,” FASEB J 2025 39, 4: e70396. doi: 10.1096/fj.202401604RRR
Chaves JCS et al., “Di]erential Cytokine Responses of APOE3 and APOE4 Blood–
brain Barrier Cell Types to SARS-CoV-2 Spike Proteins,” J. Neuroimmune Pharmacol.
2024, 19, 22. doi: https://doi.org/10.1007/s11481-024-10127-9
Correa Y et al., “SARS-CoV-2 spike protein removes lipids from model membranes
and interferes with the capacity of high-density lipoprotein to exchange lipids,” J.
Colloid Interface Sci. 2021, 602: 732-739. doi: 10.1016/j.jcis.2021.06.056
DeOre BJ et al., “SARS-CoV-2 Spike Protein Disrupts Blood-Brain Barrier Integrity via
RhoA Activation,” J Neuroimmune Pharmacol. 2021, 16, 4:722-728. Doi:
https://doi.org/10.1007/s11481-021-10029-0
Fajloun Z et al., “COVID-19 and Ehlers-Danlos Syndrome: The Dangers of the Spike
Protein of SARS-CoV-2,” Infect. Disord. Drug Targets 2023, 23, 3: 26-28. doi:
https://doi.org/10.2174/1871526523666230104145108
Guo Y and V Kanamarlapudi, “Molecular Analysis of SARS-CoV-2 Spike ProteinInduced Endothelial Cell Permeability and vWF Secretion,” Int. J. Mol. Sci. 2023, 24,
6: 5664. doi: https://doi.org/10.3390/ijms24065664
Luchini A et al., “Lipid bilayer degradation induced by SARS-CoV-2 spike protein as
revealed by neutron reflectometry,” Sci. Rep. 2021, 11: 14867. doi:
https://doi.org/10.1038/s41598-021-93996-x
Luo Y et al., “SARS-Cov-2 spike induces intestinal barrier dysfunction through the
interaction between CEACAM5 and Galectin-9,” Front. Immunol. 2024, 15. doi:
https://doi.org/10.3389/fimmu.2024.1303356
Magro N et al., “Disruption of the blood-brain barrier is correlated with spike
endocytosis by ACE2 + endothelia in the CNS microvasculature in fatal COVID-19.
Scientific commentary on ‘Detection of blood-brain barrier disruption in brains of
patients with COVID-19, but no evidence of brain penetration by SARS-CoV-2’,” Acta
Neuropathol. 2024, 147, 1: 47. doi: https://doi.org/10.1007/s00401-023-02681-y
Raghavan S et al., “SARS-CoV-2 Spike Protein Induces Degradation of Junctional
Proteins That Maintain Endothelial Barrier Integrity,” Front. Cardiovasc.
Med. 2021, 8, 687783. doi: https://doi.org/10.3389/fcvm.2021.687783
Ruben ML 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. 2021, 321, 2: L477-L484.
doi: https://doi.org/10.1152/ajplung.00223.2021
Yang K et al., “SARS-CoV-2 spike protein receptor-binding domain perturbates
intracellular calcium homeostasis and impairs pulmonary vascular endothelial
cells, ” Signal Transduct. Target. Ther. 2023, 8, 276. doi: 10.1038/s41392-023-01556-
8

H. Cerebral, cerebrovascular, neurologic, blood-brain barrier, cognitive

Bellucci M et al., “Post-SARS-CoV-2 infection and post-vaccine-related neurological
complications share clinical features and the same positivity to anti-ACE2
antibodies,” Front. Immunol. 2024, 15 (Sec. Multiple Sclerosis and
Neuroimmunology). doi: https://doi.org/10.3389/fimmu.2024.1398028
Burnett FN et al., “SARS-CoV-2 Spike Protein Intensifies Cerebrovascular
Complications in Diabetic hACE2 Mice through RAAS and TLR Signaling Activation,”
Int. J. Mol. Sci. 2023, 24, 22: 16394. doi: https://doi.org/10.3390/ijms242216394
Choi JY et al., “SARS-CoV-2 spike S1 subunit protein-mediated increase of betasecretase 1 (BACE1) impairs human brain vessel cells,” Biochem. Biophys. Res.
Commun. 2022, 625, 20: 66-71. doi: https://doi.org/10.1016/j.bbrc.2022.07.113
Clough E et al., “Mitochondrial Dynamics in SARS-COV2 Spike Protein Treated
Human Microglia: Implications for Neuro-COVID,” J. Neuroimmune Pharmacol.
2021, 4, 16: 770–784. doi: https://doi.org/10.1007/s11481-021-10015-6
Coly M, et al., “Subacute monomelic radiculoplexus neuropathy following
Comirnaty(c) (Pfizer-BioNTech COVID-19) vaccination: A case report,” Revue
Neurologique 2023, 179, 6: 636-639. doi: 10.1016/j.neurol.2023.02.063
DeOre BJ et al., “SARS-CoV-2 Spike Protein Disrupts Blood-Brain Barrier Integrity via
RhoA Activation,” J Neuroimmune Pharmacol. 2021, 16, 4: 722-728. Doi:
https://doi.org/10.1007/s11481-021-10029-0
Erdogan MA, “Prenatal SARS-CoV-2 Spike Protein Exposure Induces Autism-Like
Neurobehavioral Changes in Male Neonatal Rats,” J Neuroimmune Pharmacol.
2023, 18, 4: 573-591. doi: 10.1007/s11481-023-10089-4
Erickson MA et al., “Blood-brain barrier penetration of non-replicating SARS-CoV-2
and S1 variants of concern induce neuroinflammation which is accentuated in a
mouse model of Alzheimer’s disease,” Brain Behav Immun 2023, 109: 251-268. doi:
https://doi.org/10.1016/j.bbi.2023.01.010
Fontes-Dantas FL, “SARS-CoV-2 Spike Protein Induces TLR4-Mediated Long- Term
Cognitive Dysfunction Recapitulating Post-COVID-19 Syndrome in Mice,” Cell
Reports 2023, 42, 3: 112189. doi: https://doi.org/10.1016/j.celrep.2023.112189
Foster K et al., “Abstract 111: Cerebrovascular E]ects Of Pre/post-losartan
Treatment In Humanized ACE2 Knock-in Mice After SARS-CoV-2 Spike Protein
Injection,” Stroke 2023, 54. doi: https://doi.org/10.1161/str.54.suppl_1.11
Frank MG et al., “Exploring the immunogenic properties of SARS-CoV-2 structural
proteins: PAMP:TLR signaling in the mediation of the neuroinflammatory and
neurologic sequelae of COVID-19,” Brain Behav Immun 2023, 111. doi:
https://doi.org/10.1016/j.bbi.2023.04.009
Frank MG et al., “SARS-CoV-2 S1 subunit produces a protracted priming of the
neuroinflammatory, physiological, and behavioral responses to a remote immune
challenge: A role for corticosteroids,” Brain Behav. Immun. 2024, 121: 87-103. doi:
https://doi.org/10.1016/j.bbi.2024.07.034
Heath SP et al., “SARS-CoV-2 Spike Protein Exacerbates Thromboembolic
Cerebrovascular Complications in Humanized ACE2 Mouse Model,” Transl Stroke
Res. 2024. doi: https://doi.org/10.1007/s12975-024-01301-5
Hillard P et al., “Abstract WP400: SARS-CoV-2 Spike Protein Accelerates Alzheimer’s
Disease-Related Dementia Through Increased Cerebrovascular Inflammation in
hACE2 Mice,” Stroke 2025, 56. doi: https://doi.org/10.1161/str.56.suppl_1.WP400
Jabi MSA et al., “Abstract 53: Covid-19 Spike-protein Causes Cerebrovascular
Rarefaction And Deteriorates Cognitive Functions In A Mouse Model Of Humanized
ACE2,” Stroke 2022, 53. doi: https://doi.org/10.1161/str.53.suppl_1.53
Khaddaj-Mallat R et al., “SARS-CoV-2 deregulates the vascular and immune
functions of brain pericytes via Spike protein,” Neurobiol. Dis. 2021, 161, 105561.
doi: https://doi.org/10.1016/j.nbd.2021.105561
Kim ES et al., “Spike Proteins of SARS-CoV-2 Induce Pathological Changes in
Molecular Delivery and Metabolic Function in the Brain Endothelial Cells,” Viruses
2021, 13, 10: 2021. doi: https://doi.org/10.3390/v13102021
Lykhmus O et al., “Immunization with 674–685 fragment of SARS-Cov-2 spike
protein induces neuroinflammation and impairs episodic memory of
mice,” Biochem. Biophys. Res. Commun. 2022, 622: 57–63. doi:
https://doi.org/10.1016/j.bbrc.2022.07.016
Magro N et al., “Disruption of the blood-brain barrier is correlated with spike
endocytosis by ACE2 + endothelia in the CNS microvasculature in fatal COVID-19.
Scientific commentary on ‘Detection of blood-brain barrier disruption in brains of
patients with COVID-19, but no evidence of brain penetration by SARS-CoV-2’,” Acta
Neuropathol. 2024, 147, 1: 47. doi: https://doi.org/10.1007/s00401-023-02681-y
Oh J et al., “SARS-CoV-2 Spike Protein Induces Cognitive Deficit and Anxiety-Like
Behavior in Mouse via Non-cell Autonomous Hippocampal Neuronal Death,”
Scientific Reports 2022, 12, 5496. doi: https://doi.org/10.1038/s41598-022-09410-7
Oka N et al., “SARS-CoV-2 S1 protein causes brain inflammation by reducing
intracerebral acetylcholine production,” iScience 2023, 26, 6: 106954. doi:
10.1016/j.isci.2023.106954
Ota N et al., “Expression of SARS-CoV-2 spike protein in cerebral Arteries:
Implications for hemorrhagic stroke Post-mRNA vaccination,” J. Clin. Neurosci.
2025, 136: 111223. doi: https://doi.org/10.1016/j.jocn.2025.111223
Peluso MJ et al., “SARS-CoV-2 and mitochondrial proteins in neural-derived
exosomes of COVID-19,” Ann Neurol 2022, 91, 6: 772-781. doi: 10.1002/ana.26350
Petrovszki D et al., “Penetration of the SARS-CoV-2 Spike Protein across the BloodBrain Barrier, as Revealed by a Combination of a Human Cell Culture Model System
and Optical Biosensing,” Biomedicines 2022, 10, 1: 188. doi:
https://doi.org/10.3390/biomedicines10010188
Posa A, “Spike protein-related proteinopathies: A focus on the neurological side of
spikeopathies,” Ann Anat. – Anatomischer Anzeiger 2025, 260: 152662. doi:
https://doi.org/10.1016/j.aanat.2025.152662
Rong Z et al., “Persistence of spike protein at the skull-meninges-brain axis may
contribute to the neurological sequelae of COVID-19,” Cell Host Microbe 2024, 26:
S1931-3128(24)00438-4. doi: 10.1016/j.chom.2024.11.007
Suprewicz L et al., “Blood-brain barrier function in response to SARS-CoV-2 and its
spike protein,” Neurol. Neurochir Pol. 2023, 57: 14–25. doi:
10.5603/PJNNS.a2023.0014
Suprewicz L et al., “Recombinant human plasma gelsolin reverses increased
permeability of the blood-brain barrier induced by the spike protein of the SARSCoV-2 virus,” J Neuroinflamm. 2022, 19, 1: 282. doi: 10.1186/s12974-022-02642-4
Wu ML et al., “Mast cell activation triggered by SARS-CoV-2 causes inflammation in
brain microvascular endothelial cells and microglia,” Front. Cell. Infect. Microbiol.
2024, 14. doi: https://doi.org/10.3389/fcimb.2024.1358873

I. Clinical pathology

Baumeier C et al., “Intramyocardial Inflammation after COVID-19 Vaccination: An
Endomyocardial Biopsy-Proven Case Series,” Int. J. Mol. Sci. 2022, 23: 6940. doi:
https://doi.org/10.3390/ijms23136940
Burkhardt A, “Pathology Conference: Vaccine-Induced Spike Protein Production in
the Brain, Organs etc., now Proven,” Report24.news. 2022,
https://report24.news/pathologie-konferenz-impfinduzierte-spike-produktion-ingehirn-u-a-organen-nun-erwiesen/
Codoni G et al., “Histological and serological features of acute liver injury after
SARS-CoV-2 vaccination,” JHP Rep. 2023, 5, 1: 100605. doi:
10.1016/j.jhepr.2022.100605
Craddock V et al., “Persistent circulation of soluble and extracellular vesicle-linked
Spike protein in individuals with postacute sequelae of COVID-19,” J Med. Virol.
2023, 95, 2: e28568. doi: https://doi.org/10.1002/jmv.28568
De Michele M et al., “Evidence of SARS-CoV-2 Spike Protein on Retrieved Thrombi
from COVID-19 Patients,” J. Hematol. Oncol. 2022, 15, 108. doi:
https://doi.org/10.1186/s13045-022-01329-w
De Sousa PMB et al., “Fatal Myocarditis following COVID-19 mRNA Immunization: A
Case Report and Di]erential Diagnosis Review,” Vaccines 2024, 12, 2: 194.
doi: https://doi.org/10.3390/vaccines12020194
Gamblicher T et al., “SARS-CoV-2 spike protein is present in both endothelial and
eccrine cells of a chilblain-like skin lesion,” J Eur Acad Dermatol Venereol. 2020, 1,
10: e187-e189. doi: https://doi.org/10.1111/jdv.16970
Gawaz A et al., “SARS-CoV-2–Induced Vasculitic Skin Lesions Are Associated with
Massive Spike Protein Depositions in Autophagosomes,” J Invest Dermatol. 2024,
144, 2: 369-377.e4. doi: https://doi.org/10.1016/j.jid.2023.07.018
Hulscher N et al., “Autopsy findings in cases of fatal COVID-19 vaccine-induced
myocarditis,” ESC Heart Failure 2024. doi: https://doi.org/10.1002/ehf2.14680
Ko CJ et al., “Discordant anti-SARS-CoV-2 spike protein and RNA staining in
cutaneous perniotic lesions suggests endothelial deposition of cleaved spike
protein,” J. Cutan Pathol 2021, 48, 1: 47–52. doi: https://doi.org/10.1111/cup.13866
Magen E et al., “Clinical and Molecular Characterization of a Rare Case of
BNT162b2 mRNA COVID-19 Vaccine-Associated Myositis,” Vaccines 2022, 10: 1135.
doi: https://doi.org/10.3390/vaccines10071135
Magro N et al., “Disruption of the blood-brain barrier is correlated with spike
endocytosis by ACE2 + endothelia in the CNS microvasculature in fatal COVID-19.
Scientific commentary on ‘Detection of blood-brain barrier disruption in brains of
patients with COVID-19, but no evidence of brain penetration by SARS-CoV-2’,” Acta
Neuropathol. 2024, 147, 1: 47. doi: https://doi.org/10.1007/s00401-023-02681-y
Matschke J et al., “Neuropathology of patients with COVID-19 in Germany: a postmortem case series,” Lancet Neurol. 2020, 19, 11: 919-929. doi: 10.1016/S1474-
4422(20)30308-2
Mörz M, “A Case Report: Multifocal Necrotizing Encephalitis and Myocarditis after
BNT162b2 mRNA Vaccination against COVID-19,” Vaccines 2022, 10, 10: 1651. doi:
https://doi.org/10.3390/vaccines10101651
Rong Z et al., “Persistence of spike protein at the skull-meninges-brain axis may
contribute to the neurological sequelae of COVID-19,” Cell Host Microbe 2024, 26:
S1931-3128(24)00438-4. doi: 10.1016/j.chom.2024.11.007
Sano H et al., “A case of persistent, confluent maculopapular erythema following a
COVID-19 mRNA vaccination is possibly associated with the intralesional spike
protein expressed by vascular endothelial cells and eccrine glands in the deep
dermis,” J. Dermatol. 2023, 50: 1208–1212. doi: 10.1111/1346-8138.16816
Sano S et al., “SARS-CoV-2 spike protein found in the acrosyringium and eccrine
gland of repetitive miliaria-like lesions in a woman following mRNA vaccination,” J.
Dermatol. 2024, 51, 9: e293-e295. doi: https://doi.org/10.1111/1346-8138.17204
Santonja C et al., “COVID-19 chilblain-like lesion: immunohistochemical
demonstration of SARS-CoV-2 spike protein in blood vessel endothelium and sweat
gland epithelium in a polymerase chain reaction-negative patient,” Br J
Dermatol. 2020, 183, 4: 778-780. doi: https://doi.org/10.1111/bjd.19338
Soares CD et al., “Oral vesiculobullous lesions as an early sign of COVID-19:
immunohistochemical detection of SARS-CoV-2 spike protein,” Br. J. Dermatol.
2021, 184, 1: e6. doi: https://doi.org/10.1111/bjd.19569
Wu H et al., “Molecular evidence suggesting the persistence of residual SARS-CoV-2
and immune responses in the placentas of pregnant patients recovered from
COVID-19,” Cell Prolif. 2021, 54, 9: e13091. doi: https://doi.org/10.1111/cpr.13091
Yamamoto M et al., “Persistent varicella zoster virus infection following mRNA
COVID-19 vaccination was associated with the presence of encoded spike protein
in the lesion,” J. Cutan Immunol. Allergy. 2022: 1-6. doi: 10.1002/cia2.12278
Yonker LM et al., “Circulating Spike Protein Detected in Post–COVID-19 mRNA
Vaccine Myocarditis,” Circulation 2023, 147, 11. doi:
https://doi.org/10.1161/CIRCULATIONAHA.122.061025
Yonker LM et al., “Multisystem inflammatory syndrome in children is driven by
zonulin-dependent loss of gut mucosal barrier,” J Clin Invest. 2021, 131, 14:
e149633. doi: https://doi.org/10.1172/JCI149633

