Tag: Epstein-Barr

Mitochondrial DNA Missense Mutations ChrMT: 8981A > G and ChrMT: 6268C > T Identified in a Caucasian Female with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Triggered by the Epstein–Barr Virus

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem disabling disease with unclear etiology and pathophysiology, whose typical symptoms include prolonged debilitating recovery from fatigue or postexertional malaise (PEM). Disrupted production of adenosine triphosphate (ATP), the intracellular energy that fuels cellular activity, is a cause for fatigue.

Here, we present a long-term case of ME/CFS: a 75-year-old Caucasian female patient, whose symptoms of ME/CFS were clearly triggered by an acute infection of the Epstein–Barr virus 24 years ago (mononucleosis). Before then, the patient was a healthy professional woman.

A recent DNA sequence analysis identified missense variants of mitochondrial respiratory chain enzymes, including ATP6 (ChrMT: 8981A > G; Q152R) and Cox1 (ChrMT: 6268C > T; A122V). Protein subunits ATP6 and Cox1 are encoded by mitochondrial DNA outside of the nucleus: the Cox1 gene encodes subunit 1 of complex IV (CIV: cytochrome c oxidase) and the ATP6 gene encodes subunit A of complex V (CV: ATP synthase). CIV and CV are the last two of five essential enzymes that perform the mitochondrial electron transport respiratory chain reaction to generate ATP.

Further analysis of the blood sample using transmission electron microscopy demonstrated abnormal, circulating, extracellular mitochondria. These results indicate that the patient had dysfunctional mitochondria, which may contribute directly to her major symptoms, including PEM and neurological and cognitive changes. Furthermore, the identified variants of ATP6 (ChrMT: 8981A > G; Q152R) and Cox1 (ChrMT: 6268C > T; A122V), functioning at a later stage of mitochondrial ATP production, may play a role in the abnormality of the patient’s mitochondria and the development of her ME/CFS symptoms.

Source: Gaoyan G. Tang-Siegel, David W. Maughan, Milah B. Frownfelter, Alan R. Light, “Mitochondrial DNA Missense Mutations ChrMT: 8981A > G and ChrMT: 6268C > T Identified in a Caucasian Female with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Triggered by the Epstein–Barr Virus”, Case Reports in Genetics, vol. 2024, Article ID 6475425, 10 pages, 2024. https://doi.org/10.1155/2024/6475425 https://www.hindawi.com/journals/crig/2024/6475425/ (Full text)

Epigenetic reprograming in myalgic encephalomyelitis/chronic fatigue syndrome: A narrative of latent viruses

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease presenting with severe fatigue, post-exertional malaise, and cognitive disturbances-among a spectrum of symptoms-that collectively render the patient housebound or bedbound. Epigenetic studies in ME/CFS collectively confirm alterations and/or malfunctions in cellular and organismal physiology associated with immune responses, cellular metabolism, cell death and proliferation, and neuronal and endothelial cell function.

The sudden onset of ME/CFS follows a major stress factor that, in approximately 70% of cases, involves viral infection, and ME/CFS symptoms overlap with those of long COVID. Viruses primarily linked to ME/CFS pathology are the symbiotic herpesviruses, which follow a bivalent latent-lytic lifecycle. The complex interaction between viruses and hosts involves strategies from both sides: immune evasion and persistence by the viruses, and immune activation and viral clearance by the host. This dynamic interaction is imperative for herpesviruses that facilitate their persistence through epigenetic regulation of their own and the host genome.

In the current article, we provide an overview of the epigenetic signatures demonstrated in ME/CFS and focus on the potential strategies that latent viruses-particularly Epstein-Barr virus-may employ in long-term epigenetic reprograming in ME/CFS. Epigenetic studies could aid in elucidating relevant biological pathways impacted in ME/CFS and reflect the physiological variations among the patients that stem from environmental triggers, including exogenous viruses and/or altered viral activity.

Source: Apostolou E, Rosén A. Epigenetic reprograming in myalgic encephalomyelitis/chronic fatigue syndrome: A narrative of latent viruses. J Intern Med. 2024 May 1. doi: 10.1111/joim.13792. Epub ahead of print. PMID: 38693641. https://onlinelibrary.wiley.com/doi/10.1111/joim.13792 (Full text)

Detrimental effects of COVID-19 in the brain and therapeutic options for long COVID: The role of Epstein–Barr virus and the gut–brain axis

Abstract:

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in a serious public health burden worldwide. In addition to respiratory, heart, and gastrointestinal symptoms, patients infected with SARS-CoV-2 experience a number of persistent neurological and psychiatric symptoms, known as long COVID or “brain fog”. Studies of autopsy samples from patients who died from COVID-19 detected SARS-CoV-2 in the brain. Furthermore, increasing evidence shows that Epstein–Barr virus (EBV) reactivation after SARS-CoV-2 infection might play a role in long COVID symptoms.

