Abnormal T-Cell Activation And Cytotoxic T-Cell Frequency Discriminates Symptom Severity In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating but poorly-understood disease. ME/CFS symptoms can range from mild to severe, and include immune system effects alongside incapacitating fatigue and post-exertional disease exacerbation. In this study, we examined immunological profiles of people living with ME/CFS by flow cytometry, focusing on cytotoxic cells, to determine whether people with mild/moderate (n= 43) or severe ME/CFS (n=53) expressed different immunological markers.

We found that people with mild/moderate ME/CFS had increased expression of cytotoxic effector molecules alongside enhanced proportions of early-immunosenescence cells, determined by the CD28  CD57  phenotype, indicative of persistent viral infection. In contrast, people with severe ME/CFS had higher proportions of activated circulating lymphocytes, determined by CD69 + and CD38 + expression, and expressed more pro-inflammatory cytokines, including IFNγ, TNF and IL-17, following stimulation in vitro , indicative of prolonged non-specific inflammation.

These changes were consistent across different cell types including CD8 + T cells, mucosal associated invariant T cells and Natural Killer cells, indicating generalised altered cytotoxic responses across the innate and adaptive immune system. These immunological differences likely reflect different disease pathogenesis mechanisms occurring in the two clinical groups, opening up opportunities for the development of prognostic markers and stratified treatments.

Source: Lee JS, Lacerda E, Kingdon C, Susannini G, Dockrell HM, Nacul L, Cliff JM. Abnormal T-Cell Activation And Cytotoxic T-Cell Frequency Discriminates Symptom Severity In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. medRxiv [Preprint]. 2025 Jan 6:2025.01.02.24319359. doi: 10.1101/2025.01.02.24319359. PMID: 39830245; PMCID: PMC11741448. https://pubmed.ncbi.nlm.nih.gov/39830245/

Effect of Immunoadsorption on clinical presentation and immune alterations in COVID-19-induced and/or aggravated ME/CFS

Abstract:

Autoreactive antibodies (AAB) are currently being investigated as causative or aggravating factors during post-COVID. In this study we analyze the effect of immunoadsorption therapy on symptom improvement and the relationship with immunological parameters in post-COVID patients exhibiting symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) induced or aggravated by an SARS-CoV-2 infection. This observational study includes 12 post-COVID patients exhibiting a predominance of ME/CFS symptoms alongside increased concentrations of autonomic nervous system receptors (ANSR) autoantibodies and neurological impairments.

We found that following immunoadsorption therapy, the ANSR autoantibodies were nearly eliminated from the patients’ blood. The removal of IgG antibodies was accompanied by a decrease of pro-inflammatory cytokines including IL4, IL2, IL1β, TNF and IL17A serum levels, and a significant reduction of soluble spike protein. Notably, a strong positive correlation between pro-inflammatory cytokines and ASNR-AABs β1, β2, M3, and M4 was observed in spike protein-positive patients, whereas no such correlation was evident in spike protein-negative patients.

30 days post-immunoadsorption therapy, patients exhibited notable improvement in neuropsychological function and a modest but statistically significant amelioration of hand grip strength was observed. However, neither self-reported symptoms nor scores on ME/CFS questionnaires showed a significant improvement and a rebound of the removed proteins occurring within a month.

Source: Anft M, Wiemers L, Rosiewicz KS, Doevelaar A, Skrzypczyk S, Kurek J, Kaliszczyk S, Seidel M, Stervbo U, Seibert FS, Westhoff TH, Babel N. Effect of Immunoadsorption on clinical presentation and immune alterations in COVID-19-induced and/or aggravated ME/CFS. Mol Ther. 2025 Jan 9:S1525-0016(25)00011-5. doi: 10.1016/j.ymthe.2025.01.007. Epub ahead of print. PMID: 39797400. https://www.cell.com/molecular-therapy-family/molecular-therapy/pdf/S1525-0016(25)00011-5.pdf (Full text) https://pubmed.ncbi.nlm.nih.gov/39797400/ (Abstract)

