Tag: EBV

A Network Medicine Approach to Investigating ME/CFS Pathogenesis in Severely Ill Patients: A Pilot Study

Abstract:

This pilot study harnessed the power of network medicine to unravel the complex pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). By utilizing a network analysis on whole genome sequencing (WGS) data from the Severely Ill Patient Study (SIPS), we identified ME/CFS-associated proteins and delineated the corresponding network-level module, termed the SIPS disease module, together with its relevant pathways. This module demonstrated significant overlap with genes implicated in fatigue, cognitive disorders, and neurodegenerative diseases.

Our pathway analysis revealed potential associations between ME/CFS and conditions such as COVID-19, Epstein-Barr virus (EBV) infection, neurodegenerative diseases, and pathways involved in cortisol synthesis and secretion, supporting the hypothesis that ME/CFS is a neuroimmune disorder. Additionally, our findings underscore a potential link between ME/CFS and estrogen signaling pathways, which may elucidate the higher prevalence of ME/CFS in females.

These findings provide insights into the pathogenesis of ME/CFS from a network medicine perspective and highlight potential therapeutic targets. Further research is needed to validate these findings and explore their implications for improving diagnosis and treatment.

Source: Li-Yuan Hung, Chan-Shuo Wu, Chia-Jung Chang, Peng Li, Kimberly Hicks, Becky Taurog, Joshua J Dibble, Braxton Morrison, Chimere L Smith, Ronald W Davis, Wenzhong Xiao. A Network Medicine Approach to Investigating ME/CFS Pathogenesis in Severely Ill Patients: A Pilot Study.
medRxiv 2024.09.26.24314417; doi: https://doi.org/10.1101/2024.09.26.24314417 https://www.medrxiv.org/content/10.1101/2024.09.26.24314417v1 (Full text available as PDF file)

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)

Sex differences in symptomatology and immune profiles of Long COVID

Abstract:

Strong sex differences in the frequencies and manifestations of Long COVID (LC) have been reported with females significantly more likely than males to present with LC after acute SARS-CoV-2 infection1-7. However, whether immunological traits underlying LC differ between sexes, and whether such differences explain the differential manifestations of LC symptomology is currently unknown.

Here, we performed sex-based multi-dimensional immune-endocrine profiling of 165 individuals8 with and without LC in an exploratory, cross-sectional study to identify key immunological traits underlying biological sex differences in LC.

We found that female and male participants with LC experienced different sets of symptoms, and distinct patterns of organ system involvement, with female participants suffering from a higher symptom burden. Machine learning approaches identified differential sets of immune features that characterized LC in females and males. Males with LC had decreased frequencies of monocyte and DC populations, elevated NK cells, and plasma cytokines including IL-8 and TGF-β-family members.

Females with LC had increased frequencies of exhausted T cells, cytokine-secreting T cells, higher antibody reactivity to latent herpes viruses including EBV, HSV-2, and CMV, and lower testosterone levels than their control female counterparts. Testosterone levels were significantly associated with lower symptom burden in LC participants over sex designation.

These findings suggest distinct immunological processes of LC in females and males and illuminate the crucial role of immune-endocrine dysregulation in sex-specific pathology.

Source: Julio Silva, Takehiro Takahashi, Jamie Wood, Peiwen Lu, Sasha Tabachnikova, Jeffrey Gehlhausen, Kerrie Greene, Bornali Bhattacharjee, Valter Silva Monteiro, Carolina Lucas, Rahul Dhodapkar, Laura Tabacof, Mario Pena-Hernandez, Kathy Kamath, Tianyang Mao, Dayna Mccarthy, Ruslan Medzhitov, David van Dijk, Harlan Krumholz, Leying Guan, David Putrino, Akiko Iwasaki. Sex differences in symptomatology and immune profiles of Long COVID. medRxiv 2024.02.29.24303568; doi: https://doi.org/10.1101/2024.02.29.24303568 https://www.medrxiv.org/content/10.1101/2024.02.29.24303568v1 (Full study available as PDF file)

How does post COVID differ from other post-viral conditions in childhood and adolescence (0-20 years old)? A systematic review

Abstract:

Background: Post Coronavirus disease (COVID) and other post-viral infection syndromes present an overlap of pathogenesis, onset, progression, and symptom profile. We aimed to systematically describe studies on post-viral conditions and determine the entity of post COVID compared to other post-viral conditions in children.

