Category: Pathogenesis

Human Endogenous Retroviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Emerging Roles in Pathogenesis, Immunity, Biomarkers and Therapeutics

Abstract:

Human endogenous retroviruses (HERVs) are potential driving forces of the pathophysiology of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), linking post-infectious immune dysfunction to chronic inflammation and immune and neurocognitive dysfunction that are hallmark features of ME/CFS.

Accumulating evidence from related autoimmune diseases and cancers has shown that reactivated HERVs can contribute to disease pathogenesis by amplifying immune activation through viral protein-mediated innate sensing, long terminal repeat (LTR)-driven transcription, and disrupting epigenetic silencing. HERV signatures are therefore promising biomarkers for diagnosis, patient stratification for drug-repurposing trials, and therapy monitoring.

Accumulating evidence suggests a possible correlation between HERV expression and ME/CFS symptom severity, alterations in immune phenotypes, function and inflammatory gene networks. Importantly, locus-specific HERV profiling is a promising approach for distinguishing ME/CFS from overlapping or co-morbid conditions and healthy controls. Furthermore, HERV-targeted antibodies, immune modulators, epigenetic and antiviral interventions offer promise as concomitant therapeutic strategies for ME/CFS.

Additional research incorporating viromics and other-omics validation, functional assays, and HERV-stratified clinical trials is now needed to realise this potential and to transform ME/CFS from a symptom-based syndrome into a mechanism-driven, treatable condition.

Source: Perera KD, Oltra E, Carding SR. Human Endogenous Retroviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Emerging Roles in Pathogenesis, Immunity, Biomarkers and Therapeutics. Int J Mol Sci. 2026 May 12;27(10):4309. doi: 10.3390/ijms27104309. PMID: 42196290; PMCID: PMC13207908. https://pmc.ncbi.nlm.nih.gov/articles/PMC13207908/ (Full text)

Babesia and Bartonella Species DNA in Blood and Enrichment Blood Cultures from People with Chronic Fatigue and Concurrent Neurological Symptoms

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a medical condition characterized by extreme fatigue lasting at least 6 months. Based upon case reports, patients infected with Babesia or Bartonella spp. have reported a history of chronic fatigue and concurrent neurological symptoms. In this study, 50 study participants reporting fatigue lasting from six months to 19 years and one or more neurological symptoms were selected.

PCR assays were used to amplify Babesia and Bartonella spp. DNA from blood and enrichment blood cultures. Using targeted qPCR amplification and DNA sequencing, infection with Babesia spp., Bartonella spp. or both genera was confirmed in 10, 11, and 2 individuals, respectively. Of 50 participants, 12 (24%, 95% CI: 12-36%) were infected with a Babesia species, while Bartonella species infection was documented in 13/50 individuals (26%, 95% CI: 13.8-38.2%).

This study provides documentation supporting a potential role for Babesia and Bartonella infection in patients with presentations consistent with ME/CFS. Prospective case-control studies, using highly sensitive direct pathogen detection techniques, are needed to determine whether or the extent to which infection with members of these two genera contributes to or causes ME/CFS.

Source: Breitschwerdt EB, Maggi RG, Bush JC, Kingston E. Babesia and Bartonella Species DNA in Blood and Enrichment Blood Cultures from People with Chronic Fatigue and Concurrent Neurological Symptoms. Pathogens. 2025 Dec 19;15(1):2. doi: 10.3390/pathogens15010002. PMID: 41598986; PMCID: PMC12844623. https://pmc.ncbi.nlm.nih.gov/articles/PMC12844623/ (Full text)

Autonomic Dysfunction in Patients with Acute Infection with Coxiella burnetii

Abstract:

Background: Coxiella burnetii is a common zoonotic pathogen that can lead not only to acute or chronic Q fever but also to post-infectious syndromes, where autonomic nervous system (ANS) dysfunction has been suggested as a contributing mechanism. This study aimed to assess autonomic function in patients presenting with polymorphic symptoms, dysautonomia, or ME/CFS who had serological evidence of acute infection with Coxiella burnetii.

Methods: A total of 156 participants were evaluated, including 100 seropositive patients and 56 matched controls. All subjects underwent standardized cardiovascular reflex tests (CART), beat-to-beat analysis of heart rate and blood pressure with baroreflex indices, 24 h Holter ECG with HRV assessment, and, in the Coxiella group, head-up tilt testing (HUTT).

Results: A significantly higher prevalence of autonomic dysfunction was observed in the Coxiella group, predominantly affecting parasympathetic regulation, with abnormal CART scores, reduced LF power and baroreflex effectiveness, and a high rate of positive HUTT findings characterized by extreme blood pressure variability. Although long-term HRV measures did not differ significantly between groups, short-term indices consistently indicated ANS impairment.

