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SMPDL3B-shedding Mechanistic Chain

A Systems-Level Model of ME/CFS and Long COVID

Σ Evidence-based, hypothesis-layered mechanistic synthesis

This model synthesizes evidence from immunology, glycobiology, vascular physiology, autonomic neuroscience, and membrane biophysics to illustrate how post-viral disruptions can evolve into the persistent, exertion-intolerant state characteristic of ME/CFS and Long COVID. Where appropriate, mechanistic steps are labeled as direct evidence, inference, or hypothesis.

This is a conceptual disease model. It is not medical advice and does not replace clinical decision-making or ongoing empirical research.

1. Post-Viral Immune and Glycosylation Perturbation

Evidence: Long COVID plasma contains significantly increased mannose-positive large EVs and coordinated EV production across subtypes (Pesqueira Sanchez et al., 2025).

Inference: High-mannose EV surfaces suggest persistent alterations in host glycosylation pathways, potentially reflecting unresolved ER/Golgi stress.

Computational inference: Selective removal of EV-associated miRNAs predicts - ↓ JAK–STAT - ↑ Estrogen, VEGF, PI3K, EGFR signaling (PROGENy pathway modeling).

2. Pattern-Recognition Activation (Innate Layer)

Mechanistic evidence: Viral debris, glycan-shifted EVs, and DAMP signals can activate TLR4 (VanElzakker, 2019; Che et al., 2025).

Inference: Mannose-rich EVs may modulate PRR pathways based on known glycan biology.

3. PKC → PI-PLC Activation → SMPDL3B Cleavage (Membrane Microdomain Instability)

Evidence (Rostami-Afshari et al., 2025): - PI-PLC cleaves GPI-anchored proteins such as SMPDL3B. - SMPDL3B loss destabilizes lipid rafts. - This increases TLR4 sensitivity and reduces membrane resilience.

4. Endothelial Dysfunction and Glycocalyx Fragility

Evidence: Endothelial dysfunction demonstrated in ME/CFS (Haffke et al., 2022) and Long COVID.

Inference: miRNA-driven shifts toward VEGF/PI3K/estrogen pathways may alter angiogenic and repair signaling.

Outcome: Reduced NO bioavailability, impaired capillary recruitment, and microvascular heterogeneity.

5. Impaired Perfusion → Ischemic Metabolism

Evidence: ME/CFS patients show early anaerobic threshold, abnormal lactate kinetics, and ischemic-like metabolism during exertion (Jones et al., 2010; Rutherford et al., 2016).

6. Ca²⁺ Overload and ROS Amplification

Evidence: Ca²⁺ handling abnormalities identified in ME/CFS (Syed et al., 2025).

Mechanistic physiology: Ischemia-induced Ca²⁺ accumulation → mitochondrial ROS production.

Evidence: ROS can enhance PI-PLC activity and promote further SMPDL3B cleavage (Rostami-Afshari et al., 2025).

Creates closed positive feedback.

7. Renal Volume Dysregulation and Low-Flow State

Evidence: Reduced renal perfusion, low blood volume, and abnormal venous return documented in ME/CFS (Farquhar et al., 2002; van Campen et al., 2018–2023).

Outcome: Reduced effective circulating volume → worsened perfusion deficits → amplified ischemic susceptibility.

8. Hepatic Strain and FGF21 Elevation (GLA Axis)

Evidence: Elevated FGF21, hepatic metabolic load, and ER stress markers observed in ME/CFS (Hoel et al., 2021; Azimi et al., 2025).

Inference: Hepatic strain contributes to impaired metabolic flexibility and lactate clearance.

9. Autonomic Dysfunction and Perfusion Instability

Evidence: Autonomic imbalance, β₂-AR dysfunction, α2C abnormalities, and sympathetic overactivation have been documented (Issa et al., 2025; Christopoulos et al., 2025).

Outcome: Excess vasoconstriction reduces muscle and cerebral perfusion during exertion.