Methods: We conducted a systematic search of the Embase, MEDLINE, Cochrane Library, and GoogleScholar databases (January 1946-3 November 2023), according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The main outcomes were differences in condition duration, symptom type, and development of chronic symptoms. This systematic review was registered on PROSPERO (CRD42023401789).

Findings: 35/5051 studies were included, with 42,934 children, adolescents and young adults (0-20 years old) overall. Twenty-eight studies focused on post COVID symptoms, followed by five papers on Respiratory Syncytial Virus (RSV) and Rhinovirus, one study on Epstein-Barr Virus (EBV), and one on gastrointestinal viruses. Studies on post COVID mainly reported data on older children/adolescents, describing long-lasting symptoms, including fatigue, neurologic, cardiorespiratory, musculoskeletal, mental health, and gastrointestinal symptoms. The maximum described symptoms duration was eighteen months, with an average follow-up of seven months. The development of chronic symptoms was reported by 30 studies (93.8%) for 10,473/28,474 patients (36.8%). Recovery was achieved in 18,001/28,474 cases (63.2%). The study on EBV reported persistent fatigue in adolescents for a similar duration (6 months, 46% chronic). Studies on RSV and Rhinovirus were mainly done in children under three years, with development of recurrent wheezing (up to 3 years).

Interpretation: Post-viral fatigue was a shared feature between post COVID and post EBV conditions. A better understanding of post COVID as a unique condition, sharing features with other post-viral syndromes, is needed. The healthcare burden and socio-economic consequences for children and their families warrant further investigation and development of appropriate healthcare management plans. The foremost requirement is the establishment of consistent and shareable definitions, as well as a consensus on outcomes, to effectively evaluate follow-up and quantify the burden of different viral infections.

Source: Minotti C, McKenzie C, Dewandel I, Bekker C, Sturniolo G, Doni D, Giaquinto C, Van Der Zalm MM, Donà D. How does post COVID differ from other post-viral conditions in childhood and adolescence (0-20 years old)? A systematic review. EClinicalMedicine. 2024 Feb 2;68:102436. doi: 10.1016/j.eclinm.2024.102436. PMID: 38333536; PMCID: PMC10850405. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10850405/ (Full text)

Chronic Fatigue Syndrome, Viruses and Related Conditions in Women: The Liver Link

Abstract:

Chronic Fatigue Syndrome (CFS) can be triggered by different factors and create a complex health situation. In the last decades incidence has been increasing. This situation is a clear example of how humans, viruses, and the environment are all connected.
In the 90s cases related to CFS, complaints about a feeling of chronic fatigue, inability for everyday tasks, dull pain, cephalalgia, de-pression, anxiety, poor concentration. Clinical tests for EBV, HHV, CMV, IgG, IgM, T4 and T8 subsets were tested, along with hormones and hemogram tests. Most of the cases were women. The timeline of the medical history showed also myomas, breast lumps, premenstrual syndrome previously to CFS development. The nature of these conditions promoted the idea of a possible common link among them and CFS. Some cases also suffered from allergies, food intolerances, candidiasis, intestinal impairment, thyroid implications, endometriosis.
As an initial working hypothesis, The Liver Link (TLL) was proposed in order to understand those different conditions affecting body, mind and emotional wellbeing. Considering liver implication can make a difference in treatment and recovery. Low grade inflammatory conditions are related to Th2 predominance and liver functions. Functional disharmonies are very important because they usually still do not appear in any conventional tests.
In 2002, TLL was presented as a framework to explain the concomitance of CFS and other conditions and the relationship with some viruses such as EBV, HHV, CMV, as a lecture in a congress at the University of Westminster (London). When SARS-CoV-2 outbroke, TLL helped to warn about the post-covid syndrome more likely to occur in specific individuals.
Source: Lorite-Ayán, N. Chronic Fatigue Syndrome, Viruses and Related Conditions in Women: The Liver Link. Preprints 2024, 2024011654. https://doi.org/10.20944/preprints202401.1654.v1 https://www.preprints.org/manuscript/202401.1654/v1 (Full text available as PDF file)

Heterogenous circulating miRNA changes in ME/CFS converge on a unified cluster of target genes: A computational analysis

Abstract:

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome is a debilitating, multisystem disease of unknown mechanism, with a currently ongoing search for its endocrine mediators. Circulating microRNAs (miRNA) are a promising candidate for such a mediator and have been reported as significantly different in the patient population versus healthy controls by multiple studies. None of these studies, however, agree with each other on which specific miRNA are under- or over-expressed.