Impact of age and sex on neuroinflammation following SARS-CoV-2 infection in a murine model

Abstract:

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, is known to infect people of all ages and both sexes. Senior populations have the greatest risk of severe COVID-19, and sexual dimorphism in clinical outcomes has been reported. Neurological symptoms are widely observed in COVID-19 patients, with many survivors exhibiting persistent neurological and cognitive impairment. The present study aims to investigate the impact of age and sex on the neuroinflammatory response to SARS-CoV-2 infection using a mouse model. Wild-type C57BL/6J mice were intranasally inoculated with SARS-CoV-2 lineage B.1.351, a variant known to infect mice.

Older male mice exhibited a significantly greater weight loss and higher viral loads in the lung at 3 days post infection. Notably, no viral RNA was detected in the brains of infected mice. Nevertheless, expression of IL-6, TNF-α, and CCL-2 in the lung and brain increased with viral infection. RNA-seq transcriptomic analysis of brains showed that SARS-CoV-2 infection caused significant changes in gene expression profiles, implicating innate immunity, defense response to virus, and cerebrovascular and neuronal functions.

These findings demonstrate that SARS-CoV-2 infection triggers a neuroinflammatory response, despite the lack of detectable virus in the brain. Aberrant activation of innate immune response, disruption of blood-brain barrier and endothelial cell integrity, and suppression of neuronal activity and axonogenesis underlie the impact of SARS-CoV-2 infection on the brain. Understanding the role of these affected pathways in SARS-CoV-2 pathogenesis helps identify appropriate points of therapeutic interventions to alleviate neurological dysfunction observed during COVID-19.

Source: Krishna VD, Chang A, Korthas H, Var SR, Low WC, Li L, Cheeran MC. Impact of age and sex on neuroinflammation following SARS-CoV-2 infection in a murine model. bioRxiv [Preprint]. 2023 Aug 14:2023.08.11.552998. doi: 10.1101/2023.08.11.552998. Update in: Front Microbiol. 2024 Jul 15;15:1404312. doi: 10.3389/fmicb.2024.1404312. PMID: 37645925; PMCID: PMC10462071. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10462071/ (Full text)

Impact of inflammatory response in the acute phase of COVID-19 on predicting objective and subjective post-COVID fatigue

Abstract:

The biological predictors of objective and subjective fatigue in individuals with post-COVID syndrome remains unclear. This study aims to ascertain the predictive significance of the immune response measured during the acute phase of SARS-CoV-2 infection on various dimensions of fatigue 6–9 months post-infection.

We examined the association between immune markers obtained from the serum of 54 patients (mean age: 58.69 ± 10.90; female: 31%) and objective and subjective chronic fatigue using general linear mixed models. Level of IL-1RA, IFNγ and TNFα in plasma and the percentage of monocytes measured in the acute phase of COVID-19 predicted physical and total fatigue.

Moreover, the higher the concentration of TNFα (r=-0.40 ; p = .019) in the acute phase, the greater the lack of awareness of cognitive fatigue 6–9 months post-infection. These findings shed light on the relationship between acute inflammatory response and the persistence of both objective and subjective fatigue.

Source: Julie Péron, Anthony Nuber-Champier, Gautier Breville et al. Impact of inflammatory response in the acute phase of COVID-19 on predicting objective and subjective post-COVID fatigue, 28 May 2024, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-4374986/v1] https://www.researchsquare.com/article/rs-4374986/v1 (Full text)

Diverse immunological dysregulation, chronic inflammation, and impaired erythropoiesis in long COVID patients with chronic fatigue syndrome

Abstract:

A substantial number of patients recovering from acute SARS-CoV-2 infection present serious lingering symptoms, often referred to as long COVID (LC). However, a subset of these patients exhibits the most debilitating symptoms characterized by ongoing myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS).

