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SMPDL3B Phenotypes in ME/CFS and Long COVID

These parallel mechanistic chains describe how SMPDL3B dysfunction may present as either a deficient (baseline-low) state or a shedding-dominant (dynamic-loss) state. Both converge on endothelial fragility, perfusion instability, and delayed post-exertional crashes (PEM), but differ in root drivers and amplification pathways.

Shared upstream context: EV-glycome abnormality (preprint)

biomarker anchor
  • ↑ EV abundance in post-viral illness
  • ↑ mannose-positive (GNA-binding) EVs
  • GNA affinity resin can bind and isolate a mannose-enriched EV subpopulation; in pre-clinical ex vivo plasma studies, this was associated with depletion of EV-associated inflammatory microRNAs

Interpretation: this pattern establishes a persistent alteration in EV biogenesis and surface glycosylation; it is consistent with ongoing cellular/secretory-pathway strain (ER/Golgi stress is a plausible context), but does not prove a single upstream cause.

Diagram A — Capacity dynamics under stress (“on → removed → vulnerability re-challenge → stressor on”)

Shedding shows fast state shifts (rapid drop, faster rebound, vulnerable to re-challenge). Deficient shows slower drift with slower, partial recovery (baseline doesn’t fully reset).

orientation
Y: membrane buffering / endothelial tolerance (capacity) X: time + load / exertion / inflammatory stress exposure stressor on stressor removed vulnerability re-challenge stressor on Shedding: fast dip + faster recovery, but vulnerable to re-challenge Deficient: slow decline + slower partial recovery (baseline doesn’t fully reset) Interpret as “capacity”, not symptom severity lower capacity → earlier perfusion instability and delayed PEM risk
Deficient = baseline-low capacity Shedding = state shifts + re-challenge vulnerability Both can converge downstream

Diagram B — SMPDL3B role differs by phenotype

Deficient is expression-limited (quiet). Shedding is flare-amplified (loop-capable).

mechanism
Deficient Shedding-dominant EV / secretory strain context signal ↓ transcriptional support SIRT1 / c-Myc axis Baseline-low SMPDL3B membrane buffering reduced Endothelial tolerance ↓ earlier perfusion brittleness Key: largely static vulnerability (no self-reinforcing loop shown) Stress / inflammation flare context PKC / PLC-axis ↑ flare amplifier SMPDL3B membrane loss cleavage / displacement Endothelial instability ↑ threshold fragility ROS feedback during flares
Deficient: expression-limited Shedding: flare-amplified loop-capable

Diagram C — Downstream convergence

Different roots, shared downstream physiology that produces delayed PEM.

convergence
Deficient entry baseline-low buffering Shedding entry stress-triggered loss Endothelial instability brittle tone • permeability • NO signaling fragility / tone instability Perfusion failure Ischemic metabolism Ca²⁺ / ROS bursts Delayed PEM Takeaway: different initiating failure mode → shared downstream crash machinery.
Deficient: earlier threshold Shedding: flare-driven instability Common endpoint: delayed PEM

SMPDL3B-Deficient Phenotype

Low membrane buffering is present at baseline (expression-level insufficiency). PI-PLC is treated as a secondary flare amplifier.

Baseline-low SMPDL3B Expression-control root PI-PLC: episodic
Deficient
  1. Post-viral or inflammatory stress increases innate signaling tone.
  2. EV burden and EV surface mannosylation increase (mannose-positive / GNA-binding EVs).
  3. This pattern is consistent with persistent secretory-pathway strain (ER/Golgi stress is a plausible context).
  4. Metabolic-epigenetic buffering is reduced (NAD+/redox strain can suppress SIRT1).
  5. c-Myc-dependent transcription becomes insufficient or unstable.
  6. Baseline SMPDL3B expression remains chronically low (expression-level deficiency).
  7. Membrane microdomain control weakens; innate signaling becomes easier to amplify.
  8. Endothelial stability deteriorates (NO fragility, permeability/tone instability).
  9. Perfusion becomes brittle under load; regional hypoperfusion emerges.
  10. Tissues shift intermittently toward ischemic metabolism.
  11. ATP strain impairs calcium handling; mitochondrial stress rises.
  12. Delayed mitochondrial ROS bursts occur, aligning with delayed PEM timing.
  13. ROS can engage secondary amplifiers (PKC/PLC-axis) during flares without defining the baseline state.
  14. Renal hypoperfusion destabilizes volume regulation; low effective circulating volume worsens OI.
  15. Hepatic metabolic load accumulates; FGF21 reflects sustained strain.
  16. Autonomic sympathetic bias locks perfusion instability and lowers the crash threshold.

One-line synthesis: In SMPDL3B deficiency, EV-glycome-linked cellular stress may suppress SIRT1->c-Myc transcriptional support, producing baseline-low membrane buffering; exertional stress then drives hypoperfusion → ischemic metabolism → Ca2+/ROS bursts, with secondary amplifiers deepening PEM.

SMPDL3B Shedding-Dominant Phenotype

Membrane SMPDL3B is dynamically lost during stress states. PKC/PLC-axis signaling is central to flare amplification.