J. Clotting, platelets, hemoglobin

Al-Kuraishy HM et al., “Changes in the Blood Viscosity in Patients With SARS-CoV-2
Infection,” Front. Med. 2022, 9: 876017. doi: 10.3389/fmed.2022.876017
Al-Kuraishy HM et al., “Hemolytic anemia in COVID-19,” Ann. Hematol. 2022, 101:
1887–1895. doi: 10.1007/s00277-022-04907-7
Appelbaum K et al., “SARS-CoV-2 spike-dependent platelet activation in COVID-19
vaccine-induced thrombocytopenia,” Blood Adv. 2022, 6: 2250–2253. doi:
10.1182/bloodadvances.2021005050
Becker RC et al., “The COVID-19 thrombus: distinguishing pathological,
mechanistic, and phenotypic features and management,” J. Thromb. Thrombolysis
2025, 58: 15-49. doi: https://doi.org/10.1007/s11239-024-03028-4
Boschi C et al., “SARS-CoV-2 Spike Protein Induces Hemagglutination: Implications
for COVID-19 Morbidities and Therapeutics and for Vaccine Adverse E]ects,” Int. J.
Biol. Macromol. 2022, 23, 24: 15480, doi: https://doi.org/10.3390/ijms232415480
Bye AP et al., “Aberrant glycosylation of anti-SARS-CoV-2 spike IgG is a
prothrombotic stimulus for platelets,” Blood 2021, 138, 6: 1481–9. doi:
https://doi.org/10.1182/blood.2021011871
Carnevale R et al., “Toll-Like Receptor 4-Dependent Platelet-Related Thrombosis in
SARS-CoV-2 Infection,” Circ. Res. 2023, 132, 3: 290– 305. doi:
https://doi.org/10.1161/CIRCRESAHA.122.321541
Cossenza LC et al., “Inhibitory e]ects of SARS-CoV-2 spike protein and BNT162b2
vaccine on erythropoietin-induced globin gene expression in erythroid precursor
cells from patients with β-thalassemia,” Exp. Hematol. 2024, 129, 104128. doi:
https://doi.org/10.1016/j.exphem.2023.11.002
De Michele M et al., “Vaccine-induced immune thrombotic thrombocytopenia: a
possible pathogenic role of ChAdOx1 nCoV-19 vaccine-encoded soluble SARS-CoV2 spike protein,” Haematologica 2022, 107, 7: 1687–92. doi:
https://doi.org/10.3324/haematol.2021.280180
Elrashdy F et al., “Autoimmunity roots of the thrombotic events after COVID-19
vaccination,” Autoimmun. Rev. 2021, 20, 11: 102941. doi:
10.1016/j.autrev.2021.102941
Gasparello J et al., “Assessing the interaction between hemoglobin and the receptor
binding domain of SARS-CoV-2 spike protein through MARTINI coarse-grained
molecular dynamics,” Int. J. Biol. Macromol., 2023, 253: 127088.
doi: 10.1016/j.ijbiomac.2023.127088
Grobbelaar LM et al., “SARS-CoV-2 Spike Protein S1 Induces Fibrin(ogen) Resistant
to Fibrinolysis: Implications for Microclot Formation in COVID-19,” Biosicence
Reports 2021, 41, 8: BSR20210611. doi: https://doi.org/10.1042/BSR20210611
Heath SP et al., “SARS-CoV-2 Spike Protein Exacerbates Thromboembolic
Cerebrovascular Complications in Humanized ACE2 Mouse Model,” Transl Stroke
Res. 2024. doi: https://doi.org/10.1007/s12975-024-01301-5
Iba T and JH Levy, “The roles of platelets in COVID-19-associated coagulopathy and
vaccine-induced immune thrombotic thrombocytopenia,” Trends Cardiovasc Med.
2022, 32, 1: 1-9. doi: https://doi.org/10.1016/j.tcm.2021.08.012
Huynh TV et al., “Spike Protein of SARS-CoV-2 Activates Cardiac Fibrogenesis
through NLRP3 Inflammasomes and NF-κB Signaling,” Cells 2024, 13, 16: 1331.
doi: https://doi.org/10.3390/cells13161331
Iba T and JH Levy, “The roles of platelets in COVID-19-associated coagulopathy and
vaccine-induced immune thrombotic thrombocytopenia,” Trends Cardiovasc Med.
2022, 32, 1: 1-9. doi: https://doi.org/10.1016/j.tcm.2021.08.012
Jana S et al., “Cell-free hemoglobin does not attenuate the e]ects of SARS-CoV-2
spike protein S1 subunit in pulmonary endothelial cells,” Int. J. Mol. Sci. 2021, 22,
16: 9041. doi: https://doi.org/10.3390/ijms22169041
Kim SY et al., “Characterization of heparin and severe acute respiratory syndromerelated coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions,” Antivir
Res. 2020, 181: 104873. doi: https://doi.org/10.1016/j.antiviral.2020.104873
Kircheis R, “Coagulopathies after Vaccination against SARS-CoV-2 May Be Derived
from a Combined E]ect of SARS-CoV-2 Spike Protein and Adenovirus VectorTriggered Signaling Pathways,” Int. J. Mol. Sci. 2021, 22, 19: 10791. doi:
https://doi.org/10.3390/ijms221910791
Kuhn CC et al. “Direct Cryo-ET observation of platelet deformation induced by
SARS-CoV-2 spike protein,” Nat. Commun. 2023, 14, 620. doi:
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Li T et al., “Platelets Mediate Inflammatory Monocyte Activation by SARS-CoV-2
Spike Protein,” J. Clin. Invest. 2022, 132, 4: e150101. doi: 10.1172/JCI150101
Maugeri N et al., “Unconventional CD147-Dependent Platelet Activation Elicited by
SARS-CoV-2 in COVID-19,” J. Thromb. Haemost. 2021, 20, 2: 434–448, doi:
https://doi.org/10.1111/jth.15575
Ota N et al., “Expression of SARS-CoV-2 spike protein in cerebral Arteries:
Implications for hemorrhagic stroke Post-mRNA vaccination,” J. Clin. Neurosci.
2025, 136: 111223. doi: https://doi.org/10.1016/j.jocn.2025.111223
Passariello M et al., “Interactions of Spike-RBD of SARS-CoV-2 and Platelet Factor 4:
New Insights in the Etiopathogenesis of Thrombosis,” Int. J. Mol. Sci. 2021, 22, 16:
doi: https://doi.org/10.3390/ijms22168562
Perico L et al., “SARS-CoV-2 Spike Protein 1 Activates Microvascular Endothelial
Cells and Complement System Leading to Platelet Aggregation,” Front.
Immunol. 2022, 13, 827146. doi: https://doi.org/10.3389/fimmu.2022.827146
Roytenberg R et al., “Thymidine phosphorylase mediates SARS-CoV-2 spike protein
enhanced thrombosis in K18-hACE2TG mice,” Thromb. Res. 2024, 244, 8: 109195.
doi: 10.1016/j.thromres.2024.109195
Russo A, et al., “Implication of COVID-19 on Erythrocytes Functionality: Red Blood
Cell Biochemical Implications and Morpho-Functional Aspects,” Int. J. Mol.
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Ryu JK et al., “Fibrin drives thromboinflammation and neuropathology in COVID-19,”
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Scheim, DE. “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. 2022, 23, 5: 2558. doi: 10.3390/ijms23052558
Scheim DE et al., “Sialylated Glycan Bindings from SARS-CoV-2 Spike Protein to
Blood and Endothelial Cells Govern the Severe Morbidities of COVID-19,” Int. J. Mol.
Sci. 2023, 24, 23: 17039. doi: https://doi.org/10.3390/ijms242317039
Sirsendu J et al., “Cell-Free Hemoglobin Does Not Attenuate the E]ects of SARSCoV-2 Spike Protein S1 Subunit in Pulmonary Endothelial Cells,” Int. J. Mol. Sci.,
2021, 22, 16: 9041. doi: https://doi.org/10.3390/ijms22169041
Zhang S et al., “SARS-CoV-2 Binds Platelet ACE2 to Enhance Thrombosis in COVID19,” J. Hematol. Oncol. 2020, 13, 120: 120. doi: 10.1186/s13045-020-00954-7
Zhang Z et al., “SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte
elimination,” Cell Death Diber. 2021, 28, 2765–2777. doi: 10.1038/s41418-021-
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Zheng Y 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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K. Cytokines, chemokines, inteferon, interleukins

Alghmadi A et al., “Altered Circulating Cytokine Profile Among mRNA-Vaccinated
Young Adults: A Year-Long Follow-Up Study,” Immun. Inflamm. Dis. 2025, 13, 4:
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Ao Z et al., “SARS-CoV-2 Delta spike protein enhances the viral fusogenicity and
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Azzarone B et al., “Soluble SARS-CoV-2 Spike glycoprotein: considering some
potential pathogenic e]ects,” Front. Immunol. 2025, 16 (Sec. Cytokines and Soluble
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Chaves JCS et al., “Di]erential Cytokine Responses of APOE3 and APOE4 Blood–
brain Barrier Cell Types to SARS-CoV-2 Spike Proteins,” J. Neuroimmune Pharmacol.
2024, 19, 22. doi: https://doi.org/10.1007/s11481-024-10127-9
Chittasupho C et al., “Targeting spike glycoprotein S1 mediated by NLRP3
inflammasome machinery and the cytokine releases in A549 lung epithelial cells by
nanocurcumin,” Pharmaceuticals (Basel) 2023, 16, 6: 862. doi:
10.3390/ph16060862
Das T et al., “N-glycosylation of the SARS-CoV-2 spike protein at Asn331 and Asn343
is involved in spike-ACE2 binding, virus entry, and regulation of IL-6,” Microbiol.
Immunol. 2024, 68, 5: 165-178. doi: https://doi.org/10.1111/1348-0421.13121
Duarte C, “Age-dependent e]ects of the recombinant spike protein/SARS-CoV-2 on
the M-CSF- and IL-34-di]erentiated macrophages in vitro,” Biochem. Biophys. Res.
Commun. 2021, 546: 97–102. doi: https://doi.org/10.1016/j.bbrc.2021.01.104
Forsyth CB et al., “The SARS-CoV-2 S1 spike protein promotes MAPK and NF-kB
activation in human lung cells and inflammatory cytokine production in human lung
and intestinal epithelial cells,” Microorganisms 2022, 10, 10: 1996.
doi: https://doi.org/10.3390/microorganisms10101996
Freitas RS et al., “SARS-CoV-2 Spike antagonizes innate antiviral immunity by
targeting interferon regulatory factor 3,” Front Cell Infect Microbiol. 2021, 11:
doi: https://doi.org/10.3389/fcimb.2021.789462
Gasparello J et al., “In vitro induction of interleukin-8 by SARS-CoV-2 Spike protein is
inhibited in bronchial epithelial IB3-1 cells by a miR-93-5p agomiR,” Int.
Immunopharmacol. 2021, 101: 108201. doi: 10.1016/j.intimp.2021.108201
Gasparello J et al., “Sulforaphane inhibits the expression of interleukin-6 and
interleukin-8 induced in bronchial epithelial IB3-1 cells by exposure to the SARSCoV-2 Spike protein,” Phytomedicine 2021, 87: 153583. doi:
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Ghazanfari D et al., “Mechanistic insights into SARS-CoV-2 spike protein induction
of the chemokine CXCL10,” Sci. Rep. 2024, 14: 11179. doi: 10.1038/s41598-024-
61906-6
Gracie NP et al., “Cellular signalling by SARS-CoV-2 spike protein,” Microbiology
Australia 2024, 45, 1: 13-17. doi: https://doi.org/10.1071/MA24005
Gu T et al., “Cytokine Signature Induced by SARS-CoV-2 Spike Protein in a Mouse
Model,” Front. Immunol., 2021 (Sec. Inflammation). doi:
10.3389/fimmu.2020.621441
Jugler C et al, “SARS-CoV-2 Spike Protein-Induced Interleukin 6 Signaling Is Blocked
by a Plant-Produced Anti-Interleukin 6 Receptor Monoclonal Antibody,”
Vaccines 2021, 9, 11: 1365. https://doi.org/10.3390/vaccines9111365
Kawata D et al., “Diverse pro-inflammatory ability of mutated spike protein derived
from variant strains of SARS-CoV-2,” Cytokine 2024, 178: 156592. doi:
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Lee AR et al., “SARS-CoV-2 spike protein promotes inflammatory cytokine activation
and aggravates rheumatoid arthritis,” Cell Commun Signal. 2023, 21, 1: 44. doi:
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Liang S et al., “SARS-CoV-2 spike protein induces IL-18-mediated cardiopulmonary
inflammation via reduced mitophagy,” Signal Transduct Target Ther 2023, 8, 103. doi:
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Liu T et al., “RS-5645 attenuates inflammatory cytokine storm induced by SARSCoV-2 spike protein and LPS by modulating pulmonary microbiota,” Int. J. Biol. Sci.
2021, 17, 13: 3305–3319. doi: 10.7150/ijbs.63329
Liu X et al., “SARS-CoV-2 spike protein-induced cell fusion activates the cGASSTING pathway and the interferon response,” Sci Signal. 2022, 15, 729: eabg8744.
doi: 10.1126/scisignal.abg8744
Niu C et al., “SARS-CoV-2 spike protein induces the cytokine release syndrome by
stimulating T cells to produce more IL-2,” Front. Immunol. 2024, 15: 1444643. doi:
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Norris B et al., “Evaluation of Glutathione in Spike Protein of SARS-CoV-2 Induced
Immunothrombosis and Cytokine Dysregulation,” Antioxidants 2024, 13, 3: 271.
doi: https://doi.org/10.3390/antiox13030271
Olajide OA et al., “Induction of Exaggerated Cytokine Production in Human
Peripheral Blood Mononuclear Cells by a Recombinant SARS-CoV-2 Spike
Glycoprotein S1 and Its Inhibition by Dexamethasone,” Inflammation 2021, 44:
1865–1877. doi: https://doi.org/10.1007/s10753-021-01464-5
Park YJ et al., “D-dimer and CoV-2 spike-immune complexes contribute to the
production of PGE2 and proinflammatory cytokines in monocytes,” PLoS
Pathog., 2022, 18, 4: e1010468. doi: https://doi.org/10.1371/journal.ppat.1010468
Patra T et al., “SARS-CoV-2 spike protein promotes IL-6 trans-signaling by activation
of angiotensin II receptor signaling in epithelial cells,” PLoS Pathog. 2020, 16:
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Samsudin S et al., “SARS-CoV-2 spike protein as a bacterial lipopolysaccharide
delivery system in an overzealous inflammatory cascade,” J. Mol. Biol. 2022, 14, 9:
mjac058. doi: https://doi.org/10.1093/jmcb/mjac058
Schroeder JT and AP Bieneman, “The S1 Subunit of the SARS-CoV-2 Spike protein
activates human monocytes to produce cytokines linked to COVID-19: relevance to
galectin-3,” Front Immunol. 2022, 13: 831763. doi: 10.3389/fimmu.2022.831763
Sebastio AI et al., “CuMV VLPs containing the RBM from SARS-CoV-2 spike protein
drive dendritic cell activation and Th1 polarization,” Pharmaceutics 2023, 15, 3: 825.
doi: https://doi.org/10.3390/pharmaceutics15030825
Sharma VK et al., “Nanocurcumin Potently Inhibits SARS-CoV-2 Spike ProteinInduced Cytokine Storm by Deactivation of MAPK/NF-κB Signaling in Epithelial
Cells,” ACS Appl. Bio Mater. 2022, 5, 2: 483–491. doi: 10.1021/acsabm.1c00874
Sui Y et al., “SARS-CoV-2 Spike Protein Suppresses ACE2 and Type I Interferon
Expression in Primary Cells From Macaque Lung Bronchoalveolar Lavage,” Front.
Immunol. 2021, 12. doi: https://doi.org/10.3389/fimmu.2021.658428
Tsilioni I et al., “Nobiletin and Eriodictyol Suppress Release of IL-1β, CXCL8, IL-6,
and MMP-9 from LPS, SARS-CoV-2 Spike Protein, and Ochratoxin A-Stimulated
Human Microglia,” Int. J. Mol. Sci. 2025, 26, 2: 636. doi: 10.3390/ijms26020636
Tsilioni S et al., “Recombinant SARS-CoV-2 spike protein and its receptor binding
domain stimulate release of di]erent pro-inflammatory mediators via activation of
distinct receptors on human microglia cells,” Mol Neurobiol. 2023, 60, 11: 6704–14.
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Tsilioni S et al., “Recombinant SARS-CoV-2 Spike Protein Stimulates Secretion of
Chymase, Tryptase, and IL-1beta from Human Mast Cells, Augmented by IL-33,” Int.
J. Mol. Sci. 2023, 24, 11: 9487. doi: https://doi.org/10.3390/ijms24119487
Youn JY et al., “Therapeutic application of estrogen for COVID-19: Attenuation of
SARS-CoV-2 spike protein and IL-6 stimulated, ACE2-dependent NOX2 activation,
ROS production and MCP-1 upregulation in endothelial cells,” Redox Biol. 2021, 46:
doi: https://doi.org/10.1016/j.redox.2021.102099
Zhang Q et al., “Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
membrane (M) and spike (S) proteins antagonize host type i interferon response,”
Front Cell Infect Microbiol 2021, 11: 766922. doi: 10.3389/fcimb.2021.766922
Zhang RG et al., “SARS-CoV-2 spike protein receptor binding domain promotes IL-6
and IL-8 release via ATP/P2Y2 and ERK1/2 signaling pathways in human bronchial
epithelia,” Mol. Immunol. 2024, 167: 53-61. doi: 10.1016/j.molimm.2024.02.005