Conclusions: These findings suggest that Coxiella burnetii infection may trigger persistent autonomic dysfunction, potentially contributing to the development of ME/CFS and syncope in affected individuals. Further longitudinal studies are needed to clarify pathophysiological mechanisms and clinical implications.

Source: Milovanović B, Marković N, Ristanović E, Atanasievska Kujović S, Đorđevski N, Petrovic M, Milošević M, Bulatovic S, Bojić M. Autonomic Dysfunction in Patients with Acute Infection with Coxiella burnetii. Pathogens. 2025 Dec 19;15(1):3. doi: 10.3390/pathogens15010003. PMID: 41598987. https://www.mdpi.com/2076-0817/15/1/3 (Full text)

Babesia and Bartonella Species DNA in Blood and Enrichment Blood Cultures from People with Chronic Fatigue and Concurrent Neurological Symptoms

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a medical condition characterized by extreme fatigue lasting at least 6 months. Based upon case reports, patients infected with Babesia or Bartonella spp. have reported a history of chronic fatigue and concurrent neurological symptoms.

In this study, 50 study participants reporting fatigue lasting from six months to 19 years and one or more neurological symptoms were selected. PCR assays were used to amplify Babesia and Bartonella spp. DNA from blood and enrichment blood cultures.

Using targeted qPCR amplification and DNA sequencing, infection with Babesia spp., Bartonella spp. or both genera was confirmed in 10, 11, and 2 individuals, respectively. Of 50 participants, 12 (24%, 95% CI: 12-36%) were infected with a Babesia species, while Bartonella species infection was documented in 13/50 individuals (26%, 95% CI: 13.8-38.2%).

This study provides documentation supporting a potential role for Babesia and Bartonella infection in patients with presentations consistent with ME/CFS. Prospective case-control studies, using highly sensitive direct pathogen detection techniques, are needed to determine whether or the extent to which infection with members of these two genera contributes to or causes ME/CFS.

Source: Breitschwerdt EB, Maggi RG, Bush JC, Kingston E. Babesia and Bartonella Species DNA in Blood and Enrichment Blood Cultures from People with Chronic Fatigue and Concurrent Neurological Symptoms. Pathogens. 2025 Dec 19;15(1):2. doi: 10.3390/pathogens15010002. PMID: 41598986. https://www.mdpi.com/2076-0817/15/1/2 (Full text)

Virus-induced endothelial senescence as a cause and driving factor for ME/CFS and long COVID: mediated by a dysfunctional immune system

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are two post-viral diseases, which share many common symptoms and pathophysiological alterations. Yet a mechanistic explanation of disease induction and maintenance is lacking. This hinders the discovery and implementation of biomarkers and treatment options, and ultimately the establishment of effective clinical resolution. Here, we propose that acute viral infection results in (in)direct endothelial dysfunction and senescence, which at the blood-brain barrier, cerebral arteries, gastrointestinal tract, and skeletal muscle can explain symptoms.

The endothelial senescence-associated secretory phenotype (SASP) is proinflammatory, pro-oxidative, procoagulant, primed for vasoconstriction, and characterized by impaired regulation of tissue repair, but also leads to dysregulated inflammatory processes. Immune abnormalities in ME/CFS and long COVID can account for the persistence of endothelial senescence long past the acute infection by preventing their clearance, thereby providing a mechanism for the chronic nature of ME/CFS and long COVID.

The systemic and tissue-specific effects of endothelial senescence can thus explain the multisystem involvement in and subtypes of ME/CFS and long COVID, including dysregulated blood flow and perfusion deficits. This can occur in all tissues, but especially the brain as evidenced by findings of reduced cerebral blood flow and impaired perfusion of various brain regions, post-exertional malaise (PEM), gastrointestinal disturbances, and fatigue.

Paramount to this theory is the affected endothelium, and the bidirectional sustainment of immune abnormalities and endothelial senescence. The recognition of endothelial cell dysfunction and senescence as a core element in the aetiology of both ME/CFS and Long COVID should aid in the establishment of effective biomarkers and treatment regimens.

Source: Nunes M, Kell L, Slaghekke A, Wüst RC, Fielding BC, Kell DB, Pretorius E. Virus-induced endothelial senescence as a cause and driving factor for ME/CFS and long COVID: mediated by a dysfunctional immune system. Cell Death Dis. 2026 Jan 9;17(1):16. doi: 10.1038/s41419-025-08162-2. PMID: 41513611; PMCID: PMC12789617. https://pmc.ncbi.nlm.nih.gov/articles/PMC12789617/ (Full text)

Does Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Represent a Poly-Herpesvirus Post-Virus Infectious Disease?