We specifically identified and studied ME/CFS patients from two independent LC cohorts, at least 12 months post the onset of acute disease, and compared them to the recovered group (R). ME/CFS patients had relatively increased neutrophils and monocytes but reduced lymphocytes. Selective T cell exhaustion with reduced naïve but increased terminal effector T cells was observed in these patients. LC was associated with elevated levels of plasma pro-inflammatory cytokines, chemokines, Galectin-9 (Gal-9), and artemin (ARTN). A defined threshold of Gal-9 and ARTN concentrations had a strong association with LC.

The expansion of immunosuppressive CD71+ erythroid cells (CECs) was noted. These cells may modulate the immune response and contribute to increased ARTN concentration, which correlated with pain and cognitive impairment. Serology revealed an elevation in a variety of autoantibodies in LC. Intriguingly, we found that the frequency of 2B4+CD160+ and TIM3+CD160+ CD8+ T cells completely separated LC patients from the R group.

Our further analyses using a multiple regression model revealed that the elevated frequency/levels of CD4 terminal effector, ARTN, CEC, Gal-9, CD8 terminal effector, and MCP1 but lower frequency/levels of TGF-β and MAIT cells can distinguish LC from the R group. Our findings provide a new paradigm in the pathogenesis of ME/CFS to identify strategies for its prevention and treatment.

Source: Saito S, Shahbaz S, Osman M, Redmond D, Bozorgmehr N, Rosychuk RJ, Lam G, Sligl W, Cohen Tervaert JW, Elahi S. Diverse immunological dysregulation, chronic inflammation, and impaired erythropoiesis in long COVID patients with chronic fatigue syndrome. J Autoimmun. 2024 May 25;147:103267. doi: 10.1016/j.jaut.2024.103267. Epub ahead of print. PMID: 38797051. https://www.sciencedirect.com/science/article/pii/S089684112400101X (Full text)

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Abstract:

Neuroinflammatory and neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood.

These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood-brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration.

Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders.

Source: Cohen J, Mathew A, Dourvetakis KD, Sanchez-Guerrero E, Pangeni RP, Gurusamy N, Aenlle KK, Ravindran G, Twahir A, Isler D, Sosa-Garcia SR, Llizo A, Bested AC, Theoharides TC, Klimas NG, Kempuraj D. Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders. Cells. 2024 Mar 14;13(6):511. doi: 10.3390/cells13060511. PMID: 38534355; PMCID: PMC10969521. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10969521/ (Full text)

The molecular fingerprint of neuroinflammation in COVID-19: A comprehensive discussion on molecular mechanisms of neuroinflammation due to SARS-COV2 antigens

Abstract:

Background and objective: Severe acute respiratory syndrome coronavirus 2 attacks the neural system directly and indirectly via various systems, such as the nasal cavity, olfactory system, and facial nerves. Considering the high energy requirement, lack of antioxidant defenses, and high amounts of metal ions in the brain, oxidative damage is very harmful to the brain. Various neuropathic pain conditions, neurological disorders, and neuropsychiatric complications were reported in Coronavirus disease 2019, prolonged Coronavirus disease 2019, and after Coronavirus disease 2019 immunization. This manuscript offers a distinctive outlook on the interconnectedness between neurology and neuropsychiatry through its meticulous analysis of complications.