L. Endothelial

Bhargavan B and GD Kanmogne, “SARS-CoV-2 spike proteins and cell–cell
communication inhibits TFPI and induces thrombogenic factors in human lung
microvascular endothelial cells and neutrophils: implications for COVID-19
coagulopathy pathogenesis,” Int. J. Mol. Sci. 2022, 23, 18: 10436. doi:
https://doi.org/10.3390/ijms231810436
Biancatelli RMLC, et al. “The SARS-CoV-2 spike protein subunit S1 induces COVID19-like acute lung injury in Kappa18-hACE2 transgenic mice and barrier dysfunction
in human endothelial cells,” Am. J. Physiol. Lung Cell. Mol. Physiol. 2021, 321: L477–
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Castro-Robles B et al., “Distinct response patterns of endothelial markers to the
BNT162b2 mRNA COVID-19 booster vaccine are associated with the spike-specific
IgG antibody production,” Front. Immunol. 2025, 15 (Sec. Vaccines and Molecular
Therapeutics). doi: https://doi.org/10.3389/fimmu.2024.1471401
Du Preez HN et al., “COVID-19 vaccine adverse events: Evaluating the
pathophysiology with an emphasis on sulfur metabolism and endotheliopathy,” Eur
J Clin Invest. 2024, 54, 10: e14296. doi: https://doi.org/10.1111/eci.14296
Gamblicher T et al., “SARS-CoV-2 spike protein is present in both endothelial and
eccrine cells of a chilblain-like skin lesion,” J Eur Acad Dermatol Venereol. 2020, 1,
10: e187-e189. doi: https://doi.org/10.1111/jdv.16970
Gultom M et al., “Sustained Vascular Inflammatory E]ects of SARS-CoV-2 Spike
Protein on Human Endothelial Cells,” Inflammation 2024. doi:
https://doi.org/10.1007/s10753-024-02208-x
Guo Y and V Kanamarlapudi, “Molecular Analysis of SARS-CoV-2 Spike ProteinInduced Endothelial Cell Permeability and vWF Secretion,” Int. J. Mol. Sci. 2023, 24,
6: 5664. doi: https://doi.org/10.3390/ijms24065664
Jana S et al., “Cell-free hemoglobin does not attenuate the e]ects of SARS-CoV-2
spike protein S1 subunit in pulmonary endothelial cells,” Int. J. Mol. Sci. 2021, 22,
16: 9041. doi: https://doi.org/10.3390/ijms22169041
Kulkoviene G et al., “Di]erential Mitochondrial, Oxidative Stress and Inflammatory
Responses to SARS-CoV-2 Spike Protein Receptor Binding Domain in Human Lung
Microvascular, Coronary Artery Endothelial and Bronchial Epithelial Cells,” Int. J.
Mol. Sci. 2024, 25, 6: 3188. doi: https://doi.org/10.3390/ijms25063188
Marrone L et al., “Tirofiban prevents the e]ects of SARS-CoV-2 spike protein on
macrophage activation and endothelial cell death,” Heliyon, 2024, 10, 15, e35341.
doi: 10.1016/j.heliyon.2024.e35341
Meyer K et al., “SARS-CoV-2 Spike Protein Induces Paracrine Senescence and
Leukocyte Adhesion in Endothelial Cells,” J. Virol. 2021, 95: e0079421. doi:
https://doi.org/10.1128/jvi.00794-21
Montezano AC et al., “SARS-CoV-2 spike protein induces endothelial inflammation
via ACE2 independently of viral replication,” Sci Rep. 2023, 13, 1: 14086. doi:
https://doi.org/10.1038/s41598-023-41115-3
Nuovo JG 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,” Ann.
Diagn. Pathol. 2021, 51, 151682. doi: 10.1016/j.anndiagpath.2020.151682
Perico L et al., “SARS-CoV-2 and the spike protein in endotheliopathy,” Trends
Microbiol. 2024, 32, 1: 53-67. doi: 10.1016/j.tim.2023.06.004
Perico L et al., “SARS-CoV-2 Spike Protein 1 Activates Microvascular Endothelial
Cells and Complement System Leading to Platelet Aggregation,” Front.
Immunol. 2022, 13, 827146. doi: https://doi.org/10.3389/fimmu.2022.827146
Raghavan S et al., “SARS-CoV-2 Spike Protein Induces Degradation of Junctional
Proteins That Maintain Endothelial Barrier Integrity,” Front. Cardiovasc.
Med. 2021, 8, 687783. doi: https://doi.org/10.3389/fcvm.2021.687783
Ratajczak MZ et al., “SARS-CoV-2 Entry Receptor ACE2 Is Expressed on Very Small
CD45- Precursors of Hematopoietic and Endothelial Cells and in Response to Virus
Spike Protein Activates the Nlrp3 Inflammasome,” Stem Cell Rev Rep. 2021, 17, 1:
266-277. doi: https://doi.org/10.1007/s12015-020-10010-z
Robles JP et al., “The Spike Protein of SARS-CoV-2 Induces Endothelial
Inflammation through Integrin α5β1 and NF-κB Signaling,” J. Biol. Chem. 2022, 298,
3: 101695. doi: https://doi.org/10.1016/j.jbc.2022.101695
Rotoli BM et al., “Endothelial cell activation by SARS-CoV-2 spike S1 protein: A
crosstalk between endothelium and innate immune cells,” Biomedicines 2021, 9, 9:
doi: https://doi.org/10.3390/biomedicines9091220
Ruben ML 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. 2021, 321, 2: L477-L484.
doi: https://doi.org/10.1152/ajplung.00223.2021
Sano H et al., “A case of persistent, confluent maculopapular erythema following a
COVID-19 mRNA vaccination is possibly associated with the intralesional spike
protein expressed by vascular endothelial cells and eccrine glands in the deep
dermis,” J. Dermatol. 2023, 50: 1208–1212. doi: 10.1111/1346-8138.16816
Santonja C et al., “COVID-19 chilblain-like lesion: immunohistochemical
demonstration of SARS-CoV-2 spike protein in blood vessel endothelium and sweat
gland epithelium in a polymerase chain reaction-negative patient,” Br J
Dermatol. 2020, 183, 4: 778-780. doi: https://doi.org/10.1111/bjd.19338
Scheim DE et al., “Sialylated Glycan Bindings from SARS-CoV-2 Spike Protein to
Blood and Endothelial Cells Govern the Severe Morbidities of COVID-19,” Int. J. Mol.
Sci. 2023, 24, 23: 17039. doi: https://doi.org/10.3390/ijms242317039
Sirsendu J et al., “Cell-Free Hemoglobin Does Not Attenuate the E]ects of SARSCoV-2 Spike Protein S1 Subunit in Pulmonary Endothelial Cells,” Int. J. Mol. Sci.,
2021, 22, 16: 9041. doi: https://doi.org/10.3390/ijms22169041
Stern B et al., “SARS-CoV-2 spike protein induces endothelial dysfunction in 3D
engineered vascular networks,” J. Biomed. Mater. Res. A. 2023, 112, 4: 524-533. doi:
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Villacampa A et al., “SARS-CoV-2 S protein activates NLRP3 inflammasome and
deregulates coagulation factors in endothelial and immune cells,” Cell Commun.
Signal. 2024, 22, 38. doi: https://doi.org/10.1186/s12964-023-01397-6
Wu ML et al., “Mast cell activation triggered by SARS-CoV-2 causes inflammation in
brain microvascular endothelial cells and microglia,” Front. Cell. Infect. Microbiol.
2024, 14. doi: https://doi.org/10.3389/fcimb.2024.1358873
Yang K et al., “SARS-CoV-2 spike protein receptor-binding domain perturbates
intracellular calcium homeostasis and impairs pulmonary vascular endothelial
cells,” Signal Transduct. Target. Ther. 2023, 8, 276. doi: 10.1038/s41392-023-01556-
8
Youn JY et al., “Therapeutic application of estrogen for COVID-19: Attenuation of
SARS-CoV-2 spike protein and IL-6 stimulated, ACE2-dependent NOX2 activation,
ROS production and MCP-1 upregulation in endothelial cells,” Redox Biol. 2021, 46:
doi: https://doi.org/10.1016/j.redox.2021.102099
Zekri-Nechar K et al., “Spike Protein Subunits of SARS-CoV-2 Alter Mitochondrial
Metabolism in Human Pulmonary Microvascular Endothelial Cells: Involvement of
Factor Xa,” Dis. Markers 2022, 1118195. doi: https://doi.org/10.1155/2022/1118195

M. Gastrointestinal

Forsyth CB et al., “The SARS-CoV-2 S1 spike protein promotes MAPK and NF-kB
activation in human lung cells and inflammatory cytokine production in human lung
and intestinal epithelial cells,” Microorganisms 2022, 10, 10: 1996.
doi: https://doi.org/10.3390/microorganisms10101996
Li Z et al., “SARS-CoV-2 pathogenesis in the gastrointestinal tract mediated by
Spike-induced intestinal inflammation,” Precis. Clin. Med. 2024, 7, 1: pbad034. doi:
https://doi.org/10.1093/pcmedi/pbad034
Luo Y et al., “SARS-Cov-2 spike induces intestinal barrier dysfunction through the
interaction between CEACAM5 and Galectin-9,” Front. Immunol. 2024, 15. doi:
https://doi.org/10.3389/fimmu.2024.1303356
Nascimento RR et al., “SARS-CoV-2 Spike protein triggers gut impairment since
mucosal barrier to innermost layers: From basic science to clinical relevance,”
Mucosal Immunol. 2024, 17, 4: 565-583. doi: 10.1016/j.mucimm.2024.03.00
Yilmaz A et al., “Di]erential proinflammatory responses of colon epithelial cells to
SARS-CoV-2 spike protein and Pseudomonas aeruginosa lipopolysaccharide,” Turk J
Biochem. 2024. doi: https://doi.org/10.1515/tjb-2024-0144
Yonker LM et al., “Multisystem inflammatory syndrome in children is driven by
zonulin-dependent loss of gut mucosal barrier,” J Clin Invest. 2021, 131, 14:
e149633. doi: https://doi.org/10.1172/JCI149633
Zeng FM et al., “SARS-CoV-2 spike spurs intestinal inflammation via VEGF
production in enterocytes,” EMBO Mol Med. 2022, 14: e14844. doi:
https://doi.org/10.15252/emmm.202114844
Zollner A et al., “Postacute COVID-19 is Characterized by Gut Viral Antigen
Persistence in Inflammatory Bowel Diseases,” Gastroenterology 2022, 163, 2: 495-
506.e8. doi: https://doi.org/10.1053/j.gastro.2022.04.037

N. Immune dysfunction

Baldari CT et al., “Emerging Roles of SARS-CoV-2 Spike-ACE2 in Immune Evasion
and Pathogenesis,” Trends Immunol. 2023, 44, 6. doi: 10.1016/j.it.2023.04.001
Bocquet-Garcon A, “Impact of the SARS-CoV-2 Spike Protein on the Innate Immune
System: A Review,” Cureus 2024, 16, 3: e57008. doi: 10.7759/cureus.57008
Delgado JF et al., “SARS-CoV-2 spike protein vaccine-induced immune imprinting
reduces nucleocapsid protein antibody response in SARS-CoV-2 infection,” J.
Immunol. Res. 2022: 8287087. doi: https://doi.org/10.1155/2022/8287087
Freitas RS et al., “SARS-CoV-2 Spike antagonizes innate antiviral immunity by
targeting interferon regulatory factor 3,” Front Cell Infect Microbiol. 2021, 11:
doi: https://doi.org/10.3389/fcimb.2021.789462
Irrgang P et al., “Class switch toward noninflammatory, spike-specific IgG4
antibodies after repeated SARS-CoV-2 mRNA vaccination,” Sci. Immunol. 2022, 8,
doi: 10.1126/sciimmunol.ade2798
Kim MJ et al., “The SARS-CoV-2 spike protein induces lung cancer migration and
invasion in a TLR2-dependent manner,” Cancer Commun (London), 2023, 44, 2:
273–277. doi: https://doi.org/10.1002/cac2.12485
Onnis A et al., “SARS-CoV-2 Spike protein suppresses CTL-mediated killing by
inhibiting immune synapse assembly,” J Exp Med 2023, 220, 2: e20220906. doi:
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Tu TH et al., “The identification of a SARs-CoV2 S2 protein derived peptide with
super-antigen-like stimulatory properties on T-cells,” Commun. Biol. 2025, 8, 14.
doi: https://doi.org/10.1038/s42003-024-07350-8

