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Research Digest 29/10/21

Welcome to the 78th Emerge Australia Research Digest, where you will find summaries of some of the latest research and information about ME/CFS, with links to the complete articles.

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The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in myalgic encephalomyelitis/chronic fatigue syndrome: A meta-analysis of public DNA methylation and gene expression

Authors:Malato J, Sotzny F, Bauer S, Freitag H, Fonseca A, Grabowska AD, … Sepúlveda N (Universidade de Lisboa, Portugal)
Publication: Heliyon

The evidence for ME/CFS being triggered by microbial and viral infections continues to grow, alongside hypotheses of the role of reactivation of dormant viral infections. Peripheral blood mononuclear cells (PBMCs) have altered gene expression in ME/CFS, including reduced human angiotensin-converting enzyme 2 (ACE2). Angiotensin-converting enzyme (ACE) and ACE2 have vasoconstriction and vasodilation properties respectively, with a high ACE:ACE2 ratio being a possible indicator of severe COVID-19 outcomes. This meta-analysis reviewed whether ACE2 and ACE expression is altered in ME/CFS, based on DNA methylation and gene expression data of ACE and ACE2 in PBMCs. Additionally, a comparison of the mRNA levels of these two genes was undertaken in PBMCs from a new female cohort of ME/CFS and healthy controls.

Six studies were included in the DNA methylation meta-analysis and eight in the gene expression analysis. All ME/CFS diagnoses  were based on the Fukuda criteria or the Canadian Consensus Criteria (CCC). Of the six studies, three included male and female participants and three included only female participants. The mRNA comparison undertaken for this study included 37 females with ME/CFS (CCC) and 34 female age-matched healthy controls.

The DNA methylation meta-analysis suggested that in ME/CFS there was an increase in ACE2 expression, whereas the gene expression meta-analysis indicated reduced ACE2 (but not ACE) expression in ME/CFS. The new comparative analysis of ACE/ACE2 gene expression undertaken in this study did not demonstrate a reduction in ACE2 in ME/CFS, however in nearly 30% of the ME/CFS participants, the ACE2 expression level was below the limit of detection.

The authors suggest that there is a decreased expression of ACE2 in PBMCs in ME/CFS, and that those with ME/CFS may be at increased risk of COVID-19, and should be considered a priority group for COVID-19 vaccination. Further research should focus on data collection from the main cellular targets in ME/CFS, alternative SARS-CoV-2 receptors, and investigate sex differences as males are typically more affected by COVID-19 than females.


An Audit of UK Hospital Doctors’ Knowledge and Experience of Myalgic Encephalomyelitis

Authors: Hng KN, Geraghty K, Pheby DFH (Buckinghamshire New University, UK)

A common barrier to diagnosis and management for people with ME/CFS is that many doctors consider the condition non-existent or psychosomatic. A previous literature review highlighted the extent of the problem, finding that between one third to one half of General Practitioners did not accept the reality of ME/CFS. This study aimed to assess the knowledge and understanding of ME/CFS amongst hospital doctors in the UK.
The authors conducted an audit of hospital doctors who attended a mandatory training event for doctors training in general internal medicine. A short introductory lecture on ME/CFS was included in the training, however the rest was unrelated. A questionnaire asking about attendees’ prior knowledge and experience of ME/CFS was distributed at the training event and collected at the end of the day. The questionnaire included previous education about the condition, perceived impact of the illness, approach to diagnosis and management, and understanding of epidemiology of ME/CFS. Forty four attendees completed the questionnaire.
The authors found just 27% of respondents reported previous formal teaching in ME/CFS. While 70% of respondents reported having had some experience with ME/CFS patients, 89% of respondents admitted to not knowing how to diagnose ME/CFS and 93% said they didn’t feel confident managing ME/CFS patients. In total, 81% of respondents indicated they believed  that ME/CFS was partly or wholly psychological.

Of the respondents who felt confident in diagnosing or managing ME/CFS, all thought the condition was either partly or wholly psychological, and thought it could be treated with graded exercise therapy. Some also indicated that cognitive behaviour therapy would be appropriate.