Discussion: After recovering from Coronavirus disease 2019, approximately half of the patients reported developing Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Long Coronavirus disease 2019 imaging reports illustrated the hypometabolism in various parts of the brain, such as olfactory bulbs, limbic/paralimbic domains, the brainstem, and the cerebellum. Ninety imaging and neuropathological studies of Coronavirus disease 2019 have shown evidence of white matter, brainstem, frontotemporal, and oculofrontal lesions. Emotional functions, such as pleasant, long/short-term memory, movement, cognition and cognition in decision-making are controlled by these regions. The neuroinflammation and the mechanisms of defense are well presented in the discussion. The role of microglia activation, Inducible NO synthase, Cyclooxygenases ½, Reactive oxygen species, neurotoxic toxins and pro-inflammatory cytokines, such as Interleukin-1 beta, Interleukin-6 and Tumor Necrosis Factor-alpha are highlighted in neuronal dysfunction and death. Nuclear factor kappa-light-chain-enhancer of activated B cells, Mitogen-activated protein kinase, Activator Protein 1, and Interferon regulatory factors are the main pathways involved in microglia activation in Coronavirus disease 2019 neuroinflammation.

Conclusion: The neurological aspect of Coronavirus disease 2019 should be highlighted. Neurological, psychological, and behavioral aspects of Coronavirus disease 2019, prolonged Coronavirus disease 2019, and Coronavirus disease 2019 vaccines can be the upcoming issues. We need a global awareness where this aspect of the disease should be more considered in health research.

Source: Zayeri ZD, Torabizadeh M, Kargar M, Kazemi H. The molecular fingerprint of neuroinflammation in COVID-19: A comprehensive discussion on molecular mechanisms of neuroinflammation due to SARS-COV2 antigens. Behav Brain Res. 2024 Jan 20;462:114868. doi: 10.1016/j.bbr.2024.114868. Epub ahead of print. PMID: 38246395. https://www.sciencedirect.com/science/article/abs/pii/S016643282400024X

Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome

Introduction: A group of SARS-CoV-2 infected individuals present lingering symptoms, defined as long COVID (LC), that may last months or years post the onset of acute disease. A portion of LC patients have symptoms similar to myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), which results in a substantial reduction in their quality of life. A better understanding of the pathophysiology of LC, in particular, ME/CFS is urgently needed.

Methods: We identified and studied metabolites and soluble biomarkers in plasma from LC individuals mainly exhibiting ME/CFS compared to age-sex-matched recovered individuals (R) without LC, acute COVID-19 patients (A), and to SARS-CoV-2 unexposed healthy individuals (HC).

Results: Through these analyses, we identified alterations in several metabolomic pathways in LC vs other groups. Plasma metabolomics analysis showed that LC differed from the R and HC groups. Of note, the R group also exhibited a different metabolomic profile than HC. Moreover, we observed a significant elevation in the plasma pro-inflammatory biomarkers (e.g. IL-1α, IL-6, TNF-α, Flt-1, and sCD14) but the reduction in ATP in LC patients. Our results demonstrate that LC patients exhibit persistent metabolomic abnormalities 12 months after the acute COVID-19 disease. Of note, such metabolomic alterations can be observed in the R group 12 months after the acute disease. Hence, the metabolomic recovery period for infected individuals with SARS-CoV-2 might be long-lasting. In particular, we found a significant reduction in sarcosine and serine concentrations in LC patients, which was inversely correlated with depression, anxiety, and cognitive dysfunction scores.

Conclusion: Our study findings provide a comprehensive metabolomic knowledge base and other soluble biomarkers for a better understanding of the pathophysiology of LC and suggests sarcosine and serine supplementations might have potential therapeutic implications in LC patients. Finally, our study reveals that LC disproportionally affects females more than males, as evidenced by nearly 70% of our LC patients being female.

Source: Saito Suguru, Shahbaz Shima, Luo Xian, Osman Mohammed, Redmond Desiree, Cohen Tervaert Jan Willem, Li Liang, Elahi Shokrollah. Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome. Frontiers in Immunology, Vol 15, 2024. DOI=10.3389/fimmu.2024.1341843  https://www.frontiersin.org/articles/10.3389/fimmu.2024.1341843/full (Full text)

Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study

Abstract:

Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities.

During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC.