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness with unknown etiology. An estimated 17-24 million people representing approximately 1% of the population are afflicted worldwide. In over half of cases, ME/CFS onset is associated with acute “flu-like” symptoms, suggesting a role for viruses. However, no single virus has been identified as the only etiological agent.

This may reflect the approach employed or more strongly the central dogma associated with herpesviruses replication, which states that a herpesvirus exists in two states, either lytic or latent. The purpose of this review is to address the role that abortive lytic replication may have in the pathogenesis of ME/CFS and other post-acute viral infections and also to raise awareness that these syndromes might be poly-herpesviruses mediated diseases.

Source: Ariza ME, Mena Palomo I, Williams MV. Does Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Represent a Poly-Herpesvirus Post-Virus Infectious Disease? Viruses. 2025 Dec 16;17(12):1624. doi: 10.3390/v17121624. PMID: 41472292. https://www.mdpi.com/1999-4915/17/12/1624 (Full text)

HLA and pathogens in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and other post-infection conditions

Abstract:

Viral infections have been widely implicated in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) pathogenesis. Recent evidence has also identified certain Human Leukocyte Antigen (HLA) alleles that are significantly associated with ME/CFS risk/protection. Here we tested the hypothesis that ME/CFS risk or protection conferred from those HLA alleles is associated with binding affinity to antigens of HHV viruses, a critical step in initiating the adaptive immune system response to foreign antigens.

Specifically, we determined in silico the predicted binding affinity of two susceptibility alleles (C*07:04, DQB1*03:03) and two protective alleles (B*08:01, DPB1*02:01) to > 10,000 antigens of the 9 Human Herpes Viruses (HHV1, HHV2, HHV3, HHV4, HHV5, HHV6A, HHV6B, HHV7, HHV8) which have been implicated in the etiology of ME/CFS. We found that the binding affinity of all HHV antigens to the susceptibility alleles was significantly weaker than the binding affinity to the protective alleles (P < 0.001). In fact, none of the HHV antigens showed strong binding to the susceptibility alleles, in contrast to the strong bindings showed by the protective alleles. These findings are in keeping with the hypothesis that the effect of a putative HHV insult in contributing to ME/CFS is modulated by the host’s HLA immunogenetic makeup.

We speculate that strong HLA-antigen binding likely protects against ME/CFS via elimination of virus antigens; conversely, weak HLA-antigen binding may permit persistence of foreign antigens, contributing to ME/CFS and other chronic conditions. Finally, with respect to the latter, we determined the binding affinities to the 4 HLA alleles above to pathogens causing two chronic diseases with very similar symptomatology to ME/CFS, namely Long COVID and post-treatment Lyme disease syndrome (PTLDS).

We found that the 2 ME/CFS susceptibility HLA alleles above had very weak binding with SARS-CoV-2 virus glycoprotein (involved in Long COVID) and 5 proteins of Borrelia burgdorferi (involved in PTLDS), in contrast to the ME/CFS protective alleles that showed strong bindings. These findings support the hypothesis that ME/CFS, long COVID and PTLDS are caused by persistent pathogenic antigens that could not be eliminated due to inadequate protection by the patient’s HLA makeup.

Source: Georgopoulos AP, James LM, Peterson PK. HLA and pathogens in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and other post-infection conditions. Sci Rep. 2025 Oct 24;15(1):37303. doi: 10.1038/s41598-025-21230-z. PMID: 41136524. https://www.nature.com/articles/s41598-025-21230-z (Full text)

Exploratory study on autoantibodies to arginine-rich human peptides mimicking Epstein-Barr virus in women with post-COVID and myalgic encephalomyelitis/chronic fatigue syndrom

Abstract:

Introduction: Epstein-Barr virus (EBV) infection is a well-established trigger and risk factor for both myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-COVID syndrome (PCS). In previous studies, we identified elevated IgG responses to arginine-rich (poly-R) sequences within the EBV nuclear antigens EBNA4 and EBNA6 in post-infectious ME/CFS (piME/CFS). Building on these findings, this exploratory study examines IgG reactivity to poly-R-containing EBV-derived peptides and homologous human peptides in women with PCS and ME/CFS.

Methods: IgG reactivity to poly-R containing peptides derived from EBNA4 and EBNA6, and homologous human 15-mer peptides and the corresponding full-length proteins, was assessed using a cytometric bead array (CBA) and a multiplex dot-blot assay. Serum samples were analyzed from 45 female PCS patients diagnosed according to WHO criteria, including 26 who also met the Canadian Consensus criteria for ME/CFS (pcME/CFS), 36 female patients with non-COVID post-infectious ME/CFS (piME/CFS), and 34 female healthy controls (HC).