Moreover, alterations in the microbiome after SARS-CoV-2 infection might contribute to acute and long COVID symptoms. In this article, the author reviews the detrimental effects of COVID-19 on the brain, and the biological mechanisms (e.g., EBV reactivation, and changes in the gut, nasal, oral, or lung microbiomes) underlying long COVID.

In addition, the author discusses potential therapeutic approaches based on the gut–brain axis, including plant-based diet, probiotics and prebiotics, fecal microbiota transplantation, and vagus nerve stimulation, and sigma-1 receptor agonist fluvoxamine.

Source: Hashimoto, K. Detrimental effects of COVID-19 in the brain and therapeutic options for long COVID: The role of Epstein–Barr virus and the gut–brain axis. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02161-5 https://www.nature.com/articles/s41380-023-02161-5 (Full text)

Fatigue Doesn’t Always have to be caused by SARS-CoV-2: Case Report

Abstract:

We report on a 17-year-old female adolescent who presented with marked fatigue. The cause of this was found to be Epstein-Barr virus (EBV) infection. Even during the COVID-19 pandemic, fatigue doesn’t always have to be caused by SARS-CoV‑2 but can also be induced by other adolescent-onset diseases (EBV), Up to 13.5 % of EBV sufferers develop chronic fatigue syndrome, which is why it makes sense to determine the exact cause. Diagnosis, therapy and prognosis of infectious mononucleosis are addressed.

Source: Howanietz H, Graf U, Kainz T. Fatigue muss nicht immer SARS-CoV-2-bedingt sein – eine Kasuistik [Fatigue Doesn’t Always have to be caused by SARS-CoV-2: Case Report]. Padiatr Padol. 2022 May 19:1-4. German. doi: 10.1007/s00608-022-00989-8. Epub ahead of print. PMID: 35611157; PMCID: PMC9118809. https://pubmed.ncbi.nlm.nih.gov/35611157/ [Full article in German]

Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae

Summary:

Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms.
We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.

Source: : Su, Y., Yuan, D., Chen, D.G., Ng, R.H., Wang, K., Choi, J., Li, S., Hong, S., Zhang, R., Xie, J., Kornilov, S.A., Scherler, K., Pavlovitch-Bedzyk, A.J., Dong, S., Lausted, C., Lee, I., Fallen, S., Dai, C.L., Baloni, P., Smith, B., Duvvuri, V.R., Anderson, K.G., Li, J., Yang, F., Duncombe, C.J., McCulloch, D.J., Rostomily, C., Troisch, P., Zhou, J., Mackay, S., DeGottardi, Q., May, D.H, Taniguchi, R., Gittelman, R.M, Klinger, M., Snyder, T.M, Roper, R., Wojciechowska, G., Murray, K., Edmark, R., Evans, S., Jones, L., Zhou, Y., Rowen, L., Liu, R., Chour, W., Algren, H.A, Berrington, W.R., Wallick, J.A., Cochran, R.A., Micikas, M.E., the ISB-Swedish COVID19 Biobanking Unit, Terri Wrin, Petropoulos, C.J., Cole, H.R., Fischer, T.D., Wei, W., Hoon, D.S.B., Price, N.D., Subramanian, N., Hill, J.A, Hadlock, J., Magis, A.T., Ribas, A., Lanier, L.L., Boyd, S.D., Bluestone, J.A., Chu, H., Hood, L., Gottardo, R., Greenberg, P.D., Davis, M.M., Goldman, J.D., Heath, J.R., Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae, Cell (2022), doi: https://doi.org/10.1016/j.cell.2022.01.014. (Full text)

Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) affects approximately 1% of the general population. It is a chronic, disabling, multi-system disease for which there is no effective treatment. This is probably related to the limited knowledge about its origin. Here, we summarized the current knowledge about the pathogenesis of ME/CFS and revisit the immunopathobiology of Epstein-Barr virus (EBV) infection. Given the similarities between EBV-associated autoimmune diseases and cancer in terms of poor T cell surveillance of cells with EBV latency, expanded EBV-infected cells in peripheral blood and increased antibodies against EBV, we hypothesize that there could be a common etiology generated by cells with EBV latency that escape immune surveillance.