Finally, only half of respondents were able to identify the correct diagnostic process, and just 13.6% identified the clinical features of ME/CFS. Most respondents under-estimated the level of disability and over-estimated the ability of people with ME/CFS to stay in work.

The authors conclude that their findings demonstrate a widespread lack of training and clinical understanding of ME/CFS, placing patients at risk. However, the authors note that respondents recognised the need for further training in this area and recommend priority provision of accurate and up-to-date information on ME/CFS to medical students and doctors.


The effect of IL-2 stimulation and treatment of TRPM3 on channel co-localisation with PIP2 and NK cell function in myalgic encephalomyelitis/chronic fatigue syndrome patients

Authors: Eaton-Fitch N, Cabanas H, du Preez S, Staines D, Marshall-Gradisnik S (Griffith University, Australia)
Publication:Journal of Translational Medicine

Reduced natural Killer (NK) cell cytotoxicity, impaired transient receptor potential melastatin 3 (TRPM3) and impaired calcium mobilisation have been previously identified in ME/CFS pathology. This study aimed to examine the localisation of TRPM3 at the NK cell plasma membrane and co-localisation with calcium-dependent regulator phosphatidylinositol 4,5-bisphosphate (PIP2), and to determine whether NK cell cytotoxicity is impaired due to TRPM3 dysfunction.
This study included 15 ME/CFS patients (Canadian Consensus Criteria), and 15 age and sex matched healthy controls (HC). Participants provided blood samples and completed questionnaires. NK cells were isolated and stimulated using interleukin-2 (IL-2) and treated with pregnenolone sulfate (PregS), and PregS with ononetin drug combinations. Immunofluorescent technique was used to determine co-localisation of TRPM3 with the NK cell membrane and with PIP2. NK cell cytotoxicity was analysed using flow cytometry. 
There were no significant baseline differences between the groups in blood parameters other than eosinophil count. The ME/CFS group reported reduced quality life and increased level of disability. Following priming with IL-2, co-localisation of TRPM3 with PIP2in NK cells was significantly reduced in ME/CFS compared with HC.  A significant increase in co-localisation of  TRPM3 with PIP2in PregS + ononetin treated NK cells was found in ME/CFS patients and between groups. Although baseline NK cell cytotoxicity was significantly reduced in ME/CFS patients, no significant changes following overnight incubation with IL-2, PregS and ononetin were found between groups. IL-2 stimulation significantly enhanced NK cell cytotoxicity in both groups.
The authors conclude that reduced NK cell function in ME/CFS may be a result of impaired TRPM3 channel function impeding Ca2+signalling in NK cells of ME/CFS patients. They also conclude that changes in co-localisation suggest that PIP2-dependent TRPM3 function may be impaired. The authors recommend that future research targets the crosstalk that exists between IL-2 and TRPM3 intracellular signalling pathways which are dependent on Ca2+influx and PIP2.


COVID-19 made life more accessible for people with disability. Will it stay that way?

Author: Young E
Publication: SBS News
The pandemic has seen the introduction of many services which have made life more accessible for Australians with disabilities. Now that states like NSW and Victoria are reopening, some are worried that these services may not continue to be available.

Anne Wilson, CEO of Emerge Australia, said that as we reopen, it’s crucial that nobody “throws the baby out with the bathwater”.
“As things slowly change, it doesn’t mean we should automatically turn off what has been created, which for many, has provided more freedom and greater opportunity to participate in society… we need to ensure that governments and decision-makers fully understand the needs of this very unseen target group of patients and takes them into consideration,” she said.


Long COVID is ruining lives, but it also presents Australia with an opportunity

Author: Sakzewski E
Publication: ABC News
This article articulates the link between long-COVID and ME/CFS, and highlights the devastating impact that ME/CFS has on people living with the condition, including the severe and wide-ranging symptoms, loss of income, and stigma and judgement. The article suggests that long-COVID could provide an opportunity to learn more about post-viral conditions and to improve treatments.
“After years of feeling overlooked, ME/CFS groups are optimistic that the new focus on long COVID could unearth some answers for their conditions, too.”


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