O. Macrophages, monocytes, neutrophils

Ahn WM et al., “SARS-CoV-2 Spike Protein Stimulates Macropinocytosis in Murine
and Human Macrophages via PKC-NADPH Oxidase Signaling,”
Antioxidants 2024, 13, 2: 175. doi: https://doi.org/10.3390/antiox13020175
Ait-Belkacem I et al., “SARS-CoV-2 spike protein induces a di]erential monocyte
activation that may contribute to age bias in COVID-19 severity,” Sci. Rep. 2022, 12:
doi: https://doi.org/10.1038/s41598-022-25259-2
Barhoumi T et al., “SARS-CoV-2 coronavirus Spike protein-induced apoptosis,
inflammatory, and oxidative stress responses in THP-1-like-macrophages: potential
role of angiotensin-converting enzyme inhibitor (perindopril),” Front. Immunol.
2021, 12: 728896. doi: https://doi.org/10.3389/fimmu.2021.728896
Bortolotti D et al., “SARS-CoV-2 Spike 1 Protein Controls Natural Killer Cell
Activation via the HLA-E/NKG2A Pathway,” Cells 2020, 9, 9: 1975.
doi: https://doi.org/10.3390/cells9091975
Cao X et al., “Spike protein of SARS-CoV-2 activates macrophages and contributes
to induction of acute lung inflammation in male mice,” FASEB J. 2021, 35, e21801.
doi: https://doi.org/10.1096/fj.202002742RR
Chiok K et al., “Proinflammatory Responses in SARS-CoV-2 and Soluble Spike
Glycoprotein S1 Subunit Activated Human Macrophages,” Viruses 2023, 15, 3: 754.
doi: https://doi.org/10.3390/v15030754
Cory TJ et al., “Metformin Suppresses Monocyte Immunometabolic Activation by
SARS-CoV-2 Spike Protein Subunit 1,” Front. Immunol. 2021, 12 (Sec. Cytokines and
Soluble Mediators in Immunity): 733921. doi: 10.3389/fimmu.2021.733921
Del Re A et al., “Ultramicronized Palmitoylethanolamide Inhibits NLRP3
Inflammasome Expression and Pro-Inflammatory Response Activated by SARSCoV-2 Spike Protein in Cultured Murine Alveolar Macrophages,”
Metabolites 2021, 11, 9: 592. doi: https://doi.org/10.3390/metabo11090592
Duarte C, “Age-dependent e]ects of the recombinant spike protein/SARS-CoV-2 on
the M-CSF- and IL-34-di]erentiated macrophages in vitro,” Biochem. Biophys. Res.
Commun. 2021, 546: 97–102. doi: https://doi.org/10.1016/j.bbrc.2021.01.104
Fajloun Z et al., “Unveiling the Role of SARS-CoV-2 or mRNA Vaccine Spike Protein in
Macrophage Activation Syndrome (MAS),” Infect. Disord. Drug Targets 2025, 25, 2:
E220724232138. doi: https://doi.org/10.2174/0118715265341206240722050403
Karwaciak I et al., “Nucleocapsid and Spike Proteins of the Coronavirus Sars-Cov-2
Induce Il6 in Monocytes and Macrophages—Potential Implications for Cytokine
Storm Syndrome,” Vaccines 2021, 9, 1, 54: 1–10. doi: 10.3390/vaccines9010054
Li T et al., “Platelets Mediate Inflammatory Monocyte Activation by SARS-CoV-2
Spike Protein,” J. Clin. Invest. 2022, 132, 4: e150101. doi: 10.1172/JCI150101
Liu Y et al., “The recombinant spike S1 protein induces injury and inflammation in
co-cultures of human alveolar epithelial cells and macrophages,” PLoS ONE 2025,
20, 2: e0318881. doi: https://doi.org/10.1371/journal.pone.0318881
Loh JT et al., “Dok3 restrains neutrophil production of calprotectin during TLR4
sensing of SARS-CoV-2 spike protein,” Front. Immunol. 2022, 13 (Sec. Molecular
Innate Immunity). doi: https://doi.org/10.3389/fimmu.2022.996637
Marrone L et al., “Tirofiban prevents the e]ects of SARS-CoV-2 spike protein on
macrophage activation and endothelial cell death,” Heliyon, 2024, 10, 15: e35341.
doi: 10.1016/j.heliyon.2024.e35341
Miller GM et al., “SARS-CoV-2 and SARS-CoV-2 Spike protein S1 subunit Trigger
Proinflammatory Response in Macrophages in the Absence of Productive Infection,”
J. Immunol. 2023, 210 (1_Supplement): 71.30. doi:
10.4049/jimmunol.210.Supp.71.30
Onnis A et al., “SARS-CoV-2 Spike protein suppresses CTL-mediated killing by
inhibiting immune synapse assembly,” J Exp Med 2023, 220, 2: e20220906. doi:
https://doi.org/10.1084/jem.20220906
Palestra F et al. “SARS-CoV-2 Spike Protein Activates Human Lung
Macrophages,” Int. J. Mol. Sci. 2023, 24, 3: 3036. doi: 10.3390/ijms24033036
Park C et al., “Murine alveolar Macrophages Rapidly Accumulate intranasally
Administered SARS-CoV-2 Spike Protein leading to neutrophil Recruitment and
Damage,” Elife 2024, 12, RP86764. doi: https://doi.org/10.7554/eLife.86764.3
Park YJ et al., “D-dimer and CoV-2 spike-immune complexes contribute to the
production of PGE2 and proinflammatory cytokines in monocytes,” PLoS
Pathog. 2022, 18, 4: e1010468. doi: https://doi.org/10.1371/journal.ppat.1010468
Park YJ et al., “Pyrogenic and inflammatory mediators are produced by polarized M1
and M2 macrophages activated with D-dimer and SARS-CoV-2 spike immune
complexes,” Cytokine 2024, 173: 156447. doi: 10.1016/j.cyto.2023.156447
Patterson BK et al., “Detection of S1 spike protein in CD16+ monocytes up to 245
days in SARS-CoV-2-negative post-COVID-19 vaccine syndrome (PCVS) individuals,”
Hum Vaccin Immunother. 2025, 21, 1: 2494934. doi:
10.1080/21645515.2025.2494934
Patterson BK et al., “Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in
Post-Acute Sequelae of COVID-19 (PASC) up to 15 Months Post-Infection,” Front.
Immunol. 12 (Sec. Viral Immunology). doi: 10.3389/fimmu.2021.746021
Pence B, “Recombinant SARS-CoV-2 Spike Protein Mediates Glycolytic and
Inflammatory Activation in Human Monocytes,” Innov Aging 2020, 4, sp. 1: 955. doi:
https://doi.org/10.1093/geroni/igaa057.3493
Satta S et al., “An engineered nano-liposome-human ACE2 decoy neutralizes SARSCoV-2 Spike protein-induced inflammation in both murine and human
macrophages,” Theranostics 2022, 12, 6: 2639–2657. doi: 10.7150/thno.66831
Schroeder JT and AP Bieneman, “The S1 Subunit of the SARS-CoV-2 Spike protein
activates human monocytes to produce cytokines linked to COVID-19: relevance to
galectin-3,” Front Immunol. 2022, 13: 831763. doi: 10.3389/fimmu.2022.831763
Shirato K and Takako Kizaki, “SARS-CoV-2 Spike Protein S1 Subunit Induces Proinflammatory Responses via Toll-Like Receptor 4 Signaling in Murine and Human
Macrophages,” Heliyon 2021, 7, 2: e06187. doi: 10.1016/j.heliyon.2021.e06187
Theobald SJ et al., “Long-lived macrophage reprogramming drives spike proteinmediated inflammasome activation in COVID-19,” EMBO Mol. Med. 2021, 13:
e14150. doi: https://doi.org/10.15252/emmm.202114150
Vettori M et al., “E]ects of Di]erent Types of Recombinant SARS-CoV-2 Spike
Protein on Circulating Monocytes’ Structure,” Int. J. Mol. Sci. 2023, 24, 11: 9373.
doi: https://doi.org/10.3390/ijms24119373
Youn YJ et al., “Nucleocapsid and spike proteins of SARS-CoV-2 drive neutrophil
extracellular trap formation,” Immune Netw. 2021, 21, 2: e16. doi:
https://doi.org/10.4110/in.2021.21.e16
Zaki H and S Khan, “SARS-CoV-2 spike protein induces inflammatory molecules
through TLR2 in macrophages and monocytes,” J. Immunol. 2021, 206
(1_supplement): 62.07. doi: https://doi.org/10.4049/jimmunol.206.Supp.62.07

P. MAPK/NF-kB

Arjsri P et al., “Hesperetin from root extract of Clerodendrum petasites S. Moore
inhibits SARS-CoV-2 spike protein S1 subunit-induced Nlrp3 inflammasome in A549
lung cells via modulation of the Akt/Mapk/Ap-1 pathway,” Int. J. Mol. Sci. 2022, 23,
18: 10346. doi: https://doi.org/10.3390/ijms231810346
Bhattacharyya S and JK Tobacman, “SARS-CoV-2 spike protein-ACE2 interaction
increases carbohydrate sulfotransferases and reduces N-acetylgalactosamine-4-
sulfatase by p38 MAPK,” Signal Transduct Target Ther 2024, 9, 39. doi:
https://doi.org/10.1038/s41392-024-01741-3
Forsyth CB et al., “The SARS-CoV-2 S1 spike protein promotes MAPK and NF-kB
activation in human lung cells and inflammatory cytokine production in human lung
and intestinal epithelial cells,” Microorganisms 2022, 10, 10: 1996.
doi: https://doi.org/10.3390/microorganisms10101996
Johnson EL et al., “The S1 spike protein of SARS-CoV-2 upregulates the ERK/MAPK
signaling pathway in DC-SIGN-expressing THP-1 cells,” Cell Stress Chaperones
2024, 29, 2: 227-234. doi: https://doi.org/10.1016/j.cstres.2024.03.002
Khan S et al., “SARS-CoV-2 Spike Protein Induces Inflammation via TLR2-Dependent
Activation of the NF-κB Pathway,” eLife 2021, 10: e68563. doi: 10.7554/elife.68563
Kircheis R and O Planz, “Could a Lower Toll-like Receptor (TLR) and NF-κB Activation
Due to a Changed Charge Distribution in the Spike Protein Be the Reason for the
Lower Pathogenicity of Omicron?” Int. J. Mol. Sci. 2022, 23, 11: 5966. doi:
https://doi.org/10.3390/ijms23115966
Kyriakopoulos AM et al., “Mitogen Activated Protein Kinase (MAPK) Activation, p53,
and Autophagy Inhibition Characterize the Severe Acute Respiratory Syndrome
Coronavirus 2 (SARS-CoV-2) Spike Protein Induced Neurotoxicity,” Cureus 2022, 14,
12: e32361. doi: 10.7759/cureus.32361
Robles JP et al., “The Spike Protein of SARS-CoV-2 Induces Endothelial
Inflammation through Integrin α5β1 and NF-κB Signaling,” J. Biol. Chem. 2022, 298,
3: 101695. doi: https://doi.org/10.1016/j.jbc.2022.101695
Sharma VK et al., “Nanocurcumin Potently Inhibits SARS-CoV-2 Spike ProteinInduced Cytokine Storm by Deactivation of MAPK/NF-κB Signaling in Epithelial
Cells,” ACS Appl. Bio Mater. 2022, 5, 2: 483–491. doi: 10.1021/acsabm.1c00874
Bhattacharyya S and JK Tobacman, “SARS-CoV-2 spike protein-ACE2 interaction
increases carbohydrate sulfotransferases and reduces N-acetylgalactosamine-4-
sulfatase by p38 MAPK,” Signal Transduct Target Ther 2024, 9, 39. doi:
https://doi.org/10.1038/s41392-024-01741-3

Q. Mast cells

Cao JB et al., “Mast cell degranulation-triggered by SARS-CoV-2 induces trachealbronchial epithelial inflammation and injury,” Virol. Sin. 2024, 39, 2: 309-318. doi:
https://doi.org/10.1016/j.virs.2024.03.001
Fajloun Z et al., “SARS-CoV-2 or Vaccinal Spike Protein can Induce Mast Cell
Activation Syndrome (MCAS),” Infect Disord Drug Targets, 2025, 25, 1:
e300424229561. doi: 10.2174/0118715265319896240427045026
Tsilioni S et al., “Recombinant SARS-CoV-2 Spike Protein Stimulates Secretion of
Chymase, Tryptase, and IL-1beta from Human Mast Cells, Augmented by IL-33,” Int.
J. Mol. Sci. 2023, 24, 11: 9487. doi: https://doi.org/10.3390/ijms24119487
Wu ML et al., “Mast cell activation triggered by SARS-CoV-2 causes inflammation in
brain microvascular endothelial cells and microglia,” Front. Cell. Infect. Microbiol.,
2024, 14. doi: https://doi.org/10.3389/fcimb.2024.1358873

R. Microglia

Alves V et al., “SARS-CoV-2 Spike protein alters microglial purinergic signaling
Front. Immunol. 2023, 14: 1158460. doi: 10.3389/fimmu.2023.1158460
Chang MH et al., “SARS-CoV-2 Spike Protein 1 Causes Aggregation of α-Synuclein
via Microglia-Induced Inflammation and Production of Mitochondrial ROS: Potential
Therapeutic Applications of Metformin,” Biomedicines 2024, 12, 6: 1223. doi:
https://doi.org/10.3390/biomedicines12061223
Clough E et al., “Mitochondrial Dynamics in SARS-COV2 Spike Protein Treated
Human Microglia: Implications for Neuro-COVID,” J. Neuroimmune Pharmacol.
2021, 16, 4: 770–784. doi: https://doi.org/10.1007/s11481-021-10015-6
Frank MG et al., “SARS-CoV-2 Spike S1 Subunit Induces Neuroinflammatory,
Microglial and Behavioral Sickness Responses: Evidence of PAMP-Like Properties,”
Brain Behav. Immun. 2022, 100: 267277. doi: 10.1016/j.bbi.2021.12.007
Kempuraj D et al., “Long COVID elevated MMP-9 and release from microglia by
SARS-CoV-2 Spike protein,” Transl. Neurosci. 2024, 15: 20220352. doi:
https://doi.org/10.1515/tnsci-2022-0352
Mishra R and AC Banerjea, “SARS-CoV-2 Spike targets USP33-IRF9 axis via
exosomal miR-148a to activate human microglia,” Front. Immunol. 2021, 12:
doi: https://doi.org/10.3389/fimmu.2021.656700
Olajide OA et al., “SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in
BV-2 microglia,”Mol. Neurobiol. 2022, 59: 445-458. doi: 10.1007/s12035-021-
02593-6
Tsilioni I et al., “Nobiletin and Eriodictyol Suppress Release of IL-1β, CXCL8, IL-6,
and MMP-9 from LPS, SARS-CoV-2 Spike Protein, and Ochratoxin A-Stimulated
Human Microglia,” Int. J. Mol. Sci. 2025, 26, 2: 636. doi:
https://doi.org/10.3390/ijms26020636
Tsilioni S et al., “Recombinant SARS-CoV-2 spike protein and its receptor binding
domain stimulate release of di]erent pro-inflammatory mediators via activation of
distinct receptors on human microglia cells,” Mol Neurobiol. 2023, 60, 11: 6704–14.
doi: 10.1007/s12035-023-03493-7
Wu ML et al., “Mast cell activation triggered by SARS-CoV-2 causes inflammation in
brain microvascular endothelial cells and microglia,” Front. Cell. Infect. Microbiol.
2024, 14. doi: https://doi.org/10.3389/fcimb.2024.1358873