Albeit inconclusive, multiple studies in patients with ME/CFS have suggested an altered cellular immunity and augmented Th2 response that could result from mechanisms of evasion to some pathogens such as EBV, which has been identified as a risk factor in a subset of ME/CFS patients. Namely, cells with latency may evade the immune system in individuals with genetic predisposition to develop ME/CFS and in consequence, there could be poor CD4 T cell immunity to mitogens and other specific antigens, as it has been described in some individuals.

Ultimately, we hypothesize that within ME/CFS there is a subgroup of patients with DRB1 and DQB1 alleles that could confer greater susceptibility to EBV, where immune evasion mechanisms generated by cells with latency induce immunodeficiency. Accordingly, we propose new endeavors to investigate if anti-EBV therapies could be effective in selected ME/CFS patients.

Source: Ruiz-Pablos M, Paiva B, Montero-Mateo R, Garcia N, Zabaleta A. Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome. Front Immunol. 2021 Nov 15;12:656797. doi: 10.3389/fimmu.2021.656797. PMID: 34867935; PMCID: PMC8634673. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634673/ (Full text)

Pain in adolescent chronic fatigue following Epstein-Barr virus infection

Abstract:

Objectives: Acute Epstein-Barr virus (EBV) infection is a trigger of Chronic Fatigue (CF) and Chronic Fatigue Syndrome (CFS). The aim of this cross-sectional study was to investigate pain symptoms and pressure pain thresholds in fatigued and non-fatigued adolescents six months after acute EBV-infection, and in healthy controls. This study is part of the CEBA-project (CF following acute EBV infection in adolescents).

Methods: A total of 195 adolescents (12-20 years old) that had undergone an acute EBV infection six months prior to assessment were divided into fatigued (EBV CF+) and non-fatigued (EBV CF-) cases based on questionnaire score. The EBV CF+ cases were further sub-divided according to case definitions of CFS. In addition, a group of seventy healthy controls was included. Symptoms were mapped with questionnaires. Pressure pain thresholds were measured through pressure algometry. One way ANOVA were used for between-group analyses. Linear regression analyses were used to explore associations between Pediatric Quality of Life (dependent variable), pain symptoms and other variables within the EBV (CF+) group.

Results: The EBV CF+ group had significantly higher scores for pain symptoms as compared with the EBV CF- group and healthy controls, but pressure pain threshold did not differ significantly. The number of pain symptoms as well as pain severity were strongly and independently associated with quality of life.

Conclusions: CF and CFS following acute EBV-infection in adolescents is characterized by high pain symptom burden, which in turn is associated with a decline in quality of life. Pain in CF and CFS is of considerable clinical importance, and should be a focal point for further investigation and intervention in these patient groups.

Source: Brodwall EM, Pedersen M, Asprusten TT, Wyller VBB. Pain in adolescent chronic fatigue following Epstein-Barr virus infection [published online ahead of print, 2020 Sep 7]. Scand J Pain. 2020;/j/sjpain.ahead-of-print/sjpain-2020-0031/sjpain-2020-0031.xml. doi:10.1515/sjpain-2020-0031  https://pubmed.ncbi.nlm.nih.gov/32892183/

Cytomegalovirus, Epstein-Barr Virus and Human Herpesvirus 6 Infections in Patients with Myalgic Еncephalomyelitis/Chronic Fatigue Syndrom

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling multisystem chronic disease. The etiology and pathogenesis of ME/CFS are unknown. Infections of cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human herpesvirus-6 (HHV-6) are suspected as etiological agents for ME/CFS. This study aims to estimate prevalence and type (active/latent) of EBV, CMV and HHV-6 infections in Bulgarian ME/CFS patients.

In the study were included 58 ME/CFS patients and 50 healthy controls. Virus-specific antibodies were detected by ELISA and viral genomic sequences in PBMCs and plasma samples – by nPCR. We did not observe any significant differences in virus specific IgG and IgM positivity rates between ME/CFS patients and control group. In ME/CFS plasma samples EBV DNA was found in 24.1%, CMV DNA – in 3.4% and HHV-6 DNA in 1.7% of samples. EBV DNA was detected in 4%, CMV and HHV-6 DNA were not found in plasma samples of controls. The frequency of viral genome detection in PBMCs of patients and controls was 74% vs 78% for CMV, 81% vs 84% for EBV, and 82.8% vs 82% for HHV-6. The difference in frequency of EBV active infection in ME/CFS and control group was statistically significant (p=0.0027). No ME/CFS and control individuals with active CMV and HHV-6 infection were observed.