This discrepancy is the subject of the computational study presented here, in which a deep dive into the predicted gene targets and their functional interactions is conducted, revealing that the aberrant circulating miRNAs in ME/CFS, although different between patients, seem to mainly target the same specific set of genes (p ≈ 0.0018), which are very functionally related to each other (p ≲ 0.0001).

Further analysis of these functional relations, based on directional pathway information, points to impairments in exercise hyperemia, angiogenic adaptations to hypoxia, antioxidant defenses, and TGF-β signaling, as well as a shift towards mitochondrial fission, corroborating and explaining previous direct observations in ME/CFS. Many transcription factors and epigenetic modulators are implicated as well, with currently uncertain downstream combinatory effects.

As the results show significant similarity to previous research on latent herpesvirus involvement in ME/CFS, the possibility of a herpesvirus origin of these miRNA changes is also explored through further computational analysis and literature review, showing that 8 out of the 10 most central miRNAs analyzed are known to be upregulated by various herpesviruses. In total, the results establish an appreciable and possibly central role for circulating microRNAs in ME/CFS etiology that merits further experimental research.

Source: Kaczmarek MP. Heterogenous circulating miRNA changes in ME/CFS converge on a unified cluster of target genes: A computational analysis. PLoS One. 2023 Dec 29;18(12):e0296060. doi: 10.1371/journal.pone.0296060. PMID: 38157384; PMCID: PMC10756525. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10756525/ (Full text)

IgG Antibody Responses to Epstein-Barr Virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Their Effective Potential for Disease Diagnosis and Pathological Antigenic Mimicry

Abstract:

The diagnosis and the pathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) remain under debate. However, there is a growing body of evidence for an autoimmune component in ME/CFS caused by the Epstein-Barr virus (EBV) and other viral infections.
In this work, we took advantage of a large public dataset on the IgG antibodies to 3,054 EBV peptides to understand whether these immune responses could be used as putative biomarkers for disease diagnosis and triggers of pathological autoimmunity in ME/CFS patients using healthy controls (HCs) as a comparator cohort. We then aimed at predicting disease status of study participants using a Super Learner algorithm targeting an accuracy of 85% when splitting data into train and test datasets.
When we compared data of all ME/CFS patients or data of a subgroup of these patients with non-infectious or unknown disease trigger to the dataset of HC, we could not find an antibody-based classifier that would meet the desired accuracy in the test dataset. In contrast, we could identify a 26-antibody classifier that could distinguish ME/CFS patients with an infectious disease trigger from HCs with 100% and 90% accuracies on the train and test sets, respectively.
We finally performed a bioinformatic analysis of the EBV peptides associated with these 26 antibodies. We found no correlation between the importance metric of the selected antibodies in the classifier and the maximal sequence homology between human proteins and each EBV peptide recognized by these antibodies.
In conclusion, these 26 antibodies against EBV have an effective potential for disease diagnosis of a subset of patients, but they are less likely to trigger pathological autoimmune responses that could explain the pathogenesis of ME/CFS.
Source: Fonseca, A.; Szysz, M.; Ly, H.T.; Cordeiro, C.; Sepúlveda, N. IgG Antibody Responses to Epstein-Barr Virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Their Effective Potential for Disease Diagnosis and Pathological Antigenic Mimicry. Preprints 2023, 2023111523. https://doi.org/10.20944/preprints202311.1523.v1 https://www.preprints.org/manuscript/202311.1523/v1 (Full text available as PDF file)

Sequential activation of DNA viruses by the RNA virus SARS-CoV-2 in patients with long COVID syndrome

Abstract:

