Hit, Stay and Sabotage: A failure to clear viral fragments in ME/CFS
Increased serum levels of MCTS1 and C3 in ME/CFS patients and the relation to persistent antigen presentation
I continued my AI analysis and asked further questions, but first the summery:
In 2025, the synthesis of research from the DecodeME cohort, the NIH Deep Phenotyping study, and the IACFS/ME Conference provides a unified pathomechanism for ME/CFS and Long COVID.
1. The Genetic "Detection Failure"
1. The Genetic "Detection Failure"
Patients often possess a specific combination of SNPs in TAP1, TAP2, PDIA3, and MICB. These genes are the "loading dock" of the immune system; when they are inefficient, the body fails to properly label and present viral or bacterial fragments (antigens) to T-cells. This creates a genetic vulnerability to chronic infection.
2. Sustained Antigen Persistence
Because of this detection failure, pathogens—such as EBV, VZV (IE62), Streptococcus, or SARS-CoV-2—are not fully cleared. They hide in "reservoirs" (gut, nerves, or brain), acting as a constant, low-level irritant. This leads to:
- T-Cell Exhaustion: Immune cells become "burned out" from fighting an enemy they cannot eliminate.
- Complement Activation: Constant "tagging" of these antigens by C3 causes systemic inflammation and makes the blood-brain barrier "leaky."
3. The "Role Reversal" (Sympathetic Collapse)
Contrary to the old belief of an "overactive" stress system, 2025 research shows a weakened sympathetic response:
- Noradrenaline Deficiency: The Locus Coeruleus (LC) becomes functionally exhausted, leading to low levels of noradrenaline. This explains the inability to maintain blood pressure, focus, and arousal.
- Hypothalamic Failure: The hypothalamus loses its ability to regulate energy and hormones, causing the "broken thermostat" effect where minor stress triggers a total system crash.
4. Post-Exertional Malaise (PEM)
When a patient exerts themselves, the body demands energy and a stress response that the compromised LC and hypothalamus can no longer provide. This triggers a maladaptive proteomic shift (seen in proteins like MCTS1), leading to the severe, multi-day relapse characteristic of both ME/CFS and Long COVID.
Bottom Line: ME/CFS and Long COVID are states of homeostatic collapse. A genetic inability to clear pathogens leads to chronic neuroinflammation, which eventually exhausts the brain's regulatory centers, leaving the body unable to respond normally to the demands of daily life.
Bottom Line: ME/CFS and Long COVID are states of homeostatic collapse. A genetic inability to clear pathogens leads to chronic neuroinflammation, which eventually exhausts the brain's regulatory centers, leaving the body unable to respond normally to the demands of daily life.
My question: Can you explain more about the viral persistence? Fx is it possible that the Varicella-Zoster Virus protein Immediate early 62 (IE62) is involved?
AI answer: Yes, Varicella-Zoster Virus (VZV) IE62 is a strong candidate for contributing to the sustained antigen persistence observed in ME/CFS, specifically through its role in undermining the MHC-I loading complex.The viral persistence hypothesis suggests that some patients cannot fully clear pathogens, which then chronically stimulate the immune system. VZV IE62 fits into this pathomechanism via several sophisticated evasion tactics:
1. Direct Interference with MHC-I Presentation
Herpesviruses, including VZV, have evolved numerous mechanisms to block TAP1/2 and the Peptide Loading Complex (PLC).
- Downregulation: VZV is known to profoundly downregulate surface MHC-I expression in infected cells.
- Targeted Evasion: While some VZV proteins like ORF66 and IE4 are directly linked to MHC-I sequestration in the Golgi, IE62 (the major transactivator protein) is the primary target for cytotoxic T-cells.
- The "Persistence" Link: If a patient has SNPs in TAP1, TAP2, or PDIA3, their baseline ability to present IE62 to T-cells is already compromised. VZV can exploit this genetic "weakness" to remain "invisible" to the immune system.