Results: Autoantibodies targeting poly-R peptide sequences of the neuronal antigen SRRM3, the ion channel SLC24A3, TGF-β signaling regulator TSPLY2, and the angiogenesis-related protein TSPYL5, as well as full-length α-adrenergic receptor (ADRA) proteins, were more frequently detected in patient groups. Several of these autoantibodies showed positive correlations with core symptoms, including autonomic dysfunction, fatigue, cognitive impairment, and pain.

Conclusion: This exploratory study identify autoantibodies directed against EBV mimicking arginine-rich sequences in human proteins, suggesting a potential role for molecular mimicry in the pathogenesis of PCS and ME/CFS.

Source: Hoheisel Friederike , Fleischer Kathrin Maria , Rubarth Kerstin , Sepúlveda Nuno , Bauer Sandra , Konietschke Frank , Kedor Peters Claudia , Stein Annika Elisa , Wittke Kirsten , Seifert Martina , Bellmann-Strobl Judith , Mautner Josef , Behrends Uta , Scheibenbogen Carmen , Sotzny Franziska. Exploratory study on autoantibodies to arginine-rich human peptides mimicking Epstein-Barr virus in women with post-COVID and myalgic encephalomyelitis/chronic fatigue syndrome. Frontiers in Immunology, Volume 16 – 2025. DOI=10.3389/fimmu.2025.1650948 ISSN=1664-3224 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1650948/full (Full text)

The emerging role of exosomal LncRNAs in chronic fatigue syndrome: from intercellular communication to disease biomarkers

Abstract:

Chronic fatigue syndrome (CFS) is a complex disease involving multiple systems throughout the body with unknown pathogenesis and is characterized by chronic fatigue. To date, no effective treatment for CFS has been found, as well as biomarkers for early identification of diagnosis. However, exosomes, a subpopulation of extracellular vesicles (EVs), are membranous vesicles secreted by cells into the surrounding environment, and long noncoding RNAs (LncRNAs) in EVs can mediate inter-organ and inter-cellular communication, which maybe associate with CFS.

Therefore, this study aims to review the association between EV-LncRNAs and CFS, and to explore whether LncRNAs can be used as potential biomarkers for early identification and diagnosis of CFS, which put forward new ideas and a theoretical basis for the pathogenesis of CFS, as well as the identification of novel targeted therapies.

Source: Wang Lei , Xu Yujia , Zhong Xiang , Wang Guiping , Shi Zijun , Mei Can , Chen Linwanyue , Zhan Jianbo , Cheng Jing. The emerging role of exosomal LncRNAs in chronic fatigue syndrome: from intercellular communication to disease biomarkers. Frontiers in Molecular Biosciences. Volume 12 – 2025 https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2025.1653627/full (Full text)

A Mechanical Basis: Brainstem Dysfunction as a Potential Etiology of ME/CFS and Long COVID

Abstract:
The underlying pathologies driving post-acute infectious syndromes (e.g. myalgic encephalomyelitis / chronic fatigue syndrome, long COVID, etc) remain poorly understood. Given the extreme burden these illnesses impose on suffers, and the dramatic increase in cases following the COVID-19 pandemic, it is important to establish a deeper understanding of these pathologies.
We propose a model of how ME/CFS (and related illnesses), might emerge following a viral insult. Central to this hypothesis is the recognition that the core diagnostic features of ME/CFS involve bodily systems known to be governed by the brainstem. This is consistent with the growing literature suggesting that spinal and craniocervical pathologies are over-represented in people with ME/CFS and other post-infectious disorders.
We hypothesize that a non-trivial number of cases of ME/CFS and Long Covid (LC) may have a “mechanical basis.” We propose that an infectious insult may trigger an initial loss of connective tissue integrity in susceptible individuals (e.g. those with pre-existing hypermobility spectrum disorders), which in turn leads to instability at the craniocervical junction, and ultimately mechanical deformation of the brainstem. This ultimately causes widespread autonomic nervous system and immune system dysfunction due to aberrant signaling from the deformed nuclei.
This causal chain may also lead to a vicious cycle: if the dysregulation produced by the initial brainstem deformation leads to a deranged immune response or state of chronic hyper-inflammation, further expression of connective tissue degrading and remodeling factors such as MMPs and mast cells may be triggered. This could further degrade the connective tissues of the craniocervical junction and, in turn, increase mechanical deformation of the brainstem, leading to symptom exacerbation over time and leading to the chronic, lifelong presentation typical of ME/CFS.
Source: Wood, J., Varley, T., Hartman, J., Melia, N., Kaufman, D., & Falor, T. (2025). A Mechanical Basis: Brainstem Dysfunction as a Potential Etiology of ME/CFS and Long COVID. Preprints. https://doi.org/10.20944/preprints202506.0874.v1 https://www.preprints.org/manuscript/202506.0874/v1 (Full text)