S. Microvascular

Avolio E 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. 2021, 135, 24: 2667–
doi: https://doi.org/10.1042/CS20210735
Bhargavan B and GD Kanmogne, “SARS-CoV-2 spike proteins and cell–cell
communication inhibits TFPI and induces thrombogenic factors in human lung
microvascular endothelial cells and neutrophils: implications for COVID-19
coagulopathy pathogenesis,” Int. J. Mol. Sci. 2022, 23, 18: 10436. doi:
https://doi.org/10.3390/ijms231810436
Kulkoviene G et al., “Di]erential Mitochondrial, Oxidative Stress and Inflammatory
Responses to SARS-CoV-2 Spike Protein Receptor Binding Domain in Human Lung
Microvascular, Coronary Artery Endothelial and Bronchial Epithelial Cells,” Int. J.
Mol. Sci. 2024, 25, 6: 3188. doi: https://doi.org/10.3390/ijms25063188
Magro N et al., “Disruption of the blood-brain barrier is correlated with spike
endocytosis by ACE2 + endothelia in the CNS microvasculature in fatal COVID-19.
Scientific commentary on ‘Detection of blood-brain barrier disruption in brains of
patients with COVID-19, but no evidence of brain penetration by SARS-CoV-2’,” Acta
Neuropathol. 2024, 147, 1: 47. doi: https://doi.org/10.1007/s00401-023-02681-y
Panigrahi S et al., “SARS-CoV-2 Spike Protein Destabilizes Microvascular
Homeostasis,” Microbiol Spectr. 2021, 9, 3: e0073521. doi:
10.1128/Spectrum.00735-21
Perico L et al., “SARS-CoV-2 Spike Protein 1 Activates Microvascular Endothelial
Cells and Complement System Leading to Platelet Aggregation,” Front.
Immunol. 2022, 13, 827146. doi: https://doi.org/10.3389/fimmu.2022.827146
Wu ML et al., “Mast cell activation triggered by SARS-CoV-2 causes inflammation in
brain microvascular endothelial cells and microglia,” Front. Cell. Infect. Microbiol.
2024, 14. doi: https://doi.org/10.3389/fcimb.2024.1358873
Zekri-Nechar K et al., “Spike Protein Subunits of SARS-CoV-2 Alter Mitochondrial
Metabolism in Human Pulmonary Microvascular Endothelial Cells: Involvement of
Factor Xa,” Dis. Markers 2022: 1118195. doi: https://doi.org/10.1155/2022/1118195

T. MIS-C, pediatric

Chang A et al., “Recovery from antibody-mediated biliary ductopenia and
multiorgan inflammation after COVID-19 vaccination,” NPJ Vaccines 2024, 9, 75.
doi: https://doi.org/10.1038/s41541-024-00861-9
Colmenero I et al., “SARS-CoV-2 endothelial infection causes COVID-19
chilblains: histopathological, immunohistochemical and ultrastructural study of
seven paediatric cases,” Br J Dermatol. 2020, 183: 729-737. doi:
https://doi.org/10.1111/bjd.19327/
Dadonite B et al., “SARS-CoV-2 neutralizing antibody specificities di]er
dramatically between recently infected infants and immune-imprinted
individuals,” J. Virol. 2025, 99, 4. doi: https://doi.org/10.1128/jvi.00109-25
De Sousa PMB et al., “Fatal Myocarditis following COVID-19 mRNA Immunization:
A Case Report and Di]erential Diagnosis Review,” Vaccines 2024, 12, 2: 194.
doi: https://doi.org/10.3390/vaccines12020194
Mayordomo-Colunga J et al., “SARS-CoV-2 spike protein in intestinal cells of a
patient with coronavirus disease 2019 multisystem inflammatory syndrome,” J
Pediatr. 2022, 243: 214-18e215. doi: https://doi.org/10.1016/j.jpeds.2021.11.058
Rivas MN et al., “COVID-19–associated multisystem inflammatory syndrome in
children (MIS-C): A novel disease that mimics toxic shock syndrome—the
superantigen hypothesis,” J Allergy Clin Immunol 2021, 147, 1: 57-59.
doi: 10.1016/j.jaci.2020.10.008
Rivas MN et al., “Multisystem Inflammatory Syndrome in Children and Long
COVID: The SARS-CoV-2 Viral Superantigen Hypothesis,” Front Immunol. 2022,
13 (Sec. Molecular Innate Immunity). doi: 10.3389/fimmu.2022.941009
Sacco K et al., “Immunopathological signatures in multisystem inflammatory
syndrome in children and pediatric COVID-19,” Nat. Med. 2022, 28: 1050-1062.
doi: https://doi.org/10.1038/s41591-022-01724-3
Yonker LM et al., “Multisystem inflammatory syndrome in children is driven by
zonulin-dependent loss of gut mucosal barrier,” J Clin Invest. 2021, 131, 14:
e149633. doi: https://doi.org/10.1172/JCI149633

U. Mitochondria/metabolism

Cao X et al., “The SARS-CoV-2 spike protein induces long-term transcriptional
perturbations of mitochondrial metabolic genes, causes cardiac fibrosis, and
reduces myocardial contractile in obese mice,” Mol. Metab. 2023, 74, 101756. doi:
https://doi.org/10.1016/j.molmet.2023.101756
Chang MH et al., “SARS-CoV-2 Spike Protein 1 Causes Aggregation of α-Synuclein
via Microglia-Induced Inflammation and Production of Mitochondrial ROS: Potential
Therapeutic Applications of Metformin,” Biomedicines 2024, 12, 6: 1223. doi:
https://doi.org/10.3390/biomedicines12061223
Clough E et al., “Mitochondrial Dynamics in SARS-COV2 Spike Protein Treated
Human Microglia: Implications for Neuro-COVID,” Journal of Neuroimmune
Pharmacology 2021, 16, 4: 770–784. doi: 10.1007/s11481-021-10015-6
Huynh TV et al., “Spike Protein Impairs Mitochondrial Function in Human
Cardiomyocytes: Mechanisms Underlying Cardiac Injury in COVID19,” Cells 2023, 12, 877. doi: https://doi.org/10.3390/cells12060877
Kulkoviene G et al., “Di]erential Mitochondrial, Oxidative Stress and Inflammatory
Responses to SARS-CoV-2 Spike Protein Receptor Binding Domain in Human Lung
Microvascular, Coronary Artery Endothelial and Bronchial Epithelial Cells,” Int. J.
Mol. Sci. 2024, 25, 6: 3188. doi: https://doi.org/10.3390/ijms25063188
Mercado-Gómez M et al., “The spike of SARS-CoV-2 promotes metabolic rewiring in
hepatocytes,” Commun. Biol. 2022, 5, 827. doi: 10.1038/s42003-022-03789-9
Nguyen V, “The Spike Protein of SARS-CoV-2 Impairs Lipid Metabolism and
Increases Susceptibility to Lipotoxicity: Implication for a Role of Nrf2,”
Cells 2022, 11, 12: 1916. doi: https://doi.org/10.3390/cells11121916
Yeung-Luk BH et al., “SARS-CoV-2 infection alters mitochondrial and cytoskeletal
function in human respiratory epithelial cells mediated by expression of spike
protein,” mBio 2023, 14, 4: e00820-23. doi: https://doi.org/10.1128/mbio.00820-23
Zekri-Nechar K et al., “Spike Protein Subunits of SARS-CoV-2 Alter Mitochondrial
Metabolism in Human Pulmonary Microvascular Endothelial Cells: Involvement of
Factor Xa,” Dis. Markers 2022, 1118195. doi: https://doi.org/10.1155/2022/1118195

V. Myocarditis/cardiac/cardiomyopathy

Abdi A et al., “Biomed Interaction of SARS-CoV-2 with cardiomyocytes: Insight into
the underlying molecular mechanisms of cardiac injury and pharmacotherapy,”
Pharmacother. 2022, 146: 112518. doi: 10.1016/j.biopha.2021.112518
Avolio E 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. 2021, 135, 24: 2667–
doi: https://doi.org/10.1042/CS20210735
Baumeier C et al., “Intramyocardial Inflammation after COVID-19 Vaccination: An
Endomyocardial Biopsy-Proven Case Series,” Int. J. Mol. Sci. 2022, 23: 6940. doi:
https://doi.org/10.3390/ijms23136940
Bellavite P et al., “Immune response and molecular mechanisms of cardiovascular
adverse e]ects of spike proteins from SARS-coV-2 and mRNA vaccines,”
Biomedicines 2023, 11, 2: 451. doi: https://doi.org/10.3390/biomedicines11020451
Boretti A. “PQQ Supplementation and SARS-CoV-2 Spike Protein-Induced Heart
Inflammation,” Nat. Prod. Commun. 2022, 17, 1934578×221080929. doi:
https://doi.org/10.1177/1934578X221080929
Buoninfante A et al., “Myocarditis associated with COVID-19 vaccination,” npj
Vaccines 2024, 122. doi: https://doi.org/10.1038/s41541-024-00893-1
Cao X et al., “The SARS-CoV-2 spike protein induces long-term transcriptional
perturbations of mitochondrial metabolic genes, causes cardiac fibrosis, and
reduces myocardial contractile in obese mice,” Mol. Metab. 2023, 74, 101756. doi:
https://doi.org/10.1016/j.molmet.2023.101756
Clemens DJ et al., “SARS-CoV-2 spike protein-mediated cardiomyocyte fusion may
contribute to increased arrhythmic risk in COVID-19,” PLoS One 2023, 18, 3:
e0282151. doi: https://doi.org/10.1371/journal.pone.0282151
De Sousa PMB et al., “Fatal Myocarditis following COVID-19 mRNA Immunization: A
Case Report and Di]erential Diagnosis Review,” Vaccines 2024, 12, 2: 194.
doi: https://doi.org/10.3390/vaccines12020194
Forte E, “Circulating spike protein may contribute to myocarditis after COVID-19
vaccination,” Nat. Cardiovasc. Res. 2023, 2: 100. doi: 10.1038/s44161-023-00222-0
Huang X et al., “Sars-Cov-2 Spike Protein-Induced Damage of hiPSC-Derived
Cardiomyocytes,” Adv. Biol. 2022, 6, 7: e2101327. doi: 10.1002/adbi.202101327
Hulscher N et al., “Autopsy findings in cases of fatal COVID-19 vaccine-induced
myocarditis,” ESC Heart Failure 2024. doi: https://doi.org/10.1002/ehf2.14680
Huynh TV et al., “Spike Protein Impairs Mitochondrial Function in Human
Cardiomyocytes: Mechanisms Underlying Cardiac Injury in COVID19,” Cells 2023, 12, 877. doi: https://doi.org/10.3390/cells12060877
Huynh TV et al., “Spike Protein of SARS-CoV-2 Activates Cardiac Fibrogenesis
through NLRP3 Inflammasomes and NF-κB Signaling,” Cells 2024, 13, 16: 1331.
doi: https://doi.org/10.3390/cells13161331
Imig JD, “SARS-CoV-2 spike protein causes cardiovascular disease independent of
viral infection,” Clin Sci (Lond) 2022, 136, 6: 431–434. doi: 10.1042/CS20220028
Kato Y et al., “TRPC3-Nox2 Protein Complex Formation Increases the Risk of SARSCoV-2 Spike Protein-Induced Cardiomyocyte Dysfunction through ACE2
Upregulation,” Int. J. Mol. Sci. 2023, 24, 1: 102. doi: 10.3390/ijms24010102
Kawano H et al., “Fulminant Myocarditis 24 Days after Coronavirus Disease
Messenger Ribonucleic Acid Vaccination,” Intern. Med. 2022, 61, 15: 2319-2325.
doi: https://doi.org/10.2169/internalmedicine.9800-22
Li C. et al., “Intravenous Injection of Coronavirus Disease 2019 (COVID-19) MRNA
Vaccine Can Induce Acute Myopericarditis in Mouse Model,” Clin. Infect.
Dis. 2022, 74, 11: 1933-1950. doi: https://doi.org/10.1093/cid/ciab707
Lin Z, “More than a key—the pathological roles of SARS-CoV-2 spike protein in
COVID-19 related cardiac injury,” Sports Med Health Sci 2023, 6, 3: 209-220.
doi: https://doi.org/10.1016/j.smhs.2023.03.004
Rzymski P and Andrzej Fal, “To aspirate or not to aspirate? Considerations for the
COVID-19 vaccines,” Pharmacol. Rep 2022, 74: 1223–1227. doi:
https://doi.org/10.1007/s43440-022-00361-4
Schreckenberg R et al., “Cardiac side e]ects of RNA-based SARS-CoV-2 vaccines:
Hidden cardiotoxic e]ects of mRNA-1273 and BNT162b2 on ventricular myocyte
function and structure,” Br. J. Pharmacol. 2024, 181, 3: 345-361. doi:
https://doi.org/10.1111/bph.16262
Yonker LM et al., “Circulating Spike Protein Detected in Post–COVID-19 mRNA
Vaccine Myocarditis,” Circulation 2023, 147, 11. doi:
10.1161/CIRCULATIONAHA.122.061025

W. NLRP3

Albornoz EA et al., “SARS-CoV-2 drives NLRP3 inflammasome activation in human
microglia through spike protein,” Mol. Psychiatr. 2023, 28: 2878–2893. doi:
https://doi.org/10.1038/s41380-022-01831-0
Arjsri P et al., “Hesperetin from root extract of Clerodendrum petasites S. Moore
inhibits SARS-CoV-2 spike protein S1 subunit-induced Nlrp3 inflammasome in A549
lung cells via modulation of the Akt/Mapk/Ap-1 pathway,” Int. J. Mol. Sci. 2022, 23,
18: 10346. doi: https://doi.org/10.3390/ijms231810346
Chittasupho C et al., “Inhibition of SARS-CoV-2-Induced NLRP3 InflammasomeMediated Lung Cell Inflammation by Triphala-Loaded Nanoparticle Targeting Spike
Glycoprotein S1,” Pharmaceutics 2024, 16, 6: 751. doi:
10.3390/pharmaceutics16060751
Chittasupho C et al., “Targeting spike glycoprotein S1 mediated by NLRP3
inflammasome machinery and the cytokine releases in A549 lung epithelial cells by
nanocurcumin,” Pharmaceuticals (Basel) 2023, 16, 6: 862. doi:
10.3390/ph16060862
Corpetti C et al., “Cannabidiol inhibits SARS-Cov-2 spike (S) protein-induced
cytotoxicity and inflammation through a PPARγ-dependent TLR4/NLRP3/Caspase-1
signaling suppression in Caco-2 cell line,” Phytother. Res. 2021, 35, 12: 6893–
doi: https://doi.org/10.1002/ptr.7302
Del Re A et al., “Ultramicronized Palmitoylethanolamide Inhibits NLRP3
Inflammasome Expression and Pro-Inflammatory Response Activated by SARSCoV-2 Spike Protein in Cultured Murine Alveolar Macrophages,”
Metabolites 2021, 11, 9: 592. dsoi: https://doi.org/10.3390/metabo11090592
Dissook S et al., “Luteolin-rich fraction from Perilla frutescens seed meal inhibits
spike glycoprotein S1 of SARS-CoV-2-induced NLRP3 inflammasome lung cell
inflammation via regulation of JAK1/STAT3 pathway: A potential anti-inflammatory
compound against inflammation-induced long-COVID,” Front. Med. 2023, 9:
doi: https://doi.org/10.3389/fmed.2022.1072056
Huynh TV et al., “Spike Protein of SARS-CoV-2 Activates Cardiac Fibrogenesis
through NLRP3 Inflammasomes and NF-κB Signaling,” Cells 2024, 13, 16: 1331.
doi: https://doi.org/10.3390/cells13161331
Jiang Q et al., “SARS-CoV-2 spike S1 protein induces microglial NLRP3-dependent
neuroinflammation and cognitive impairment in mice,” Exp. Neurol. 2025, 383:
doi: https://doi.org/10.1016/j.expneurol.2024.115020
Kucia M et al. “An evidence that SARS-Cov-2/COVID-19 spike protein (SP) damages
hematopoietic stem/progenitor cells in the mechanism of pyroptosis in Nlrp3
inflammasome-dependent manner,” Leukemia 2021, 35: 3026-3029. doi:
https://doi.org/10.1038/s41375-021-01332-z
Ratajczak MZ et al., “SARS-CoV-2 Entry Receptor ACE2 Is Expressed on Very Small
CD45- Precursors of Hematopoietic and Endothelial Cells and in Response to Virus
Spike Protein Activates the Nlrp3 Inflammasome,” Stem Cell Rev Rep. 2021, 17, 1:
266-277. doi: https://doi.org/10.1007/s12015-020-10010-z
Semmarath W et al., “Cyanidin-3-O-glucoside and Peonidin-3-O-glucoside-Rich
Fraction of Black Rice Germ and Bran Suppresses Inflammatory Responses from
SARS-CoV-2 Spike Glycoprotein S1-Induction In Vitro in A549 Lung Cells and THP-1
Macrophages via Inhibition of the NLRP3 Inflammasome Pathway,” Nutrients 2022,
14, 13: 2738. doi: https://doi.org/10.3390/nu14132738
Villacampa A et al., “SARS-CoV-2 S protein activates NLRP3 inflammasome and
deregulates coagulation factors in endothelial and immune cells,” Cell Commun.
Signal. 2024, 22, 38. doi: https://doi.org/10.1186/s12964-023-01397-6