10. Downstream Effector Failure: Na⁺/K⁺-ATPase Dysfunction (“Depolarization Trap”)

Model (Wirth & Steinacker, 2025): - β₂-AR dysfunction + reduced ATP + ROS → Na⁺/K⁺-ATPase fails. - Intracellular Na⁺ rises → membrane depolarizes → reverse-mode NCX → Ca²⁺ influx. - Ca²⁺ overload → mitochondrial injury → ATP decline → further pump failure.

Produces core ME/CFS symptoms: - loss of force at first contraction - fasciculations - orthostatic intolerance - delayed PEM crashes

This is the final common pathway.

Self-Reinforcing Disease Loops

Innate Loop

TLR4 → PKC → PI-PLC → SMPDL3B loss → ↑ TLR4 sensitivity.

Endothelial Loop

Endothelial dysfunction → hypoperfusion → ischemia → ROS → SMPDL3B loss → more dysfunction.

Volume–Autonomic Loop

Low blood volume → orthostatic stress → sympathetic overdrive → vasoconstriction → lower perfusion.

EV-Glycome Loop

High-mannose EVs + pathogenic miRNAs alter immune/vascular signaling → encourage pathological EV release.

Na⁺/K⁺ Pump Loop

Pump failure → Na⁺ overload → Ca²⁺ overload → mitochondrial injury → more pump failure.

Final Summary
ME/CFS and Long COVID emerge from a network of interdependent processes—post-viral glycosylation drift, EV-mediated signaling abnormalities, SMPDL3B loss, endothelial dysfunction, autonomic dysregulation, and downstream Na⁺/K⁺-ATPase failure—that mutually reinforce one another and prevent physiological recovery.

Diagrams

Diagram 1 – Layered Architecture (Initiation → Maintenance → Effector)

Top-level overview showing how post-viral glycosylation and EV changes (Initiation Layer) drive organ-axis dysregulation (Maintenance Layer) and culminate in Na⁺/K⁺-ATPase failure and PEM physiology (Effector Layer).

Initiation Layer Post-viral ER/Golgi stress, high-mannose EVs, EV miRNA shifts PRR activation (TLR4), PKC → PI-PLC → SMPDL3B loss Maintenance Layer Endothelial dysfunction, microvascular instability Low volume & renal dysregulation Hepatic strain, FGF21, autonomic imbalance Effector Layer Na⁺/K⁺-ATPase dysfunction, depolarization trap Ca²⁺ overload, mitochondrial injury PEM, fasciculations, exertion-intolerant state
Diagram 2 – Feedback Loop Map

Circular representation of the major self-reinforcing loops: Innate, Endothelial, Volume–Autonomic, EV-Glycome, and Na⁺/K⁺ pump loops.

Innate Loop TLR4 → PKC → PI-PLC → SMPDL3B↓ Endothelial Loop Dysfunction → ischemia → ROS Volume–Autonomic Loop Low volume ↔ sympathetic overdrive EV-Glycome Loop High-mannose EVs + miRNA signaling Na⁺/K⁺ Pump Loop Pump failure → Na⁺/Ca²⁺ overload
Diagram 3 – Linear Mechanistic Chain

A simplified left-to-right view of the mechanistic chain from viral trigger and EV glycosylation, through SMPDL3B loss and endothelial dysfunction, to ischemia, Ca²⁺/ROS, autonomic/volume effects, and Na⁺/K⁺-ATPase failure.

Viral & EV trigger High-mannose EVs TLR4 / PRR PKC → PI-PLC SMPDL3B cleavage Endothelial dysfunction microvascular instability Ischemic metabolism Ca²⁺ overload & ROS Na⁺/K⁺-ATPase dysfunction & depolarization trap Volume / Autonomic Low volume, sympathetic ↑