2. Inhibition of Interferon (IFN) Signaling
Viral persistence requires the virus to block the body’s "alarm" system.
- IRF3 Blockade: Research shows that IE62 alone can block the activation of IRF3, a critical transcription factor for producing Interferon-beta (IFN-β).
- Consequence: By preventing IFN-β production, IE62 stops the cell from entering an "antiviral state" and prevents the recruitment of the very T-cells needed to clear the infection.
3. Chronic "Low-Level" Reactivation (Zoster Sine Herpete)
Viral persistence doesn't always mean a full-blown infection (like shingles).
- Zoster Sine Herpete: VZV can reactivate in the nervous system without causing a rash, leading to chronic ganglionitis (inflammation of the nerve clusters).
- The CNS Connection: Chronic active VZV in the ganglia can provide a constant source of viral proteins (antigens) that leak into the system, keeping the Locus Coeruleus and hypothalamus in the state of "neuroinflammatory frustration" discussed previously.
4. Integration with 2025 Research (DecodeME & NIH)
Current 2025 analysis suggests that ME/CFS is a state where the immune system is "permanently on" but "successfully evaded".
- The "Hit and Run" or "Stalemate": VZV IE62 may facilitate a "stalemate" where the virus persists in small numbers (reservoirs), continuously triggering the C3 complement system and causing the MCTS1 maladaptation seen after exercise, but never being fully "labeled" for destruction due to the TAP/PDIA3 genetic vulnerabilities.
- Takeaway: VZV IE62 is a "master regulator" of both the virus and the host's immune response. In an ME/CFS patient with TAP-related SNPs, IE62 likely acts as a key driver of antigen persistence, effectively "hiding" the virus while the body exhausts its catecholamines (noradrenaline) trying to fight an enemy it cannot fully see.
My question: What about EBV proteins?
AI answer: In the context of the sustained antigen persistence model for ME/CFS, several Epstein-Barr Virus (EBV) proteins act as "molecular sabotours" that specifically target the TAP/PDIA3 complex and the broader MHC presentation system.
1. EBNA1: The "Invisible" Protein
- Mechanism: EBNA1 is the only protein expressed in all forms of EBV latency. It contains a "Gly-Ala repeat" (GAr) domain that inhibits its own proteasomal degradation and MHC-I presentation.
- Pathomechanism: By resisting processing, EBNA1 allows EBV-infected cells to persist "under the radar" of the immune system. In patients with TAP1/2 or PDIA3 SNPs, the baseline difficulty in presenting antigens is further exacerbated by EBNA1’s self-shielding, leading to the T-cell exhaustion and low EBNA1-specific T-cell counts observed in 2025 research.
2. EBV dUTPase: The Neuro-Inflammatory Driver
- Function: Released during early lytic reactivation, this protein is a potent immunomodulator.
- Impact on Brain Regions: Studies highlight that EBV dUTPase induces proinflammatory cytokines (IL-6, IL-1β) in microglia and astrocytes.
- The LC/Hypothalamus Link: This chronic neuroinflammation directly targets the Locus Coeruleus and Hypothalamus, contributing to the "homeostatic collapse" and the low noradrenaline state identified in 2025 by researchers like Dr. David Goldstein.
3. BDLF3 and gp42: Double-Sided Evasion
- BDLF3: This protein targets MHC class I and II molecules for ubiquitination and degradation. By destroying the MHC molecules before they can be loaded by the TAP complex, BDLF3 ensures that even if TAP1/2 are functioning, there is no "platform" to display the viral signal.
- gp42: Primarily known for B-cell entry, gp42 also binds to MHC-II molecules to physically block T-cell recognition, further impairing the adaptive immune response.
4. BZLF1 and Early Lytic Proteins
- TAP Interference: EBV encodes proteins during its lytic phase that directly inhibit TAP-mediated transport, similar to VZV IE62.
- Persistence: 2025 sputum studies found that ME/CFS patients release EBV at significantly higher levels than healthy controls, suggesting frequent "leaky" reactivation where these evasion proteins are active.