X. Ocular, ophthalmic, conjunctival

Golob-Schwarzl N et al., “SARS-CoV-2 spike protein functionally interacts with
primary human conjunctival epithelial cells to induce a pro-inflammatory
response,” Eye 2022, 36: 2353–5. doi: https://doi.org/10.1038/s41433-022-02066-7
Grishma K and Das Sarma, “The Role of Coronavirus Spike Protein in Inducing Optic
Neuritis in Mice: Parallels to the SARS-CoV-2 Virus,” J Neuroophthalmol 2024, 44, 3:
319-329. doi: 10.1097/WNO.0000000000002234
Zhu G et al., “SARS-CoV-2 spike protein-induced host inflammatory response
signature in human corneal epithelial cells,” Mol. Med. Rep. 2021, 24: 584. doi:
https://doi.org/10.3892/mmr.2021.12223

Y. Other cell signaling

Caohuy H et al., “Inflammation in the COVID-19 airway is due to inhibition of CFTR
signaling by the SARS-CoV-2 spike protein,” Sci. Rep. 2024, 14: 16895. doi:
https://doi.org/10.1038/s41598-024-66473-4
Choi JY et al., “SARS-CoV-2 spike S1 subunit protein-mediated increase of betasecretase 1 (BACE1) impairs human brain vessel cells,” Biochem. Biophys. Res.
Commun. 2022, 625, 20: 66-71. doi: https://doi.org/10.1016/j.bbrc.2022.07.113
Chrestia JF et al., “A Functional Interaction Between Y674-R685 Region of the SARSCoV-2 Spike Protein and the Human α7 Nicotinic Receptor,” Mol. Neurobiol. 2022,
59: 676-690. doi: https://doi.org/10.1007/s12035-022-02947-8
Corpetti C et al., “Cannabidiol inhibits SARS-Cov-2 spike (S) protein-induced
cytotoxicity and inflammation through a PPARγ-dependent TLR4/NLRP3/Caspase-1
signaling suppression in Caco-2 cell line,” Phytother. Res. 2021, 35, 12: 6893–
doi: https://doi.org/10.1002/ptr.7302
Gracie NP et al., “Cellular signalling by SARS-CoV-2 spike protein,” Microbiology
Australia 2024, 45, 1: 13-17. doi: https://doi.org/10.1071/MA24005
Hasan MZ et al., “SARS-CoV-2 infection induces adaptive NK cell responses by spike
protein-mediated induction of HLA-E expression,” Emerg Microbes Infect. 2024, 13:
doi: https://doi.org/10.1080/22221751.2024.2361019
Li F et al., “SARS-CoV-2 Spike Promotes Inflammation and Apoptosis Through
Autophagy by ROS-Suppressed PI3K/AKT/mTOR Signaling,” Biochim Biophys Acta
BBA – Mol Basis Dis 2021, 1867: 166260. doi: 10.1016/j.bbadis.2021.166260
Li K et al., “SARS-CoV-2 Spike protein promotes vWF secretion and thrombosis via
endothelial cytoskeleton-associated protein 4 (CKAP4),” Signal Transduct Targ Ther.
2022, 7, 332. doi: https://doi.org/10.1038/s41392-022-01183-9
Moutal A et al., “SARS-CoV-2 Spike protein co-opts VEGF-A/Neuropilin-1 receptor
signaling to induce analgesia,” Pain 2020, 162, 1: 243–252. doi:
10.1097/j.pain.0000000000002097
Munavilli GG et al., “COVID-19/SARS-CoV-2 virus spike protein-related delayed
inflammatory reaction to hyaluronic acid dermal fillers: a challenging clinical
conundrum in diagnosis and treatment,” Arch. Dermatol. Res. 2022, 314: 1-15. doi:
https://doi.org/10.1007/s00403-021-02190-6
O’Brien BCV et al., “SARS-CoV-2 spike ectodomain targets α7 nicotinic
acetylcholine receptors,” J. Biol. Chem. 2023, 299, 5: 104707. doi:
10.1016/j.jbc.2023.104707
Oliveira ASF et al., “A potential interaction between the SARS-CoV-2 spike protein
and nicotinic acetylcholine receptors,” Biophys. J. 2021, 120, 6: 983-993.
doi: 10.1016/j.bpj.2021.01.037
Prieto-Villalobos J et al., “SARS-CoV-2 spike protein S1 activates Cx43
hemichannels and disturbs intracellular Ca2+ dynamics,” Biol Res. 2023, 56, 1: 56.
doi: https://doi.org/10.1186/s40659-023-00468-9
Rotoli BM et al., “Endothelial cell activation by SARS-CoV-2 spike S1 protein: A
crosstalk between endothelium and innate immune cells,” Biomedicines 2021, 9, 9:
doi: https://doi.org/10.3390/biomedicines9091220
Singh N and Anuradha Bharara Singh, “S2 Subunit of SARS-nCoV-2 Interacts with
Tumor Suppressor Protein p53 and BRCA: An in Silico Study,” Translational Oncology
2020, 13, 10: 100814. doi: https://doi.org/10.1016/j.tranon.2020.100814
Singh RD, “The spike protein of sars-cov-2 induces heme oxygenase-1:
pathophysiologic implications,” Biochim Biophys Acta, Mol Basis Dis 2022, 1868, 3:
doi: https://doi.org/10.1016/j.bbadis.2021.166322
Solis O et al., “The SARS-CoV-2 spike protein binds and modulates estrogen
receptors,” Sci. Adv. 2022, 8, 48: eadd4150. doi: 10.1126/sciadv.add4150
Suzuki YJ et al., “SARS-CoV-2 spike protein-mediated cell signaling in lung vascular
cells,” Vascul. Pharmacol. 2021, 137: 106823. doi: 10.1016/j.vph.2020.106823
Suzuki YJ and SG Gychka, “SARS-CoV-2 Spike Protein Elicits Cell Signaling in Human
Host Cells: Implications for Possible Consequences of COVID-19 Vaccines,”
Vaccines 2021, 9, 1: 36. doi: https://doi.org/10.3390/vaccines9010036
Tillman TS et al., “SARS-CoV-2 Spike Protein Downregulates Cell Surface
alpha7nAChR through a Helical Motif in the Spike Neck,” ACS Chem.
Neurosci. 2023, 14, 4: 689–698. doi: 10.1021/acschemneuro.2c00610

Z. PASC, post COVID, long COVID

Bellucci M et al., “Post-SARS-CoV-2 infection and post-vaccine-related neurological
complications share clinical features and the same positivity to anti-ACE2
antibodies,” Front. Immunol. 2024, 15 (Sec. Multiple Sclerosis and
Neuroimmunology). doi: https://doi.org/10.3389/fimmu.2024.1398028
Craddock V et al., “Persistent circulation of soluble and extracellular vesicle-linked
Spike protein in individuals with postacute sequelae of COVID-19,” J Med. Virol. 2023,
95, 2: e28568. doi: https://doi.org/10.1002/jmv.28568
De Melo BP et al., “SARS-CoV-2 Spike Protein and Long COVID—Part 1: Impact of
Spike Protein in Pathophysiological Mechanisms of Long COVID Syndrome,”
Viruses 2025, 17, 5: 617. doi: https://doi.org/10.3390/v17050617
Dissook S et al., “Luteolin-rich fraction from Perilla frutescens seed meal inhibits
spike glycoprotein S1 of SARS-CoV-2-induced NLRP3 inflammasome lung cell
inflammation via regulation of JAK1/STAT3 pathway: A potential anti-inflammatory
compound against inflammation-induced long-COVID,” Front. Med. 2023, 9:
doi: https://doi.org/10.3389/fmed.2022.1072056
Frank MG et al., “Exploring the immunogenic properties of SARS-CoV-2 structural
proteins: PAMP:TLR signaling in the mediation of the neuroinflammatory and
neurologic sequelae of COVID-19,” Brain Behav Immun 2023, 111. doi:
https://doi.org/10.1016/j.bbi.2023.04.009
Frank MG et al., “SARS-CoV-2 S1 subunit produces a protracted priming of the
neuroinflammatory, physiological, and behavioral responses to a remote immune
challenge: A role for corticosteroids,” Brain Behav. Immun. 2024, 121: 87-103. doi:
https://doi.org/10.1016/j.bbi.2024.07.034
Fraser ME at al., “SARS-CoV-2 Spike Protein and Viral RNA Persist in the Lung of
Patients With Post-COVID Lung Disease (abstract),” Am J Respir Crit Care Med 2024,
209: A4193. doi: 10.1164/ajrccm-conference.2024.209.1_MeetingAbstracts.A4193
Goh D et al., “Case report: Persistence of residual antigen and RNA of the SARS-CoV2 virus in tissues of two patients with long COVID,” Front. Immunol. 2022, 13 (Sec.
Viral Immunology). doi: https://doi.org/10.3389/fimmu.2022.939989
Halma MTJ et al., “Exploring autophagy in treating SARS-CoV-2 spike protein-related
pathology,” Endocrinol Metab (EnM) 2024, 14: 100163. doi:
https://doi.org/10.1016/j.endmts.2024.100163
Halma MTJ et al., “Strategies for the Management of Spike Protein-Related
Pathology,” Microorganisms 2023, 11, 5: 1308. doi:
10.3390/microorganisms11051308
Hano S et al., “A case of persistent, confluent maculopapular erythema following a
COVID-19 mRNA vaccination is possibly associated with the intralesional spike
protein expressed by vascular endothelial cells and eccrine glands in the deep
dermis,” J Dermatol 2023, 50, 9: 1208-1212. doi: 10.1111/1346-8138.16816
Kempuraj D et al., “Long COVID elevated MMP-9 and release from microglia by SARSCoV-2 Spike protein,” Transl. Neurosci. 2024, 15: 20220352. doi:
https://doi.org/10.1515/tnsci-2022-0352
Patterson BK et al., “Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in
Post-Acute Sequelae of COVID-19 (PASC) up to 15 Months Post-Infection,” Front.
Immunol. 12 (Sec. Viral Immunology). doi: 10.3389/fimmu.2021.746021
Peluso MJ et al., “Plasma-based antigen persistence in the post-acute phase of
COVID-19,” Lancet 2024, 24, 6: E345-E347. doi: 10.1016/S1473-3099(24)00211-1
Rong Z et al., “Persistence of spike protein at the skull-meninges-brain axis may
contribute to the neurological sequelae of COVID-19,” Cell Host Microbe 2024, 26:
S1931-3128(24)00438-4. doi: 10.1016/j.chom.2024.11.007
Scholkmann F and CA May, “COVID-19, post-acute COVID-19 syndrome (PACS, ‘long
COVID’) and post-COVID-19 vaccination syndrome (PCVS, ‘post-COVIDvacsyndrome’): Similarities and di]erences,” Pathol Res Pract. 2023, 246: 154497. doi:
https://doi.org/10.1016/j.prp.2023.154497
Schultheiss C et al., “Liquid biomarkers of macrophage dysregulation and circulating
spike protein illustrate the biological heterogeneity in patients with post-acute
sequelae of COVID-19,” J Med Virol 2023, 95, 1: e28364. doi: 10.1002/jmv.28364
Swank Z, et al. “Persistent Circulating Severe Acute Respiratory Syndrome
Coronavirus 2 Spike Is Associated With Post-acute Coronavirus Disease 2019
Sequelae,” Clin. Infect. Dis. 2023, 76, 3: e487–e490. doi: 10.1093/cid/ciac722
Theoharides TC, “Could SARS-CoV-2 Spike Protein Be Responsible for Long-COVID
Syndrome?” Mol. Neurobiol. 2022, 59, 3: 1850–1861. doi: 10.1007/s12035-021-
02696-0
Visvabharathy L et al., “Case report: Treatment of long COVID with a SARS-CoV-2
antiviral and IL-6 blockade in a patient with rheumatoid arthritis and SARS-CoV-2
antigen persistence,” Front. Med. 2022, 9 (Sec. Infectious Diseases – Surveillance).
doi: https://doi.org/10.3389/fmed.2022.1003103
Yamamoto M et al., “Persistent varicella zoster virus infection following mRNA
COVID-19 vaccination was associated with the presence of encoded spike protein in
the lesion,” J. Cutan Immunol. Allergy. 2022:1–6. doi: 10.1002/cia2.12278
Zollner A et al., “Postacute COVID-19 is Characterized by Gut Viral Antigen
Persistence in Inflammatory Bowel Diseases,” Gastroenterology 2022, 163, 2: 495-
506.e8. doi: https://doi.org/10.1053/j.gastro.2022.04.037

AA. Pregnancy

Erdogan MA, “Prenatal SARS-CoV-2 Spike Protein Exposure Induces Autism-Like
Neurobehavioral Changes in Male Neonatal Rats,” J Neuroimmune Pharmacol.
2023, 18, 4: 573-591. doi: 10.1007/s11481-023-10089-4
Guo X et al., “Regulation of proinflammatory molecules and tissue factor by SARSCoV-2 spike protein in human placental cells: implications for SARS-CoV-2
pathogenesis in pregnant women,” Front. Immunol. 2022, 13: 876555–876555. doi:
https://doi.org/10.3389/fimmu.2022.876555
Kammala AK et al., “In vitro mRNA-S maternal vaccination induced altered immune
regulation at the maternal-fetal interface,” Am. J. Reprod. Immunol. 2024, 91, 5:
e13861. doi: https://doi.org/10.1111/aji.13861
Karrow NA et al., “Maternal COVID-19 Vaccination and Its Potential Impact on Fetal
and Neonatal Development,” Vaccines 2021, 9: 1351. doi:
10.3390/vaccines9111351
Parcial ALN et al., “SARS-CoV-2 Is Persistent in Placenta and Causes Macroscopic,
Histopathological, and Ultrastructural Changes,” Viruses 2022, 14, 9: 1885.
doi: https://doi.org/10.3390/v14091885
Wu H et al., “Molecular evidence suggesting the persistence of residual SARS-CoV-2
and immune responses in the placentas of pregnant patients recovered from
COVID-19,” Cell Prolif. 2021, 54, 9: e13091. doi: https://doi.org/10.1111/cpr.13091
Zurlow M et al., “The anti-SARS-CoV-2 BNT162b2 vaccine suppresses mithramycininduced erythroid di]erentiation and expression of embryo-fetal globin genes in
human erythroleukemia K562 cells.” Exp Cell Res 2023, 433, 2: 113853. doi:
https://doi.org/10.1016/j.yexcr.2023.113853