References

ER Stress, Glycosylation & Mitochondrial Protection

  • Yoon, Y. M., et al. (2016). Tauroursodeoxycholic acid reduces ER stress in mesenchymal stem cells. Scientific Reports, 6, 39838. Link
  • Xie, Q., et al. (2002). Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress–induced caspase-12 activation. Hepatology, 36(3), 592–601. Link
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  • Sun, S., et al. (2020). Tauroursodeoxycholic acid attenuates liver injury via SIRT1–FXR signaling. Journal of Cellular and Molecular Medicine, 23(10), 6338–6350. Link
  • Kulkarni, S. R., et al. (2016). Activation of SIRT1 alleviates cholestatic liver injury in a mouse model of intrahepatic cholestasis. Hepatology, 64(6), 2151–2164. Link

ME/CFS Metabolic & Biomarker Findings

  • Hoel, F., et al. (2021). A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome. JCI Insight, 6(16), e149217. Link
  • Beentjes, S. V., et al. (2025). Replicated blood-based biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome are not explained by inactivity. EMBO Molecular Medicine. Link
  • Azimi, F., et al. (2025). Circulating FGF21 as a disease-modifying factor associated with distinct symptoms and cognitive profiles in myalgic encephalomyelitis and fibromyalgia. Scientific Reports, 15, 579. Link

SMPDL3B & Membrane / Innate-Immune Biology

  • Rostami-Afshari, B., et al. (2025). SMPDL3B: A novel biomarker and therapeutic target in myalgic encephalomyelitis. Journal of Translational Medicine, 23, 748. Link
  • Rostami-Afshari, B., et al. (2025). Circulating levels of SMPDL3B define metabolic endophenotypes and subclinical kidney alterations in myalgic encephalomyelitis. International Journal of Molecular Sciences, 26(18), 8882. Link

EV Biology, EV-Glycome & Glycosylation

  • Walker, S. A., et al. (2020). Glycan node analysis of plasma-derived extracellular vesicles. Cells, 9(9), 1946. Link
  • Williams, C., et al. (2018). Glycosylation of extracellular vesicles: Current knowledge, tools and clinical perspectives. Journal of Extracellular Vesicles, 7(1), 1442985. Link
  • Giloteaux, L., et al. (2024). Dysregulation of extracellular vesicle protein cargo in female myalgic encephalomyelitis/chronic fatigue syndrome cases and sedentary controls in response to maximal exercise. Journal of Extracellular Vesicles, 13(1), e12403. Link
  • Glass, K. A., et al. (2025). Extracellular vesicle proteomics uncovers energy metabolism, complement system, and endoplasmic reticulum stress response dysregulation postexercise in males with ME/CFS. Clinical and Translational Medicine, 15(5), e70346. Link
  • Pesqueira Sanchez, M. A., et al. (2025). Increased mannosylation of extracellular vesicles in Long COVID plasma provides a potential therapeutic target for Galanthus nivalis agglutinin (GNA) affinity resin. bioRxiv preprint. Link

Innate Immunity, Cytokines & Neuroinflammation

  • Che, X., et al. (2025). Heightened innate immunity may trigger chronic inflammation, fatigue, and post-exertional malaise in ME/CFS. npj Metabolic Health and Disease, 3, 34. Link
  • Hardcastle, S. L., et al. (2015). Serum immune proteins in moderate and severe chronic fatigue syndrome/myalgic encephalomyelitis patients. International Journal of Medical Sciences, 12(10), 764–772. Link
  • Blundell, S., et al. (2015). Chronic fatigue syndrome and circulating cytokines: A systematic review. Brain, Behavior, and Immunity, 50, 186–195. Link
  • Roerink, M. E., et al. (2017). Cytokine signatures in chronic fatigue syndrome patients: A case–control study and the effect of anakinra treatment. Journal of Translational Medicine, 15, 267. Link
  • VanElzakker, M. B., et al. (2019). Neuroinflammation and cytokines in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A critical review of research methods. Frontiers in Neurology, 9, 1033. Link