Background: Reactivation of Epstein-Barr virus (EBV) has been suggested to play role in long lasting multiorgan symptoms several months after the initial COVID-19 illness.
Purpose: The aim of our prospective study was to 1) to evaluate the reactivation of DNA viruses of EBV, Cytomegalovirus, Herpes simplex, Varicella zoster and Parvovirus-B19 by SARS-CoV-2 in patients with the diagnosis of long-COVID syndrome, 2) to investigate the effect of supposed virus reactivation on clinical conditions and long COVID syndromes.
Methods: Patients with long COVID syndrome were prospectively included into the Vienna PostCoV Registry between March 15th 2021 and September 30th 2021. – The time between COVID-19 infection and first clinical visit was 219±98 days (7±3 months). Clinical symptoms were documented and patients were divided into symptoms-oriented subgroups with dominantly respiratory, cardiovascular or neuropsychologic complaints. Qualitative and quantitative viral IgG and IgM titer of the selected DNA viruses of n=105 patients were compared with age and sex-matched healthy (non-infected, non-vaccinated, n=105) controls, who had neither spike- nor nucleocapsid antibodies, nor clinical history of COVID-19 disease.
Results: Long Covid patients had significantly higher cumulative number of IgM positivity of the DNA viruses (18.1% vs 6.7%, p=0.02), and significantly elevated quantitative EBV IgG (420±296 vs 339±282 mg/dL, p=0.033) and Parvo-B19 IgM (0.28±0.29 vs 0.03±0.12 mg/dL, p<0.001) titer as compared to healthy controls. Significantly more patients with long COVID symptoms had an EBV IgG titer above the detection limit as compared with healthy controls (40% vs 28%, p=0.018), suggesting EBV virus reactivation and chronic EBV infection. EBV IgG titer was significantly higher in patients with dominant respiratory symptoms, while elevated Parvo-B19 IgM titer was observed in patients with dominant cardiovascular complaints. In patients with long-COVID syndrome the quantitative EBV IgG titer increased with the time between infection and blood sampling (logarithmic correlation, p=0.011), suggesting the subclinical continuous EBV activation by the SARS-CoV2 RNA virus, while the quantitative Parvo-B19 IgM titer decreased linearly during the observation period
Conclusions: In this study of patients with long-COVID syndrome, SARS-CoV-2 infection apparently activated certain types of DNA viruses (EBV, and Parvo-B19), as demonstrated by the significantly higher incidence of cumulative IgM positivity, and elevated EBV IgG and parvovirus-B19 IgM titers, in long-COVID patients compared to healthy controls.
Source: M Gyongyosi, E Hasimbegovic, D Lukovic, K Zlabinger, A Spannbauer, E Samaha, J Bergler-Klein, C Hengstenberg, P Mucher, H Haslacher, M Breuer, R Strassl, M Riesenhuber, C Nitsche, T A Zelniker, Sequential activation of DNA viruses by the RNA virus SARS-CoV-2 in patients with long COVID syndrome, European Heart Journal, Volume 44, Issue Supplement_2, November 2023, ehad655.1823, https://doi.org/10.1093/eurheartj/ehad655.1823 https://academic.oup.com/eurheartj/article/44/Supplement_2/ehad655.1823/7393979 (Full text available as PDF file)

Case Report: Rapid and partially persistent, improvements of anorexia nervosa and probable myalgic encephalo-myelitis/chronic fatigue syndrome upon metreleptin treatment during two dosing episodes

Abstract

A comorbidity of anorexia nervosa (AN) and myalgic encephalomyelitis (ME/CSF) is uncommon. A 17-year-old male adolescent with possible onset of ME/CFS after an Epstein Barr Virus infection (EBV) and later onset of AN during a second period of weight loss was twice treated off-label with metreleptin for 15 and 11 days, respectively.

As in previous cases, eating disorder specific cognitions and mood improved. Interestingly, fatigue and post-exertional muscle pain (P-EMP) improved, too. We discuss potential mechanisms. Treatment with metreleptin may prove beneficial in AN and in ME/CSF associated with substantial weight loss.

Source: Jochen Antel, Johannes Hebebrand, Linda Von Piechowski, Cordula Kiewert, Burkhard Stüve, Gertraud Gradl-Dietsch. Rapid and partially persistent, improvements of anorexia nervosa and probable myalgic encephalo-myelitis/chronic fatigue syndrome upon metreleptin treatment during two dosing episodes. Front. Psychiatry, Sec. Adolescent and Young Adult Psychiatry, Volume 14 – 2023. https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1267495/abstract