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Research Digest | Issue 105

Welcome to the 105th edition of Emerge Australia’s Digest. In this month’s issue, we delve into a single-cell RNA sequencing project aimed at understanding the impact of exercise on PEM in individuals living with ME/CFS. Furthermore, we feature a review highlighting the parallels between ME/CFS and Long COVID, along with a media report emphasising the urgency for increased research into Long COVID in Australia. Be sure to take advantage of the recently implemented ‘text-to-speech’ technology for the Digest summaries – Just click the button pertaining to the summary below, and the research summaries are read to you.

Contributing Digesters: Solène, Shan and Simone.

Digest Editor: Simone Eyssens.

You can also join our community and choose to have the Digest delivered straight to your inbox at the end of every month, by signing up to our mailing list here. We appreciate the support of everyone who reads the Digest – we encourage regular subscribers to support us with a monthly suggested donation of $2.

Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation

Authors: Vu LT, Ahmed F, Zhu H, Iu DSH, Fogarty EA, Kwak Y, … Grimson A (Cornell University, USA)
Cell Reports Medicine

Despite evidence suggesting immune system issues, it is unclear how the immune system is affected in ME/CFS. In this article, the authors examined immune cells from ME/CFS patients and matched controls using single-cell RNA sequencing (scRNA-seq) to identify immune cell types with dysregulated transcriptomes in ME/CFS. Because post-exertional malaise (PEM) is a hallmark symptom of ME/CFS, they also performed scRNA-seq analyses before and after an exercise challenge to characterise changes during PEM.

Thirty patients (ten men) with ME/CFS (Canadian Consensus Criteria) and 28 healthy controls (eight men) were recruited for this study. Participants donated blood and participated in a cardiopulmonary exercise test (CPET). All samples were obtained before the COVID-19 pandemic, which means that none of the participants had Long-COVID rather than ME/CFS. Blood samples were obtained at baseline (before CPET) and 24h after CPET.

Certain cell types showed strong signals of transcriptome dysregulation in ME/CFS patients when compared to controls, particularly CD4+ T cells, monocytes, and cytotoxic natural killer cells. Several gene set enrichment analyses revealed that monocytes were highly dysregulated in ME/CFS, and ribosomal protein genes and core translational machinery were downregulated in multiple cell types from ME/CFS patients. In ME/CFS, monocyte genes related to chemokine signalling, migration, and activation were over-expressed while the ones associated with IFN-γ signalling were suppressed.

Genes associated with IL-10, an anti-inflammatory cytokine, were also expressed leading to a combination of conflicting inputs in monocytes from ME/CFS patients. Further analyses of the genes involved in monocyte response, recruitment, or differentiation suggest that monocytes in ME/CFS are pro-migratory and inflammatory at baseline. This constant activation of monocytes in ME/CFS was further confirmed at the protein level. The authors also observed that monocyte dysregulation was heterogeneous within and between ME/CFS patients. Finally, when comparing gene expression changes across cells between baseline and 24 h after CPET, the authors identified a strong dysregulation of platelet-related genes in ME/CFS patients suggesting that exercise alters platelets in ME/CFS.

Monocytes exhibited the strongest immune dysregulation in ME/CFS participants in this study. The authors recommend further studies to investigate whether monocyte dysregulation is also the strongest signal in Long-COVID and whether the identified gene sets altered in ME/CFS are also identified in monocytes from Long-COVID patients.

Figure. Illustration highlighting the study’s research findings.

A phenomenological study on the lived experience of men with chronic fatigue syndrome

Authors: Snell GE, Seage CH, Mercer J (Cardiff Metropolitan University, UK).
Journal of Health Psychology

Notions of masculinity, requiring males to be tough both mentally and physically, frequently influence whether men admit illness or seek medical help. With ME/CFS historically having been labelled hysteria, been considered “all in one’s head”, and something women experience, it would be understandable for men to have been reluctant to admit to themselves, or others, that they have experienced similar symptoms. There have been few studies of the lived experience of men experiencing ME/CFS. This study aimed to better understand the male experience of ME/CFS, with a particular focus on diagnosis and receiving support.   

Participants were five cisgender adult males diagnosed within the past ten years. Individual interviews were conducted using an inductive approach, with open-ended questions and prompts to elicit a deep understanding of each participant’s experience of their journey to diagnosis and how this has affected them socially and emotionally.

Using interpretive phenomenological analysis (IPA), the authors identified six themes: fighting the symptoms to maintain male competency, perceptions of healthcare inequality, limited professional recognition of ME/CFS symptoms, challenges in accepting a new life, challenges to masculinity, and importance of support networks. Phrases associated with masculinity, such as “battle through” and “man up”, were common throughout the interviews.

The authors found that the symptoms of all participants were consistent with ME/CFS, and yet they all had difficulty obtaining a diagnosis, as well as treatment and support. Whilst this was partly due to healthcare professionals still having limited understanding of ME/CFS, this was further impacted by a reluctance to believe their own symptoms, and by the belief that healthcare professionals are less sympathetic to men. This is important as earlier diagnosis leads to better prognosis.

