Pathological Mechanisms

Comprehensive mechanisms from Halma et al. (2025) Advances in Virology — Table 1 core interactions plus system-specific pathways for cardiovascular, neurologic, reproductive, autoimmune, and oncologic injury.

Primary source: Halma MTJ, et al. (2025)Opens in new tab · Supporting autophagy review: Halma MTJ, Marik PE, Saleeby YM (2024)Opens in new tab

Table 1 — Core pathological mechanisms

From Halma MTJ, et al. (2025)Opens in new tab (Advances in Virology, 2025). Reproduced from Halma et al. autophagy review [95] under CC BY 4.0.

ACE-2

Evidence: High

Cardiovascular / vascular

Interaction: Spike RBD binding to ACE2
Physiological impact: Cell entry (infection), thrombosis, myocarditis/pericarditis, vasculitis/endotheliitis
Clinical evidence: Myocarditis, thrombosis/thrombocytopenia, vasculitis, endotheliitis
Source: Theoharides TC, Conti P (2021)Opens in new tab Hoffmann M, et al. (2020)Opens in new tab

CD-147 (Basigin)

Evidence: Medium

Cardiovascular / hematologic

Interaction: Spike RBD binding; inhibition of CD-147
Physiological impact: Myocarditis/pericarditis, microvascular disease, hemolytic anemia
Clinical evidence: Myocarditis, microvascular disease (cardiac pericytes), hemolytic anemia
Source: Wang K, et al. (2020)Opens in new tab Avolio E, et al. (2021)Opens in new tab

Toll-like receptors (TLR2, TLR4)

Evidence: Medium

Immune / systemic inflammation

Interaction: Binding/activation of TLR4 and TLR2 by spike/S1
Physiological impact: Cytokine release and systemic inflammation
Clinical evidence: Inflammatory disorders, vaccine-associated inflammation
Source: Shirato K, Kizaki T (2021)Opens in new tab

Estrogen receptor α (ERα)

Evidence: Medium

Reproductive / endocrine

Interaction: Binding/modulation via S2 LXD-like motif
Physiological impact: Menstrual irregularities, hormonal dysregulation
Clinical evidence: Menstrual cycle changes (~40% of vaccinated menstruating women); heavy bleeding
Source: Solis O, et al. (2022)Opens in new tab

p53 BP1 / BRCA1 / BRCA2

Evidence: Low

Oncology (hypothesis)

Interaction: S2 subunit interaction (in silico); spike DNA effects on p53 pathway
Physiological impact: Potential inhibition of tumor suppression mechanisms
Clinical evidence: Non-Hodgkin lymphoma, myeloproliferative disorders (case reports; causality debated)
Source: Singh N, Bharara Singh A (2020)Opens in new tab Various (2024)Opens in new tab

Prion protein / amyloid-β

Evidence: Low

Neurologic / coagulation

Interaction: Prion-like propagation of spike aggregates; interaction with PrP and Aβ
Physiological impact: Potential neurodegeneration and blood microclots
Clinical evidence: Dementia associations (hypothesis); fibrin-resistant microclots
Source: Tetz G, Tetz V (2022)Opens in new tab Grobbelaar LM, Venter C, Pretorius E (2021)Opens in new tab

α7 nicotinic AChR (α7nAChR)

Evidence: Medium

Neurologic / psychiatric

Interaction: Helical motif in spike neck downregulates cell-surface α7nAChR
Physiological impact: Neuropsychiatric symptoms, cholinergic dysregulation
Clinical evidence: Chronic fatigue, cognitive deficits
Source: Tillman TS, Chen Q, Bondarenko V, Coleman JA, Xu Y, Tang P (2023)Opens in new tab Various (2023)Opens in new tab

Blood–brain barrier (BBB)

Evidence: Medium

Neurologic

Interaction: Barrier degradation; spike permeability through and across BBB
Physiological impact: Neurologic manifestations, neuro-COVID
Clinical evidence: Neurologic complications, brain fog, cognitive issues
Source: Rhea EM, et al. (2021)Opens in new tab

Molecular mimicry (multiple human epitopes)

Evidence: Medium

Autoimmune / multisystem

Interaction: Spike epitopes share similarity with human proteins (TQLPP/thrombopoietin, ELDKY/PRKG1, etc.)
Physiological impact: Autoantibody formation, varied symptomatology
Clinical evidence: Long COVID severity correlates with autoantibodies (ADR, muscarinic receptors, ACE2, etc.)
Source: Vojdani A, Vojdani E, Kharrazian D (2021)Opens in new tab

Mitochondria

Evidence: Medium

Metabolic / neurologic

Interaction: Mitochondrial damage (mechanism incompletely defined)
Physiological impact: Fatigue, brain fog, metabolic dysfunction
Clinical evidence: Chronic fatigue, cognitive deficits in PASC subsets
Source: Various (2025)Opens in new tab

System-specific & additional mechanisms

Cardiovascular (§3.1), neurologic (§3.3), BBB (§3.4), reproductive (§3.5), oncology (§3.6), and pharmacogenomic interaction pathways.