In conclusion, our study using both serological and PCR-based techniques for distinguishing between active and latent infection, showed high rate of active EBV infection among ME/CFS patients indicating that at least in a subset of cases EBV is important factor for development of disease.

Source: Shikova E, Reshkova V, Kumanova А, Raleva S, Alexandrova D, Capo N, Murovska M; European Network on ME/CFS (EUROMENE). Cytomegalovirus, Epstein-Barr Virus and Human Herpesvirus 6 Infections in Patients with Myalgic Еncephalomyelitis/Chronic Fatigue Syndrome. J Med Virol. 2020 Mar 4. doi: 10.1002/jmv.25744. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/32129496

Clinical symptoms and markers of disease mechanisms in adolescent chronic fatigue following Epstein-Barr virus infection: An exploratory cross-sectional study

Abstract:

INTRODUCTION: Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue (CF) and Chronic Fatigue Syndrome (CFS). The aim of this cross-sectional study was to explore clinical symptoms as well as markers of disease mechanisms in fatigued and non-fatigued adolescents 6 months after EBV-infection, and in healthy controls.

MATERIALS AND METHODS: A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed 6 months after the initial infectious event and divided into fatigued (EBV CF+) and non-fatigued (EBV CF-) cases based on questionnaire score. The EBV CF+ cases were further sub-divided according to case definitions of CFS. In addition, a group of 70 healthy controls with similar distribution of sex and age was included. Symptoms were mapped with a questionnaire. Laboratory assays included EBV PCR and serology; detailed blood leukocyte phenotyping and serum high-sensitive C-reactive protein; and plasma and urine cortisol and catecholamines. Assessment of autonomic activity was performed with continuous, non-invasive monitoring of cardiovascular variables during supine rest, controlled breathing and upright standing. Differences between EBV CF+ and EBV CF- were assessed by simple and multiple linear regression adjusting for sex as well as symptoms of depression and anxiety. A p-value ≤ 0.05 was considered statistically significant. This study is part of the CEBA-project (Chronic fatigue following acute Epstein-Barr virus infection in adolescents).

RESULTS: The EBV CF+ group had significantly higher scores for all clinical symptoms. All markers of infection and most immune, neuroendocrine and autonomic markers were similar across the EBV CF+ and EBV CF- group. However, the EBV CF+ group had slightly higher serum C-reactive protein (0.48 vs 0.43 mg/L, p=0.031, high-sensitive assay), total T cell (CD3+) count (median 1573 vs 1481 x 106 cells/L, p=0.012), plasma norepinephrine (1420 vs 1113 pmol/L, p=0.01) and plasma epinephrine (363 vs 237 nmol/L, p=0.032); lower low-frequency:high frequency (LF/HF) ratio of heart rate variability at supine rest (0.63 vs 0.76, p=0.008); and an attenuated decline in LF/HF ratio during controlled breathing (-0.11 vs -0.25, p=0.002). Subgrouping according to different CFS diagnostic criteria did not significantly alter the results. Within the EBV CF+ group, there were no strong correlations between clinical symptoms and markers of disease mechanisms. In a multiple regression analysis, serum CRP levels were independently associated with serum cortisol (B= 4.5 x 10-4, p<0.001), urine norepinephrine (B=9.6 x 10-2, p=0.044) and high-frequency power of heart rate variability (B= -3.7 x 10-2, p=0.024).

CONCLUSIONS: In adolescents, CF and CFS 6 months after acute EBV infection are associated with high symptom burden, but no signs of increased viral load and only subtle alterations of immune, autonomic, and neuroendocrine markers of which no one is strongly correlated with symptom scores. A slight sympathetic over parasympathetic predominance is evident in CF and might explain slightly increased CRP levels.

Copyright © 2019. Published by Elsevier Inc.

Source: Kristiansen MS, Stabursvik J, O’Leary EC, Pedersen M, Asprusten TT, Leegaard T, Osnes LT, Tjade T, Skovlund E, Godang K, Wyller VBB. Clinical symptoms and markers of disease mechanisms in adolescent chronic fatigue following Epstein-Barr virus infection: An exploratory cross-sectional study.Brain Behav Immun. 2019 Apr 27. pii: S0889-1591(19)30133-3. doi: 10.1016/j.bbi.2019.04.040. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31039432