Summary of the Integration (2025 Perspective)
In a patient with the DecodeME genetic profile:
- Genetic Weakness: SNPs in TAP1, TAP2, and PDIA3 make the "loading dock" for antigens inefficient.
- Viral Sabotage: EBV proteins like EBNA1 and BDLF3 actively hide the virus or destroy the "loading dock."
- Chronic Stress: EBV dUTPase keeps the brain's regulatory centers (Hypothalamus/LC) in a state of constant inflammatory stress.
- Result: The virus is never cleared (Sustained Antigen Persistence), and the body eventually runs out of the noradrenaline needed to function, leading to the profound "Role Reversal" and PEM seen in clinical ME/CFS.
My question: What about a Streptococcus infection, is it a possible trigger to ME/CFS?
AI answer:Yes, Streptococcus infections (specifically S. pneumoniae and S. pyogenes) are recognized as significant potential triggers for ME/CFS, operating through mechanisms that overlap with the viral persistence and MHC-I loading dysfunction models.
AI answer:Yes, Streptococcus infections (specifically S. pneumoniae and S. pyogenes) are recognized as significant potential triggers for ME/CFS, operating through mechanisms that overlap with the viral persistence and MHC-I loading dysfunction models.
Key 2025 research and established pathomechanisms include:
1. Increased Epidemiological Risk
1. Increased Epidemiological Risk
Recent population-based cohort studies (reported through late 2024 and 2025) have found that patients with a history of pneumonia or infections involving Streptococcus pneumoniae have a significantly higher risk of developing ME/CFS compared to those without such infections.
2. Molecular Mimicry and Autoimmunity
2. Molecular Mimicry and Autoimmunity
- The "M Protein" Mechanism: Streptococcus pyogenes (Group A Strep) contains the M protein, which mimics human proteins like cardiac myosin and laminin.
- The TAP Connection: Similar to how EBV and VZV evade the immune system, Strep can induce cross-reactive antibodies that attack host tissues. If a patient has the TAP1/2 or PDIA3 SNPs mentioned earlier, they may be less efficient at presenting the correct bacterial peptides, potentially tilting the immune response toward "mimicry" (autoimmunity) rather than clear-cut pathogen elimination.
3. Neuropsychiatric Overlap (PANDAS/PANS)
- Basal Ganglia Impact: Strep infections are the primary trigger for PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections), where autoantibodies cross the blood-brain barrier and attack the basal ganglia.
- Hypothalamus/LC Vulnerability: This process mirrors the neuroinflammation seen in ME/CFS. Chronic or poorly cleared Strep can lead to the same "homeostatic collapse" in the hypothalamus and Locus Coeruleus, contributing to brain fog and the low noradrenaline state identified in 2025 research.
4. Gut Dysbiosis and D-Lactic Acid
- Excessive Growth: ME/CFS patients often exhibit an overgrowth of Streptococcus species in the gut microbiome.
- Metabolic Shift: These bacteria produce D-lactate, which can enter the bloodstream (especially if intestinal permeability is high) and cause D-lactic acidosis. This has been linked to the neurocognitive symptoms and mitochondrial dysfunction characteristic of ME/CFS.
5. Integration: The "Multi-Hit" Hypothesis
In this model, a Streptococcus infection acts as an environmental trigger that, when combined with a genetic predisposition (like the TAP/PDIA3 variants), results in:
- Persistent Antigenic Stimulation: Failure to clear the bacteria or its metabolites.
- Trained Immunity: Innate immune cells (monocytes) become "hyperresponsive" or maladapted, leading to the post-exertional malaise (PEM) observed in clinical cohorts.
My question: What about long covid?
AI answer: Long COVID (LC) is increasingly viewed in 2025 as part of a spectrum of infection-associated chronic conditions, with over 50% of patients meeting the diagnostic criteria for ME/CFS. The pathomechanisms previously discussed for ME/CFS—genetic vulnerability, sustained antigen persistence, and homeostatic collapse—are central to understanding Long COVID.