Dynamic membrane loss PKC/PLC-axis central ROS feedback loop
Shedding-dominant
  1. Post-viral or inflammatory stress increases innate signaling tone.
  2. EV burden and EV surface mannosylation increase (mannose-positive / GNA-binding EVs).
  3. This pattern is consistent with persistent secretory-pathway strain (ER/Golgi stress is a plausible context).
  4. Inflammatory kinase tone rises (PKC-family bias).
  5. PKC/PLC-axis signaling can become pathologically active during flares.
  6. This signaling context can promote SMPDL3B membrane loss (cleavage and/or displacement).
  7. Membrane instability amplifies innate signaling and endothelial sensitivity.
  8. Endothelial stability deteriorates (NO impairment, permeability/tone instability).
  9. Perfusion becomes brittle under load; regional hypoperfusion emerges.
  10. Tissues shift toward ischemic metabolism during stress.
  11. ATP strain impairs calcium handling; mitochondrial stress rises.
  12. Delayed mitochondrial ROS bursts occur, aligning with delayed PEM timing.
  13. ROS further amplifies kinase/lipid signaling, accelerating SMPDL3B loss and closing a self-reinforcing loop.
  14. Renal hypoperfusion destabilizes volume regulation; low effective circulating volume worsens OI.
  15. Hepatic metabolic load accumulates; FGF21 reflects sustained strain.
  16. Autonomic sympathetic bias locks perfusion instability and lowers the crash threshold.

One-line synthesis: In shedding dominance, innate activation drives PKC/PLC-axis signaling that promotes SMPDL3B membrane loss, destabilizing endothelium and perfusion; exertional stress then produces ischemic metabolism → Ca2+/ROS bursts, with ROS feeding back to accelerate SMPDL3B loss and PEM.

Patient summary (plain-language) Tap to expand

These two chains describe two common ways the same “stress intolerance” biology can show up in ME/CFS or Long COVID. Both patterns can lead to unstable blood flow, and that can trigger delayed crashes (PEM).

Deficient (baseline-low) pattern

  • Think: “the membrane buffering is low most of the time.”
  • The system starts fragile, so even small stressors can push blood flow and energy delivery out of range.
  • Crashes are often driven by hypoperfusion → low-oxygen metabolism → delayed oxidative stress.

Shedding-dominant (dynamic-loss) pattern

  • Think: “the membrane buffering drops during flares.”
  • Stress signaling can actively reduce protective membrane control during a bad day or after exertion.
  • This can make crashes feel more abrupt, with stronger feedback loops during flares.

Common endpoint: Both patterns can reduce stable perfusion (especially upright or during exertion), increase cellular stress after activity, and create the delayed crash pattern that defines PEM.

Note: This is an explanatory framework intended for research and education. It summarizes hypotheses that integrate multiple findings and does not constitute medical advice.

Convergence: Despite different roots, both phenotypes converge on endothelial instability → brittle perfusion → ischemic metabolism → Ca2+/ROS bursts → delayed PEM.

References

Links are provided as DOI / PubMed / PMC when available. This list includes only references directly relevant to the mechanisms discussed on this page.

Extracellular vesicles & glycosylation

GNA affinity resin binding of extracellular vesicles and depletion of inflammatory microRNAs in Long COVID plasma

Aethlon Medical (2025). Pre-clinical data / bioRxiv preprint (via press release)

Source summary

Increased mannosylation of extracellular vesicles in Long COVID plasma

Pesqueira-Sanchez, M.A.P., et al. (2025). bioRxiv (preprint)

DOI Full text PubMed

ER stress, PKC / PLC permissive biology

Glycosylation-directed quality control of protein folding

Xu, C., & Ng, D.T.W. (2015). Nat Rev Mol Cell Biol

DOI PubMed

Protein kinase Cθ is required for autophagy in response to ER stress

Sakaki, K., et al. (2008). J Biol Chem

PubMed Full text

Oxidative stress-induced phospholipase C-γ1 activation enhances cell survival

Wang, X.T., et al. (2001). J Biol Chem

DOI PubMed

Mechanisms for redox-regulation of protein kinase C

Steinberg, S.F. (2015). Front Pharmacol

DOI PubMed PMC

SMPDL3B & endothelial instability

SMPDL3B as a biomarker and therapeutic target in myalgic encephalomyelitis

Rostami-Afshari, B., et al. (2025). J Transl Med

DOI PubMed PMC

Endothelial dysfunction and altered biomarkers in post-COVID-19 syndrome and ME/CFS

Haffke, M., et al. (2022). J Transl Med

DOI PubMed PMC

Perfusion failure, metabolism & PEM

Cerebral blood flow is reduced in ME/CFS during head-up tilt testing

van Campen, C.L.M.C., et al. (2020).

PubMed

A map of metabolic phenotypes in patients with ME/CFS

Hoel, F., et al. (2021). JCI Insight

DOI PubMed

Pathophysiology of skeletal muscle disturbances in ME/CFS

Wirth, K.J., & Scheibenbogen, C. (2021). J Transl Med

DOI PubMed PMC

Oxidative stress is a shared characteristic of ME/CFS and Long COVID

Shankar, V., et al. (2025). PNAS

DOI PubMed PMC

Exertional exhaustion (post-exertional malaise)

Baraniuk, J.N. (2025). Int J Mol Sci

DOI PubMed PMC

Autonomic regulation

Does the chronic fatigue syndrome involve the autonomic nervous system?

Freeman, R., & Komaroff, A.L. (1997). Am J Med

DOI

Framework documents