Anti-PF4 antibodies (platelet factor 4)

Evidence: High

Hematologic / thrombotic

Interaction: Autoantibody formation (primarily adenovirus-vector vaccines; polyanion-related)
Physiological impact: Vaccine-induced thrombosis and thrombocytopenia (VITT)
Clinical evidence: VITT case series (AstraZeneca, J&J)
Source: Greinacher A, et al. (2021)Opens in new tab

Complement system

Evidence: Medium

Coagulation / inflammation

Interaction: S1 activates microvascular endothelium and complement → platelet aggregation
Physiological impact: Thromboinflammation, endothelial injury
Clinical evidence: In vitro and clinical coagulopathy markers (D-dimer, CRP)
Source: Perico L, et al. (2022)Opens in new tab

Fibrin(ogen)

Evidence: Medium

Coagulation

Interaction: S1 induces amyloidogenic fibrin resistant to fibrinolysis
Physiological impact: Microclot formation, impaired clot breakdown
Clinical evidence: Long COVID microclot hypotheses; elevated D-dimer
Source: Grobbelaar LM, Venter C, Pretorius E (2021)Opens in new tab

Mast cells

Evidence: Low

Immune / allergic

Interaction: SARS-CoV-2/spike activates mast cells; MCAS-like symptom overlap
Physiological impact: Multisystem inflammation, histamine-mediated symptoms
Clinical evidence: Long COVID symptom overlap with MCAS patients
Source: Theoharides TC, Conti P (2021)Opens in new tab

Neutrophil extracellular traps (NETosis)

Evidence: Medium

Immune / thrombotic

Interaction: Spike-associated NET formation
Physiological impact: Thrombosis, autoimmunity, vascular inflammation
Clinical evidence: COVID-19 severity and autoimmunity literature
Source: Zuo Y, et al. (2020)Opens in new tab

TMPRSS2

Evidence: High

Entry / tropism

Interaction: Spike cleavage at S1/S2 site enables membrane fusion
Physiological impact: Tissue tropism, infectivity, pharmacogenomic susceptibility
Clinical evidence: GWAS-linked severity variants; fusion inhibitor rationale
Source: Hoffmann M, et al. (2020)Opens in new tab

Integrins (α5β1) / RGD motifs

Evidence: Low

Vascular

Interaction: Spike RGD sequences disrupt cell adhesion
Physiological impact: Endothelial and leukocyte dysfunction
Clinical evidence: In vitro adhesion studies
Source: Various (2022)Opens in new tab

Neuropilin-1

Evidence: Medium

Entry / neurologic

Interaction: Spike binding enhances ACE2-dependent entry
Physiological impact: Enhanced infectivity, vascular/neurological effects
Clinical evidence: Preclinical entry studies
Source: Daly JL, et al. (2020)Opens in new tab

Exosomes

Evidence: Medium

Immune

Interaction: Spike-bearing exosomes propagate inflammatory signaling
Physiological impact: Sustained immune activation
Clinical evidence: Immunogenic exosomal spike in vitro
Source: Bansal S, et al. (2022)Opens in new tab

Autophagy / lysosomal clearance

Evidence: Low

Cellular clearance

Interaction: Impaired clearance of spike aggregates; mRNA persistence
Physiological impact: Prolonged antigen presence, post-vaccine sequelae
Clinical evidence: Autophagy-upregulation proposed as therapeutic (Halma 2024)
Source: Halma MTJ, Marik PE, Saleeby YM (2024)Opens in new tab

Gut microbiome / GI reservoir

Evidence: Low

GI / microbiome

Interaction: Possible bacterial transfection of plasmid DNA; gut barrier effects
Physiological impact: Prolonged spike expression (hypothesis)
Clinical evidence: Gut dysbiosis associated with long COVID severity
Source: Various (2024)Opens in new tab

Genomic instability / p53 pathway

Evidence: Low

Oncology (hypothesis)

Interaction: Spike DNA may inhibit p53-mediated apoptosis pathways
Physiological impact: Chemotherapy resistance, oncologic concerns (hypothesis)
Clinical evidence: In vitro; case reports only
Source: Various (2024)Opens in new tab