Source: Ozonoff, A., Jayavelu, N.D., Liu, S. et al. Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study. Nat Commun 15, 216 (2024). https://doi.org/10.1038/s41467-023-44090-5 https://www.nature.com/articles/s41467-023-44090-5 (Full text)

Long-COVID-19: the persisting imprint of SARS-CoV-2 infections on the innate immune system

In a recent Cell publication, Cheong et al. uncover how COVID-19 causes IL-6 induced epigenetic reprogramming of human immune stem cells, which causes lasting alterations in the composition and response characteristics of circulating immune cells.1 The study provides important insights into the mechanisms by which SARS-CoV-2 infections impact the human immune system and is an important hook into unraveling the mechanisms of post-acute sequelae of COVID-19 (PASC) commonly referred to as long-COVID.

While vaccination and drugs are reducing the societal impact of acute SARS-CoV-2 infections, between 10 and 40% of patients continue to suffer long after the acute infection has been cleared. The diverse PASC symptoms range from short breath and headaches to cognitive impairment (‘brain fog’) and debilitating fatigue. Not only are no treatments for PASC available but also the underlying molecular mechanisms remain opaque.2

Cheong et al. investigated in patients’ circulating immune cells if detectable changes persisted after clearance of the acute SARS-CoV-2 infection 3 weeks after the first symptoms. They assembled a cohort of COVID-19 convalescent patients, which was sampled between 1–3 and 4–12 months after SARS-CoV-2 infections requiring intensive care unit (ICU) admission and compared these patients to non-infected controls and to patients that had been on the ICU for different reasons. Focusing on peripheral blood mononuclear cells (PBMC) they investigated transcriptional or epigenetic changes using an integrated pipeline of single-nuclei transcriptome analysis and ATAC-seq sequencing, which identifies accessible chromatin regions. Among PBMCs CD14+ monocytes exhibited the most drastic changes. CD14+ monocytes are a group of heterogenous, short-lived antigen presenting cells that help orchestrating immune responses. Among these the authors could distinguish one cluster, M.SC3, which was more abundant even 12 months after the infection. Cells in this cluster resembled intermediate-type monocytes with functions that altogether resemble dendritic cells, the most effective amongst professional antigen presenting cells. In response to stimuli indicating viral infections, post-COVID monocytes showed up to 100-fold increased secretion of proinflammatory cytokines and enhanced transcriptional responses relating to cytokine signaling and monocyte activation. ATAC-seq also revealed a persistent pattern of differentially accessible chromatin which increased in abundance in early convalescent patients and did not return to the low levels observed in healthy individuals even 12 months after the acute infection. Thus, following severe SARS-CoV-2 infections, patients’ CD14+ monocytes carry specific and persistent epigenetic changes that puts them into an alerted state with heightened response characteristics.

Given that monocytes have a lifespan of a single day, the discovery of persistent epigenetic changes is notable and may reflect altered hematopoiesis and inheritance of epigenetic states from hematopoietic stem and progenitor cells (HSPC). To overcome the challenges associated with obtaining bone marrow resident HSPC, Cheong et al. developed a platform to enrich rare circulating HSPCs from PBMC and demonstrated that these faithfully represent the diversity and functional characteristics of their bone marrow-derived counterparts. With this platform, they discovered lasting epigenetic changes in HSPC of post-COVID patients that resembled those observed in mature monocytes. Especially late post-COVID HSPC exhibited skewed hematopoiesis with a significant increase of granulocyte monocyte precursor (GMP) cells. Intriguingly, the stem cells and the mature monocytes shared epigenetic signatures indicating that epigenetic and transcriptional programs are inherited by the mature progeny. The previously identified M.SC3 module activity was similarly increased in stem cells of the same patients.

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Source: Boes, M., Falter-Braun, P. Long-COVID-19: the persisting imprint of SARS-CoV-2 infections on the innate immune system. Sig Transduct Target Ther 8, 460 (2023). https://doi.org/10.1038/s41392-023-01717-9 https://www.nature.com/articles/s41392-023-01717-9 (Full text)