BB. Pulmonary, respiratory

Bhargavan B and GD Kanmogne, “SARS-CoV-2 spike proteins and cell–cell
communication inhibits TFPI and induces thrombogenic factors in human lung
microvascular endothelial cells and neutrophils: implications for COVID-19
coagulopathy pathogenesis,” Int. J. Mol. Sci. 2022, 23, 18: 10436. doi:
https://doi.org/10.3390/ijms231810436
Biancatelli RMLC et al., “The SARS-CoV-2 spike protein subunit S1 induces COVID19-like acute lung injury in Kappa18-hACE2 transgenic mice and barrier dysfunction
in human endothelial cells,” Am. J. Physiol. Lung Cell. Mol. Physiol. 2021, 321: L477–
L484. doi: https://doi.org/10.1152/ajplung.00223.2021
Cao JB et al., “Mast cell degranulation-triggered by SARS-CoV-2 induces trachealbronchial epithelial inflammation and injury,” Virol. Sin. 2024, 39, 2: 309-318. doi:
https://doi.org/10.1016/j.virs.2024.03.001
Cao X et al., “Spike protein of SARS-CoV-2 activates macrophages and contributes
to induction of acute lung inflammation in male mice,” FASEB J. 2021, 35, e21801.
doi: https://doi.org/10.1096/fj.202002742RR
Caohuy H et al., “Inflammation in the COVID-19 airway is due to inhibition of CFTR
signaling by the SARS-CoV-2 spike protein,” Sci. Rep. 2024, 14: 16895. doi:
https://doi.org/10.1038/s41598-024-66473-4
Chittasupho C et al., “Inhibition of SARS-CoV-2-Induced NLRP3 InflammasomeMediated Lung Cell Inflammation by Triphala-Loaded Nanoparticle Targeting Spike
Glycoprotein S1,” Pharmaceutics 2024, 16, 6: 751. doi:
10.3390/pharmaceutics16060751
Chittasupho C et al., “Targeting spike glycoprotein S1 mediated by NLRP3
inflammasome machinery and the cytokine releases in A549 lung epithelial cells by
nanocurcumin,” Pharmaceuticals (Basel) 2023, 16, 6: 862. doi:
10.3390/ph16060862
DeVries A et al., “SARS-CoV-2 Spike Protein is Su]icient to Induce Enhanced Proinflammatory Transcriptional Responses in Nasal Epithelial Cells from Atopic
Asthmatics,” J Allergy Clin Immunol 2025, 155, 2: AB85. doi:
10.1016/j.jaci.2024.12.271
Del Re A et al., “Intranasal delivery of PEA-producing Lactobacillus paracasei
F19 alleviates SARS-CoV-2 spike protein-induced lung injury in mice,” Transl. Med.
Commun. 2024, 9, 9. doi: https://doi.org/10.1186/s41231-024-00167-x
Forsyth CB et al., “The SARS-CoV-2 S1 spike protein promotes MAPK and NF-kB
activation in human lung cells and inflammatory cytokine production in human lung
and intestinal epithelial cells,” Microorganisms 2022, 10, 10: 1996.
doi: https://doi.org/10.3390/microorganisms10101996
Fraser ME at al., “SARS-CoV-2 Spike Protein and Viral RNA Persist in the Lung of
Patients With Post-COVID Lung Disease (abstract),” Am J Respir Crit Care Med 2024,
209: A4193. doi: 10.1164/ajrccm-conference.2024.209.1_MeetingAbstracts.A4193
Greenberger JS et al., “SARS-CoV-2 Spike Protein Induces Oxidative Stress and
Senescence in Mouse and Human Lung,” In Vivo 2024, 38, 4: 1546-1556. doi:
https://doi.org/10.21873/invivo.13605
Jana S et al., “Cell-free hemoglobin does not attenuate the e]ects of SARS-CoV-2
spike protein S1 subunit in pulmonary endothelial cells,” Int. J. Mol. Sci. 2021, 22,
16: 9041. doi: https://doi.org/10.3390/ijms22169041
Kulkoviene G et al., “Di]erential Mitochondrial, Oxidative Stress and Inflammatory
Responses to SARS-CoV-2 Spike Protein Receptor Binding Domain in Human Lung
Microvascular, Coronary Artery Endothelial and Bronchial Epithelial Cells,” Int. J.
Mol. Sci. 2024, 25, 6: 3188. doi: https://doi.org/10.3390/ijms25063188
Liang S et al., “SARS-CoV-2 spike protein induces IL-18-mediated cardiopulmonary
inflammation via reduced mitophagy,” Signal Transduct Target Ther 2023, 8, 103. doi:
https://doi.org/10.1038/s41392-023-01368-w
Liu T et al., “RS-5645 attenuates inflammatory cytokine storm induced by SARSCoV-2 spike protein and LPS by modulating pulmonary microbiota,” Int J Biol Sci.
2021, 17, 13: 3305–3319. doi: 10.7150/ijbs.63329
Liu Y et al., “The recombinant spike S1 protein induces injury and inflammation in
co-cultures of human alveolar epithelial cells and macrophages,” PLoS ONE 2025,
20, 2: e0318881. doi: https://doi.org/10.1371/journal.pone.0318881
Palestra F et al. “SARS-CoV-2 Spike Protein Activates Human Lung
Macrophages,” Int. J. Mol. Sci. 2023, 24, 3: 3036. doi: 10.3390/ijms24033036
Park C et al., “Murine alveolar Macrophages Rapidly Accumulate intranasally
Administered SARS-CoV-2 Spike Protein leading to neutrophil Recruitment and
Damage,” Elife 2024, 12: RP86764. doi: https://doi.org/10.7554/eLife.86764.3
Puthia MTL et al., “Experimental model of pulmonary inflammation induced by
SARS-CoV-2 spike protein and endotoxin,” ACS Pharmacol Transl Sci. 2022, 5,
3: 141–8. doi: https://doi.org/10.1021/acsptsci.1c00219
Rahman M et al., “Di]erential E]ect of SARS-CoV-2 Spike Glycoprotein 1 on Human
Bronchial and Alveolar Lung Mucosa Models: Implications for Pathogenicity,”
Viruses 2021, 13, 12: 2537. doi: https://doi.org/10.3390/v13122537
Roy A et al., “Ultradiluted Eupatorium perfoliatum Prevents and Alleviates SARSCoV-2 Spike Protein-Induced Lung Pathogenesis by Regulating Inflammatory
Response and Apoptosis,” Diseases 2025, 13, 2: 36.
doi: 10.3390/diseases13020036
Ruben ML 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. 2021, 321, 2: L477-L484.
doi: https://doi.org/10.1152/ajplung.00223.2021
Segura-Villalobos D et al., “Jacareubin inhibits TLR4-induced lung inflammatory
response caused by the RBD domain of SARS-CoV-2 Spike protein,” Pharmacol.
Rep. 2022, 74: 1315–1325. doi: https://doi.org/10.1007/s43440-022-00398-5
Semmarath W et al., “Cyanidin-3-O-glucoside and Peonidin-3-O-glucoside-Rich
Fraction of Black Rice Germ and Bran Suppresses Inflammatory Responses from
SARS-CoV-2 Spike Glycoprotein S1-Induction In Vitro in A549 Lung Cells and THP-1
Macrophages via Inhibition of the NLRP3 Inflammasome Pathway,” Nutrients 2022,
14, 13: 2738. doi: https://doi.org/10.3390/nu14132738
Sirsendu J et al., “Cell-Free Hemoglobin Does Not Attenuate the E]ects of SARSCoV-2 Spike Protein S1 Subunit in Pulmonary Endothelial Cells,” Int. J. Mol. Sci.
2021, 22, 16: 9041. doi: https://doi.org/10.3390/ijms22169041
Solopov et al., “Alcohol increases lung angiotensin-converting enzyme 2 expression
and exacerbates severe acute respiratory syndrome coronavirus 2 spike protein
subunit 1-induced acute lung injury in K18-hACE2 transgenic mice,” Am J Pathol
2022, 192, 7: 990-1000. doi: 10.1016/j.ajpath.2022.03.012
Sui Y et al., “SARS-CoV-2 Spike Protein Suppresses ACE2 and Type I Interferon
Expression in Primary Cells From Macaque Lung Bronchoalveolar Lavage,” Front.
Immunol. 2021, 12. doi: https://doi.org/10.3389/fimmu.2021.658428
Sung PS et al., “CLEC5A and TLR2 Are Critical in SARS-CoV-2-Induced NET
Formation and Lung Inflammation,” J. Biomed. Sci. 2022, 29, 52. doi:
https://doi.org/10.1186/s12929-022-00832-z
Suzuki YJ et al., “SARS-CoV-2 spike protein-mediated cell signaling in lung vascular
cells,” Vascul. Pharmacol. 2021, 137: 106823. doi: 10.1016/j.vph.2020.106823
Yang K et al., “SARS-CoV-2 spike protein receptor-binding domain perturbates
intracellular calcium homeostasis and impairs pulmonary vascular endothelial
cells,” Signal Transduct Target Ther. 2023, 8, 276. doi: 10.1038/s41392-023-01556-8
Yeung-Luk BH et al., “SARS-CoV-2 infection alters mitochondrial and cytoskeletal
function in human respiratory epithelial cells mediated by expression of spike
protein,” mBio 2023, 14, 4: e00820-23. doi: https://doi.org/10.1128/mbio.00820-23
Zekri-Nechar K et al., “Spike Protein Subunits of SARS-CoV-2 Alter Mitochondrial
Metabolism in Human Pulmonary Microvascular Endothelial Cells: Involvement of
Factor Xa,” Dis. Markers 2022, 1118195. doi: https://doi.org/10.1155/2022/1118195

CC. Renin-Angiotensin-Aldosterone System

Burnett FN et al., “SARS-CoV-2 Spike Protein Intensifies Cerebrovascular
Complications in Diabetic hACE2 Mice through RAAS and TLR Signaling Activation,”
Int. J. Mol. Sci. 2023, 24, 22: 16394. doi: https://doi.org/10.3390/ijms242216394
Lehmann KJ, “SARS-CoV-2-Spike Interactions with the Renin-AngiotensinAldosterone System – Consequences of Adverse Reactions of Vaccination,” J Biol
Today’s World 2023, 12/4: 001-013. doi: https://doi.org/10.31219/osf.io/27g5h
Matsuzawa Y et al., “Impact of Renin–Angiotensin–Aldosterone System Inhibitors on
COVID-19,” Hypertens. Res. 2022, 45, 7: 1147–1153. doi: 10.1038/s41440-022-
00922-3

DD. Senescence/aging

Duarte C, “Age-dependent e]ects of the recombinant spike protein/SARS-CoV-2 on
the M-CSF- and IL-34-di]erentiated macrophages in vitro,” Biochem. Biophys. Res.
Commun. 2021, 546: 97–102. doi: https://doi.org/10.1016/j.bbrc.2021.01.104
Greenberger JS et al., “SARS-CoV-2 Spike Protein Induces Oxidative Stress and
Senescence in Mouse and Human Lung,” In Vivo 2024, 38, 4: 1546-1556. doi:
https://doi.org/10.21873/invivo.13605
Meyer K et al., “SARS-CoV-2 Spike Protein Induces Paracrine Senescence and
Leukocyte Adhesion in Endothelial Cells,” J. Virol. 2021, 95, e0079421. doi:
https://doi.org/10.1128/jvi.00794-21

EE. Stem cells

Balzanelli MG et al., “The Role of SARS-CoV-2 Spike Protein in Long-term Damage of
Tissues and Organs, the Underestimated Role of Retrotransposons and Stem Cells,
a Working Hypothesis,” Endocr Metab Immune Disord Drug Targets 2025, 25, 2: 85-
doi: 10.2174/0118715303283480240227113401
Kucia M et al. “An evidence that SARS-Cov-2/COVID-19 spike protein (SP) damages
hematopoietic stem/progenitor cells in the mechanism of pyroptosis in Nlrp3
inflammasome-dependent manner,” Leukemia 2021, 35: 3026-3029. doi:
https://doi.org/10.1038/s41375-021-01332-z
Ropa J et al., “Human Hematopoietic Stem, Progenitor, and Immune Cells Respond
Ex Vivo to SARS-CoV-2 Spike Protein,” Stem Cell Rev Rep. 2021, 17, 1: 253-265. doi:
https://doi.org/10.1007/s12015-020-10056-z

FF. Syncytia/cell fusion

Braga L et al., “Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced
syncytia,” Nature 2021, 594: 88–93. doi: 10.1038/s41586-021-03491-6
Cattin-Ortolá J et al., “Sequences in the cytoplasmic tail of SARS-CoV-2 Spike
facilitate expression at the cell surface and syncytia formation,” Nat Commun 2021,
12, 1: 5333. doi: https://doi.org/10.1038/s41467-021-25589-1
Clemens DJ et al., “SARS-CoV-2 spike protein-mediated cardiomyocyte fusion may
contribute to increased arrhythmic risk in COVID-19,” PLoS One 2023, 18, 3:
e0282151. doi: https://doi.org/10.1371/journal.pone.0282151
Lazebnik Y, “Cell fusion as a link between the SARS-CoV-2 spike protein, COVID-19
complications, and vaccine side e]ects,” Oncotarget 2021, 12, 25: 2476-2488. doi:
https://doi.org/10.18632/oncotarget.28088
Liu X et al., “SARS-CoV-2 spike protein-induced cell fusion activates the cGASSTING pathway and the interferon response,” Sci Signal. 2022, 15, 729: eabg8744.
doi: 10.1126/scisignal.abg8744
Martinez-Marmol R et al., “SARS-CoV-2 infection and viral fusogens cause neuronal
and glial fusion that compromises neuronal activity,” Sci. Adv. 2023, 9, 23. doi:
10.1126/sciadv.adg2248
Rajah MM et al., “SARS-CoV-2 Alpha, Beta, and Delta variants display enhanced
spike-mediated syncytia formation,” EMBO J. 2021, 40: e108944. doi:
https://doi.org/10.15252/embj.2021108944
Shirato K and Takako Kizaki, “SARS-CoV-2 Spike Protein S1 Subunit Induces Proinflammatory Responses via Toll-Like Receptor 4 Signaling in Murine and Human
Macrophages,” Heliyon 2021, 7, 2: e06187. doi: 10.1016/j.heliyon.2021.e06187
Theuerkauf SA et al., “Quantitative assays reveal cell fusion at minimal levels of
SARS-CoV-2 spike protein and fusion from without,” iScience 2021, 24, 3: 102170.
doi: https://doi.org/10.1016/j.isci.2021.102170
Zhang Z et al., “SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte
elimination,” Cell Death Diber. 2021, 28: 2765–2777. doi: 10.1038/s41418-021-
00782-3