Participants reported the loss of male-oriented activities such as sports or being the breadwinner severely impacted their sense of self. They reported the experience of living with ME/CFS to be particularly isolating. Opening up emotionally to other men helped, but support groups dominated by women felt inaccessible to many participants.

The authors emphasise the need for further societal education to legitimise ME/CFS, particularly to employers and health professionals. They also strongly suggest that support groups, both online and in person, targeted specifically to men with ME/CFS need to become more widely available, as this informal support is integral to adapting to life with the disability.

Unravelling shared mechanisms: Insights from recent ME/CFS research to illuminate long COVID pathologies

Authors: Annesley SJ, Missailidis D, Heng B, Josev EK, Armstrong CW (University of Melbourne, Australia)
Publication: Trends in Molecular Medicine

In this review, the authors discuss the current knowledge of ME/CFS and highlight the proposed pathologies shared with Long COVID (LC).

Immune system dysfunction

ME/CFS is linked to immune system dysfunction triggered by various infectious agents. Active viral infections in these patients and the presence of autoantibodies targeting the adrenergic receptors are both associated with fatigue and neurocognitive impairment. Impaired immune responses in ME/CFS patients include reduced metabolic activity in T-cells, resulting in a lower capacity to respond to pathogens, and disrupted cytotoxic capability in NK-cells. The role of innate immune cells and cytokines remains inconclusive, and more studies are needed.

LC is associated with persistent systemic inflammation, chronic T-cell activation and exhaustion.

In both ME/CFS and LC, viral reactivation correlates with fatigue symptoms.

Metabolic abnormalities

In ME/CFS, glycolysis and mitochondrial respiration are reduced in several cell types including CD4+ and CD8+ T cells, and peripheral blood mononuclear cells. T-cells and NK-cells both use increased lipids to produce energy, and CPT1a (a fatty acid transport protein) is associated with the disease duration. WASF3, a protein of the Wiskott–Aldrich syndrome protein family, is elevated in ME/CFS muscle cells and a study on transgenic mice suggests that WASF3 causes fatigue.

Patients with LC present impaired mitochondrial function with altered metabolites and catabolism.

An increase in reactive oxygen species (ROS) has been found in both ME/CFS and LC. ROS and resultant oxidative stress have been hypothesised as a possible cause of many symptoms, including post-exertional malaise, which is common to both conditions.

Microbiota dysbiosis

ME/CFS patients present markers of intestinal damage, and bacteria of the genera Paraprevotella and Ruminococcaceae are associated with an increased risk of ME/CFS in a genome-wide association study.

Both diseases present gut microbiota changes with altered levels of butyrate-producing bacteria and elevated Bacteroides spp.

Central nervous system (CNS) dysfunction

In ME/CFS, systemic neuroinflammation leads to loss of normal homeostasis, demyelination of axons and increased activation of glial cells. Structural impacts of ME/CFS on the CNS consist of reductions in white and grey matter, cortical thickness, and reduction in both density and complexity of axons. Conversely, compensatory mechanisms of neuroinflammation include increases in myelination, functional connectivity, and cerebral blood flow following exercise provocation in diverse brain regions.

In LC, long-term sequelae in the CNS include increased perivascular space, microbleeds, white matter lesions, and reduced brain size.

Further investigation is essential to fully grasp how both diseases influence the CNS.

Vascular pathologies

ME/CFS patients present low blood pressure, orthostatic intolerance, and postural tachycardia syndrome. They also have an increased risk of heart failure and other cardiovascular diseases. ME/CFS is characterised by endothelial dysfunction, vascular abnormalities, and platelet hyperactivity although the latter may be specific to only a subset of ME/CFS patients.

LC is also associated with an increased risk of developing cardiovascular diseases including heart failure and myocarditis, among others. Vascular abnormalities such as blood morphology changes, formation of microclots, and hyperactivated platelets have been detected in LC.

Both disorders are associated with the formation of fibrous amyloid clots and hyperactivated platelets but, while these changes are prominent in LC, they have only been identified in a subset of ME/CFS patients.

Understanding the underlying pathology of both ME/CFS and LC is crucial to the development of diagnostic tests and effective treatments. LC may offer an opportunity to study early disease changes in ME/CFS, while ME/CFS research may provide insights into LC pathology over the long term.

Figure. Shared pathologies of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID.

Experts call for more research into long COVID, as study reveals high prevalence in WA

Authors:Smith EJB, Trigger R, Pin P
ABC News

An Australian National University (ANU) study of 11,000 people in Western Australia who had tested positive for COVID-19 during a 2022 Omicron outbreak found that almost 20% had persistent symptoms three months after initially becoming sick. Researchers say that this suggests that the rate of long COVID is high in WA and urges more research into the condition.

Dr Michael Livingston, a rural GP in WA’s Wheatbelt, said that people should not be complacent about COVID-19 prevention. He suggested that the government should develop a “clean air” policy, and fit air filters into spaces like offices and schools to minimise transmission.

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