1. Shared Genetic Vulnerability (2025 Findings)
AI answer: Long COVID (LC) is increasingly viewed in 2025 as part of a spectrum of infection-associated chronic conditions, with over 50% of patients meeting the diagnostic criteria for ME/CFS. The pathomechanisms previously discussed for ME/CFS—genetic vulnerability, sustained antigen persistence, and homeostatic collapse—are central to understanding Long COVID.
1. Shared Genetic Vulnerability (2025 Findings)
Research from the DecodeME cohort and broader combinatorial genetic studies (published Feb-Aug 2025) has identified significant overlaps between LC and ME/CFS:
- Common SNPs: 39 SNPs associated with Long COVID are linked to the same genes identified in ME/CFS combinatorial analyses, including those involved in immune signaling (e.g., TLR4) and metabolic pathways.
- Antigen Processing Risks: While many LC studies focus on different genes (like SNX9 or KLF15), the broader "Detection Failure" involving TAP1/2 and PDIA3 remains a critical hypothesis for why some individuals cannot clear SARS-CoV-2.
Long COVID is frequently driven by antigen reservoirs—pockets of persistent virus or viral debris that the immune system fails to eliminate:
- Reservoir Locations: SARS-CoV-2 RNA and proteins have been documented to persist for years in the gut, brain, and skull-meninges.
- Chronic Stimulation: This persistence triggers a "low-grade" cytokine storm and sustained T-cell activation, eventually leading to T-cell exhaustion, exactly as seen in ME/CFS.
- Treatment Insight: Trials of antivirals like Paxlovid have shown mixed results, suggesting that while persistence is a driver, the resulting immune dysregulation may require separate management.
3. The "Role Reversal" in Long COVID
Research presented in late 2025 (e.g., the IACFS/ME conference) indicates that LC mirrors the weakened sympathetic response of ME/CFS:
- Noradrenaline (NE) Deficiency: Patients often exhibit low levels of noradrenaline, suggesting that the Locus Coeruleus (LC) has reached a state of functional exhaustion.
- Vagal Tone & HPA Axis: Long COVID involves chronic damage to the vagus nerve and the hypothalamic-pituitary-adrenal (HPA) axis, leading to "hypocortisolism" (insufficient cortisol) which prevents the body from effectively managing physical or emotional stress.
4. Direct Biological Commonalities
- Endothelial Dysfunction: Both conditions involve microclots and vascular inflammation, which impair oxygen delivery to tissues and contribute to severe fatigue and exercise intolerance.
- Mitochondrial "Energy Drain": Lymphocytes in both LC and ME/CFS donors exhibit elevated oxidative stress and damaged mitochondria, essentially "consuming" host energy and leaving the patient profoundly depleted.
- Brain Connectivity: Both disorders show stable brainstem and cerebellar hypometabolism, explaining why cognitive symptoms ("brain fog") often persist for years without spontaneous improvement.
Key Takeaway: By 2025, Long COVID is no longer viewed as a separate mystery but as a clear example of an infection-triggered chronic illness. In genetically susceptible individuals, SARS-CoV-2 acts as the "severe stressor" that triggers a cascade from viral persistence to a total homeostatic collapse of the brain's regulatory centers.
I used artificial intelligence (AI) via https://www.google.com/ to get some answers. Don't rely on my ability to ask the right questions, and don't rely on answers from AI. But, please, be inspired to search for more information.
More information
Does Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Represent a Poly-Herpesvirus Post-Virus Infectious Disease?
Mechanistic Insights Into Long Covid: Viral Persistence, Immune Dysregulation, and Multi-Organ Dysfunction
Does Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Represent a Poly-Herpesvirus Post-Virus Infectious Disease?