GG. Therapeutics

Almehdi AM et al., “SARS-CoV-2 Spike Protein: Pathogenesis, Vaccines, and
Potential Therapies,” Infection 2021, 49, 5: 855–876. doi: 10.1007/s15010-021-
01677-8
Boretti A, “PQQ Supplementation and SARS-CoV-2 Spike Protein-Induced Heart
Inflammation,” Nat. Prod. Commun. 2022, 17, 1934578×221080929. doi:
https://doi.org/10.1177/1934578X221080929
Boschi C et al., “SARS-CoV-2 Spike Protein Induces Hemagglutination: Implications
for COVID-19 Morbidities and Therapeutics and for Vaccine Adverse E]ects,” Int. J.
Biol. Macromol. 2022, 23, 24: 15480. doi: https://doi.org/10.3390/ijms232415480
Braga L et al., “Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced
syncytia,” Nature 2021, 594: 88–93. doi: 10.1038/s41586-021-03491-6
Chang MH et al., “SARS-CoV-2 Spike Protein 1 Causes Aggregation of α-Synuclein
via Microglia-Induced Inflammation and Production of Mitochondrial ROS: Potential
Therapeutic Applications of Metformin,” Biomedicines 2024, 12, 6: 1223. doi:
https://doi.org/10.3390/biomedicines12061223
Chittasupho C et al., “Inhibition of SARS-CoV-2-Induced NLRP3 InflammasomeMediated Lung Cell Inflammation by Triphala-Loaded Nanoparticle Targeting Spike
Glycoprotein S1,” Pharmaceutics 2024, 16, 6: 751. doi:
10.3390/pharmaceutics16060751
Chittasupho C et al., “Targeting spike glycoprotein S1 mediated by NLRP3
inflammasome machinery and the cytokine releases in A549 lung epithelial cells by
nanocurcumin,” Pharmaceuticals (Basel) 2023, 16, 6: 862. doi:
10.3390/ph16060862
Corpetti C et al., “Cannabidiol inhibits SARS-Cov-2 spike (S) protein-induced
cytotoxicity and inflammation through a PPARγ-dependent TLR4/NLRP3/Caspase-1
signaling suppression in Caco-2 cell line,” Phytother. Res. 2021, 35, 12: 6893-
doi: https://doi.org/10.1002/ptr.7302
Cory TJ et al., “Metformin Suppresses Monocyte Immunometabolic Activation by
SARS-CoV-2 Spike Protein Subunit 1,” Front. Immunol. 2021, 12 (Sec. Cytokines and
Soluble Mediators in Immunity): 733921. doi: 10.3389/fimmu.2021.733921
Del Re A et al., “Intranasal delivery of PEA-producing Lactobacillus paracasei
F19 alleviates SARS-CoV-2 spike protein-induced lung injury in mice,” Transl. Med.
Commun. 2024, 9, 9. doi: https://doi.org/10.1186/s41231-024-00167-x
Del Re A et al., “Ultramicronized Palmitoylethanolamide Inhibits NLRP3
Inflammasome Expression and Pro-Inflammatory Response Activated by SARSCoV-2 Spike Protein in Cultured Murine Alveolar Macrophages,” Metabolites 2021,
11, 9: 592. doi: https://doi.org/10.3390/metabo11090592
Dhandapani S et al., “Lipid-encapsulated gold nanoparticles: an advanced strategy
for attenuating the inflammatory response in SARS-CoV-2 infection,” J.
Nanobiotechnology 2025, 23, 15. doi: https://doi.org/10.1186/s12951-024-03064-5
Ferrer MD et al., “Nitrite Attenuates the In Vitro Inflammatory Response of Immune
Cells to the SARS-CoV-2 S Protein without Interfering in the Antioxidant Enzyme
Activation,” Int. J. Mol. Sci. 2024, 25, 5: 3001. https://doi.org/10.3390/ijms25053001
Frank MG et al., “SARS-CoV-2 S1 subunit produces a protracted priming of the
neuroinflammatory, physiological, and behavioral responses to a remote immune
challenge: A role for corticosteroids,” Brain Behav. Immun. 2024, 121: 87-103. doi:
https://doi.org/10.1016/j.bbi.2024.07.034
Frühbeck G et al., “FNDC4 and FNDC5 reduce SARS-CoV-2 entry points and spike
glycoprotein S1-induced pyroptosis, apoptosis, and necroptosis in human
adipocytes,” Cell Mol Immunol. 2021, 18, 10: 2457–9. doi: 10.1038/s41423-021-
00762-0
Gasparello J et al., “Aged Garlic Extract (AGE) and Its Constituent S-Allyl-Cysteine
(SAC) Inhibit the Expression of Pro-Inflammatory Genes Induced in Bronchial
Epithelial IB3-1 Cells by Exposure to the SARS-CoV-2 Spike Protein and the
BNT162b2 Vaccine,” Molecules 2024, 29, 24: 5938. doi:
10.3390/molecules29245938
Gasparello J et al., “In vitro induction of interleukin-8 by SARS-CoV-2 Spike protein is
inhibited in bronchial epithelial IB3-1 cells by a miR-93-5p agomiR,” Int.
Immunopharmacol. 2021, 101: 108201. doi: 10.1016/j.intimp.2021.108201
Gasparello J et al., “Sulforaphane inhibits the expression of interleukin-6 and
interleukin-8 induced in bronchial epithelial IB3-1 cells by exposure to the SARSCoV-2 Spike protein,” Phytomedicine 2021, 87: 153583. doi:
https://doi.org/10.1016/j.phymed.2021.153583
Halma MTJ et al., “Exploring autophagy in treating SARS-CoV-2 spike protein-related
pathology,” Endocrinol Metab (EnM) 2024, 14: 100163. doi:
10.1016/j.endmts.2024.100163
Halma MTJ et al., “Strategies for the Management of Spike Protein-Related
Pathology,” Microorganisms 2023, 11, 5: 1308. doi:
10.3390/microorganisms11051308
Jana S et al., “Cell-free hemoglobin does not attenuate the e]ects of SARS-CoV-2
spike protein S1 subunit in pulmonary endothelial cells,” Int. J. Mol. Sci. 2021, 22,
16: 9041. doi: https://doi.org/10.3390/ijms22169041
Jugler C et al., “SARS-CoV-2 Spike Protein-Induced Interleukin 6 Signaling Is Blocked
by a Plant-Produced Anti-Interleukin 6 Receptor Monoclonal Antibody,”
Vaccines 2021, 9, 11: 1365. doi: https://doi.org/10.3390/vaccines9111365
Ken W et al., “Low dose radiation therapy attenuates ACE2 depression and
inflammatory cytokines induction by COVID-19 viral spike protein in human
bronchial epithelial cells,” Int J Radiat Biol. 2022, 98, 10:1532-1541. doi:
https://doi.org/10.1080/09553002.2022.2055806
Kumar N et al., “SARS-CoV-2 spike protein S1-mediated endothelial injury and proinflammatory state Is amplified by dihydrotestosterone and prevented by
mineralocorticoid antagonism,” Viruses 2021, 13, 11: 2209. doi: 10.3390/v13112209
Liu T et al., “RS-5645 attenuates inflammatory cytokine storm induced by SARSCoV-2 spike protein and LPS by modulating pulmonary microbiota,” Int J Biol Sci.
2021, 17, 13: 3305–3319. doi: 10.7150/ijbs.63329
Loh D, “The potential of melatonin in the prevention and attenuation of oxidative
hemolysis and myocardial injury from cd147 SARS-CoV-2 spike protein receptor
binding,” Melatonin Research 2020, 3, 3: 380-416. doi: 10.32794/mr11250069
Loh JT et al., “Dok3 restrains neutrophil production of calprotectin during TLR4
sensing of SARS-CoV-2 spike protein,” Front. Immunol. 2022, 13 (Sec. Molecular
Innate Immunity). doi: https://doi.org/10.3389/fimmu.2022.996637
Marrone L et al., “Tirofiban prevents the e]ects of SARS-CoV-2 spike protein on
macrophage activation and endothelial cell death,” Heliyon 2024, 10, 15: e35341.
doi: 10.1016/j.heliyon.2024.e35341
Norris B et al., “Evaluation of Glutathione in Spike Protein of SARS-CoV-2 Induced
Immunothrombosis and Cytokine Dysregulation,” Antioxidants 2024, 13, 3: 271.
doi: https://doi.org/10.3390/antiox13030271
Oka N et al., “SARS-CoV-2 S1 protein causes brain inflammation by reducing
intracerebral acetylcholine production,” iScience 2023, 26, 6: 106954. doi:
10.1016/j.isci.2023.106954
Olajide OA et al., “Induction of Exaggerated Cytokine Production in Human
Peripheral Blood Mononuclear Cells by a Recombinant SARS-CoV-2 Spike
Glycoprotein S1 and Its Inhibition by Dexamethasone,” Inflammation 2021, 44:
1865–1877. doi: https://doi.org/10.1007/s10753-021-01464-5
Petrosino S and N Matende, “Elimination/Neutralization of COVID-19 VaccineProduced Spike Protein: Scoping Review,” Mathews Journal of Nutrition & Dietetics
2024, 7, 2. doi: https://doi.org/10.30654/MJND.10034
Roy A et al., “Ultradiluted Eupatorium perfoliatum Prevents and Alleviates SARSCoV-2 Spike Protein-Induced Lung Pathogenesis by Regulating Inflammatory
Response and Apoptosis,” Diseases 2025, 13, 2: 36.
doi: 10.3390/diseases13020036
Satta S et al., “An engineered nano-liposome-human ACE2 decoy neutralizes SARSCoV-2 Spike protein-induced inflammation in both murine and human
macrophages,” Theranostics 2022, 12, 6: 2639–2657. doi: 10.7150/thno.66831
Segura-Villalobos D et al., “Jacareubin inhibits TLR4-induced lung inflammatory
response caused by the RBD domain of SARS-CoV-2 Spike protein,” Pharmacol.
Rep. 2022, 74: 1315–1325. doi: https://doi.org/10.1007/s43440-022-00398-5
Semmarath W et al., “Cyanidin-3-O-glucoside and Peonidin-3-O-glucoside-Rich
Fraction of Black Rice Germ and Bran Suppresses Inflammatory Responses from
SARS-CoV-2 Spike Glycoprotein S1-Induction In Vitro in A549 Lung Cells and THP-1
Macrophages via Inhibition of the NLRP3 Inflammasome Pathway,” Nutrients 2022,
14, 13: 2738. doi: https://doi.org/10.3390/nu14132738
Solopov PA et al., “KVX-053, a protein tyrosine phosphatase 4A3 inhibitor,
ameliorates SARS-CoV-2 spike protein subunit 1–induced acute lung injury in mice,”
J. Pharmacol. Exp. Ther. 2025, 392, 3: 100022. doi: 10.1124/jpet.124.002154
Suprewicz L et al., “Recombinant human plasma gelsolin reverses increased
permeability of the blood-brain barrier induced by the spike protein of the SARSCoV-2 virus,” J Neuroinflamm. 2022, 19, 1: 282. doi: 10.1186/s12974-022-02642-4
Tsilioni I et al., “Nobiletin and Eriodictyol Suppress Release of IL-1β, CXCL8, IL-6,
and MMP-9 from LPS, SARS-CoV-2 Spike Protein, and Ochratoxin A-Stimulated
Human Microglia,” Int. J. Mol. Sci. 2025, 26, 2: 636. doi: 10.3390/ijms26020636
Vargas-Castro R et al., “Calcitriol prevents SARS-CoV spike-induced inflammation
in human trophoblasts through downregulating ACE2 and TMPRSS2 expression,” J
Steroid Biochem Mol Biol 2025, 245: 106625. doi: 10.1016/j.jsbmb.2024.106625
Visvabharathy L et al., “Case report: Treatment of long COVID with a SARS-CoV-2
antiviral and IL-6 blockade in a patient with rheumatoid arthritis and SARS-CoV-2
antigen persistence,” Front. Med. 2022, 9 (Sec. Infectious Diseases – Surveillance).
doi: https://doi.org/10.3389/fmed.2022.1003103
Yonker LM et al., “Multisystem inflammatory syndrome in children is driven by
zonulin-dependent loss of gut mucosal barrier,” J Clin Invest. 2021, 131, 14:
e149633. doi: https://doi.org/10.1172/JCI149633
Youn JY et al., “Therapeutic application of estrogen for COVID-19: Attenuation of
SARS-CoV-2 spike protein and IL-6 stimulated, ACE2-dependent NOX2 activation,
ROS production and MCP-1 upregulation in endothelial cells,” Redox Biol. 2021, 46:
doi: https://doi.org/10.1016/j.redox.2021.102099
Yu J et al., “Direct activation of the alternative complement pathway by SARS-CoV-2
spike proteins is blocked by factor D inhibition,” Blood 2020, 136, 18: 2080–2089.
doi: https://doi.org/10.1182/blood.2020008248

HH. Toll-like receptors (TLRs)

Aboudounya MM and RJ Heads, “COVID-19 and Toll-Like Receptor 4 (TLR4): SARSCoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, Facilitating Entry
and Causing Hyperinflammation,” Mediators Inflamm. 2021: 8874339. doi:
https://doi.org/10.1155/2021/8874339
Burnett FN et al., “SARS-CoV-2 Spike Protein Intensifies Cerebrovascular
Complications in Diabetic hACE2 Mice through RAAS and TLR Signaling Activation,”
Int. J. Mol. Sci. 2023, 24, 22: 16394. doi: https://doi.org/10.3390/ijms242216394
Carnevale R et al., “Toll-Like Receptor 4-Dependent Platelet-Related Thrombosis in
SARS-CoV-2 Infection,” Circ. Res. 2023, 132, 3: 290– 305. doi:
https://doi.org/10.1161/CIRCRESAHA.122.321541
Corpetti C et al., “Cannabidiol inhibits SARS-Cov-2 spike (S) protein-induced
cytotoxicity and inflammation through a PPARγ-dependent TLR4/NLRP3/Caspase-1
signaling suppression in Caco-2 cell line,” Phytother. Res. 2021, 35, 12: 6893–
doi: https://doi.org/10.1002/ptr.7302
Fontes-Dantas FL, “SARS-CoV-2 Spike Protein Induces TLR4-Mediated Long- Term
Cognitive Dysfunction Recapitulating Post-COVID-19 Syndrome in Mice,” Cell
Reports 2023, 42, 3: 112189. doi: https://doi.org/10.1016/j.celrep.2023.112189
Khan S et al., “SARS-CoV-2 Spike Protein Induces Inflammation via TLR2-Dependent
Activation of the NF-κB Pathway,” eLife 2021, 10: e68563. doi: 10.7554/elife.68563
Kim MJ et al., “The SARS-CoV-2 spike protein induces lung cancer migration and
invasion in a TLR2-dependent manner,” Cancer Commun (London) 2023, 44, 2: 273–
doi: https://doi.org/10.1002/cac2.12485
Kircheis R and O Planz, “Could a Lower Toll-like Receptor (TLR) and NF-κB Activation
Due to a Changed Charge Distribution in the Spike Protein Be the Reason for the
Lower Pathogenicity of Omicron?” Int. J. Mol. Sci. 2022, 23, 11: 5966. doi:
https://doi.org/10.3390/ijms23115966
Loh JT et al., “Dok3 restrains neutrophil production of calprotectin during TLR4
sensing of SARS-CoV-2 spike protein,” Front. Immunol. 2022, 13 (Sec. Molecular
Innate Immunity). doi: https://doi.org/10.3389/fimmu.2022.996637
Segura-Villalobos D et al., “Jacareubin inhibits TLR4-induced lung inflammatory
response caused by the RBD domain of SARS-CoV-2 Spike protein,” Pharmacol.
Rep. 2022, 74: 1315–1325. doi: https://doi.org/10.1007/s43440-022-00398-5
Sirsendu J et al., “Cell-Free Hemoglobin Does Not Attenuate the E]ects of SARSCoV-2 Spike Protein S1 Subunit in Pulmonary Endothelial Cells,” Int. J. Mol. Sci.,
2021, 22, 16: 9041. doi: https://doi.org/10.3390/ijms22169041
Sung PS et al., “CLEC5A and TLR2 Are Critical in SARS-CoV-2-Induced NET
Formation and Lung Inflammation,” J. Biomed. Sci. 2022, 29, 52. doi:
https://doi.org/10.1186/s12929-022-00832-z
Zaki H and S Khan, “SARS-CoV-2 spike protein induces inflammatory molecules
through TLR2 in macrophages and monocytes,” J. Immunol. 2021, 206
(1_supplement): 62.07. doi: https://doi.org/10.4049/jimmunol.206.Supp.62.07
Zaki H and S Khan, “TLR2 senses spike protein of SARS-CoV-2 to trigger
inflammation,” J. Immunol. 2022, 208 (1_Supplement): 125.30. doi:
https://doi.org/10.4049/jimmunol.208.Supp.125.30
Zhao Y et al., “SARS-CoV-2 spike protein interacts with and activates TLR4,” Cell
Res. 2021, 31: 818–820. doi: https://doi.org/10.1038/s41422-021-00495-9

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