Endothelial & Microvascular Dysfunction

  • Haffke, M., et al. (2022). Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS). Journal of Translational Medicine, 20, 138. Link
  • Flaskamp, L., et al. (2022). Serum of post-COVID-19 syndrome patients with or without ME/CFS differentially affects endothelial cell function in vitro. Cells, 11(15), 2376. Link
  • Vassiliou, A. G., et al. (2023). Endotheliopathy in acute COVID-19 and Long COVID. International Journal of Molecular Sciences, 24(9), 8237. Link
  • Nunes, J. M., Kell, D. B., & Pretorius, E. (2023). Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses. Blood Reviews, 60, 101075. Link
  • van Campen, C. L. M. C., Rowe, P. C., & Visser, F. C. (2020). Cerebral blood flow is reduced in ME/CFS during head-up tilt testing. Clinical Neurophysiology Practice, 5, 50–58. Link
  • van Campen, C. L. M. C., Rowe, P. C., & Visser, F. C. (2020). Cerebral blood flow is reduced in severe ME/CFS during mild orthostatic stress (20° tilt). Healthcare, 8(2), 169. Link
  • Christopoulos, E. M., et al. (2025). Mapping cerebral blood flow in ME/CFS and orthostatic intolerance: Insights from a systematic review. Journal of Translational Medicine, 23, 963. PubMed

Autonomic, Blood Volume & Orthostatic Findings

  • Farquhar, W. B., et al. (2002). Blood volume and its relation to peak oxygen consumption and physical activity in chronic fatigue. Journal of Applied Physiology. PubMed
  • Issa, A., et al. (2025). Autonomic dysfunction in ME/CFS: Findings from the MCAM study. Journal of Clinical Medicine, 14(17), 6269. Link
  • Jason, L. A., McGarrigle, W. J., & Vermeulen, R. C. W. (2024). The head-up tilt table test as a measure of autonomic functioning among patients with ME/CFS. Journal of Personalized Medicine, 14, 238. Link
  • van Campen, C. L. M. C., et al. (2018). Blood volume status in ME/CFS correlates with orthostatic symptoms. Conference abstract / preliminary report. PubMed
  • van Campen, C. L. M. C., Rowe, P. C., & Visser, F. C. (2021). Cerebral blood flow remains reduced after tilt testing in ME/CFS patients. Clinical Neurophysiology Practice, 6, 245–255. PubMed
  • van Campen, C. L. M. C., Rowe, P. C., & Visser, F. C. (2023). Comparison of 20° and 70° tilt testing in adolescent ME/CFS patients. Frontiers in Pediatrics, 11, 1169447. PubMed

Muscle, Mitochondrial Dysfunction & PEM

  • Baraniuk, J. N. (2025). Exertional exhaustion (post-exertional malaise, PEM) evaluated by the effects of exercise on cerebrospinal fluid metabolomics–lipidomics and serine pathway in ME/CFS. International Journal of Molecular Sciences, 26(3), 1282. Link
  • Franklin, J. D., & Graham, M. (2022). Repeated maximal exercise tests of peak oxygen consumption in people with ME/CFS: A systematic review and meta-analysis. Fatigue: Biomedicine, Health & Behavior, 10(3), 119–135. Link
  • Jones, D. E. J., et al. (2010). Abnormalities in pH handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome. Journal of Internal Medicine, 267(4), 394–401. Link
  • Rutherford, G., Manning, P., & Newton, J. L. (2016). Understanding muscle dysfunction in chronic fatigue syndrome. Journal of Aging Research, 2016, 2497348. Link
  • Vermeulen, R. C. W., et al. (2010). Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite normal oxidative phosphorylation capacity. Journal of Translational Medicine, 8, 93. Link
  • Syed, A. M., et al. (2025). Mitochondrial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome. Physiology (Bethesda), 40(4), 319–328. Link
  • Wirth, K., & Steinacker, J. M. (2025). Skeletal muscle failure under exertion in ME/CFS: Implications for post-exertional malaise. Preprints.org, 202509.2242. Link
  • Wirth, K. J., & Scheibenbogen, C. (2021). Pathophysiology of skeletal muscle disturbances in ME/CFS. Journal of Translational Medicine, 19, 162. PubMed

Note: This page summarizes the GLA v2.3 hypothesis model and is intended for informational and research support purposes. It is not a clinical guideline or treatment recommendation.