Mechanistic Insights Into Long Covid: Viral Persistence, Immune Dysregulation, and Multi-Organ Dysfunction
Suppression of the host antiviral response by non-infectious varicella zoster virus extracellular vesicles
Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus
References
Identification of Novel Reproducible Combinatorial Genetic Risk Factors for Myalgic Encephalomyelitis in the DecodeME Patient Cohort and Commonalities with Long COVID
https://www.medrxiv.org/content/10.64898/2025.12.01.25341362v1
Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome
Genetics Delivery Team, Thibaud Boutin, Andrew D. Bretherick, Joshua J. Dibble, Esther Ewaoluwagbemiga, Emma Northwood, Gemma L. Samms, Veronique Vitart, Project and Cohort Delivery Team, Øyvind Almelid, Tom Baker, Malgorzata Clyde, Anne Connolly, Diana Garcia, Shona M. Kerr, Claire Tripp, Jareth C. Wolfe, Patient and Public Involvement, Jackie Goold, Gemma Hoyes, Sian Leary, Simon J. McGrath, Julie Milton, Anna Redshaw, Jim M. Wilson, Marketing and Communications Team, Helen Baxter, Danielle Boobyer, Claire Dransfield, Daphne Lamirel, Isabel Lewis, Nina Muirhead, Ella Ponting, Charles Shepherd, Alice Turner, University of Edinburgh Team, Sumy V. Baby, Sjoerd Beentjes, John Ireland, Ava Khamseh, Ewan McDowall, David Perry, Joshua Slaughter, Genetic Epidemiology of ME/CFS Consortium, Erik Abner, Cindy G. Boer, Estonian Biobank Research Team, Sarah Finer, Genes & Health Research Team, Hele Haapaniemi, Hanna M. Ollila, Beth Pollack, Judith Rosmalen, Erika Romppanen, Sirine Saafi, Richa Saxena, Nasa Sinnott-Armstrong, Anniina Tervi, Lea Urpa, Jesse Valliere, David A. van Heel, Management Team, Sonya Chowdhury, Andy Devereux-Cooke, Chris P. Ponting
medRxiv 2025.08.06.25333109; doi: https://doi.org/10.1101/2025.08.06.25333109
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
Walitt B, Singh K, LaMunion SR, Hallett M, Jacobson S, Chen K, Enose-Akahata Y, Apps R, Barb JJ, Bedard P, Brychta RJ, Buckley AW, Burbelo PD, Calco B, Cathay B, Chen L, Chigurupati S, Chen J, Cheung F, Chin LMK, Coleman BW, Courville AB, Deming MS, Drinkard B, Feng LR, Ferrucci L, Gabel SA, Gavin A, Goldstein DS, Hassanzadeh S, Horan SC, Horovitz SG, Johnson KR, Govan AJ, Knutson KM, Kreskow JD, Levin M, Lyons JJ, Madian N, Malik N, Mammen AL, McCulloch JA, McGurrin PM, Milner JD, Moaddel R, Mueller GA, Mukherjee A, Muñoz-Braceras S, Norato G, Pak K, Pinal-Fernandez I, Popa T, Reoma LB, Sack MN, Safavi F, Saligan LN, Sellers BA, Sinclair S, Smith B, Snow J, Solin S, Stussman BJ, Trinchieri G, Turner SA, Vetter CS, Vial F, Vizioli C, Williams A, Yang SB; Center for Human Immunology, Autoimmunity, and Inflammation (CHI) Consortium; Nath A. Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. Nat Commun. 2024 Feb 21;15(1):907. doi: 10.1038/s41467-024-45107-3. PMID: 38383456; PMCID: PMC10881493.
Germain A, Glass KA, Eckert MA, Giloteaux L, Hanson MR, Temporal dynamics of the plasma proteomic landscape reveals maladaptation in ME/CFS following exertion, Molecular & Cellular Proteomics (2025), doi: https://doi.org/10.1016/j.mcpro.2025.101467.
Charting the Circulating Proteome in ME/CFS: Cross System Profiling and Mechanistic insights
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