MEA Research Roundup

ME/CFS and Long Covid Research: 04 – 10 October 2022 

The weekly research round-up includes recent publications about ME/CFS and Long Covid. We highlight the studies that have particularly caught our interest and follow these with the full list of publications together with their abstracts (summaries).


The ME Association maintains a comprehensive index of published research on ME/CFS and Long Covid that is free to use and updated weekly.

Audio Commentary by Dr Katrina Pears

ME/CFS Research Published 4 – 10 October 2022 

It’s been a quiet week for ME/CFS research with only three new studies, however, there have been fifteen new studies on Long Covid. 

We have highlighted one ME/CFS study below and included highlights from this week’s Long Covid research: 

Paper one (1) is a systemic review on all genetic studies which has been published to date on ME/CFS and Long Covid in order to help understand the similarities, as well as to look at pathway analysis to understand the involvement of these genes in bodily functions. 

Interestingly, the review included previous data from 26 ME/CFS studies and 71 Long Covid studies, which really highlights the attention in Long Covid research. This revealed 429 genes being affected in ME/CFS and 97 genes in Long Covid. 

The study found a range of common genes being affected in both conditions: 

  • ACE (Angiotensin I-converting enzyme) – involved in controlling blood pressure by regulating body fluids. 
  • Four major histocompatibility complex genes (HLA-A, HLA-C, HLA-DQA1, HLA-DRB1) – involved in coding for the cell surface proteins in the adaptive immune system, this provides recognition to the T-cells so they do not attack them. 
  • TYK2 (Tyrosine kinase 2)- involved in regulating the immune system and is part of the cytokine signalling system. 

Together the results from this review suggest that immune dysfunction is involved in the pathogenesis of both conditions, although the number of genes shared between the two conditions was small.  

This study is limited by only using previously published data, which could be of varying quality (such as diagnostic criteria used), especially seeing as there has been a lack of investment into ME/CFS research, which this study highlights. The authors also highlight the discrepancies between findings in ME/CFS, and the expression of genes that are not involved in any one bodily system, making it hard to pinpoint any disease mechanisms. Therefore, there is hope that DecodeME could shed more light on the pathogenesis of disease. 

Several of the studies in the Long Covid reference section are of particular interest this week: 

  • Paper two (2) is a comprehensive review on the neurological causes of Long Covid, and lists many of the causative factors we already know about ME/CFS. Dr Charles Shepherd has provided a comment of this paper
  • Paper three (3) is also a comprehensive review on the causes of Long Covid with a focus on the role of mast cell activation syndrome (MCAS) but also highlights changes in the immune system being contributors. 
  • Paper four (4) study finds that Long Covid patients can be identified by the 100% reduction in the plasma expression of interleukin 8 (IL-8) (involved in attracting and activating white blood cells) and interferon-gamma cytokines (IFNγ)(involved in a modulating and inducing immune responses), as well as a smaller but significant reduction of other interleukins. An easy to read summary of this paper can be found here
  • Paper five (5) study finds kynurenine (a metabolite of the amino acid tryptophan) in the blood and saliva to be a useful biomarker for Long Covid. 

ME/CFS Research References and Abstracts  

1. Genetics of COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review 

Tziastoudi M, Cholevas C, Stefanidis I, Theoharides TC.  

Ann Clin Transl Neurol. 2022 Oct 6. [Epub ahead of print.] 


COVID-19 and ME/CFS present with some similar symptoms, especially physical and mental fatigue. In order to understand the basis of these similarities and the possibility of underlying common genetic components, we performed a systematic review of all published genetic association and cohort studies regarding COVID-19 and ME/CFS and extracted the genes along with the genetic variants investigated.  

We then performed gene ontology and pathway analysis of those genes that gave significant results in the individual studies to yield functional annotations of the studied genes using protein analysis through evolutionary relationships (PANTHER) VERSION 17.0 software. Finally, we identified the common genetic components of these two conditions.  

Seventy-one studies for COVID-19 and 26 studies for ME/CFS were included in the systematic review in which the expression of 97 genes for COVID-19 and 429 genes for ME/CFS were significantly affected.  

We found that ACE, HLA-A, HLA-C, HLA-DQA1, HLA-DRB1, and TYK2 are the common genes that gave significant results.  

The findings of the pathway analysis highlight the contribution of inflammation mediated by chemokine and cytokine signaling pathways, and the T cell activation and Toll receptor signaling pathways.  

Protein class analysis revealed the contribution of defense/immunity proteins, as well as protein-modifying enzymes. Our results suggest that the pathogenesis of both syndromes could involve some immune dysfunction. 

2. Grief in Chronic Illness: A Case Study of CFS/ME 

Byrne, Eleanor Alexandra 

Journal of Consciousness Studies, Volume 29, Numbers 9-10, September 2022, pp. 175-200(26) 


This paper points to a more expansive conception of grief by arguing that the losses of illness can be genuine objects of grief.  

I argue for this by illuminating underappreciated structural features of typical grief — that is, grief over a bereavement — which are shared but under-recognized. I offer a common chronic illness, chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), as a striking case study.  

I then use this analysis to highlight some clinical challenges that arise should this claim receive uptake in clinical practice.  

Extant literature on CFS/ME tells us that rates of comorbid depression are atypically high. If one accepts that people with CFS/ ME can grieve over losses associated with the condition, and that grief can be easily mistaken for depression in this context, this might suggest that rates of comorbid depression are inflated.  

I show, however, that the challenge of distinguishing between healthy and pathological grief arises in its place, and is just as tricky to solve. 

3. Identification of transient receptor potential melastatin 3 proteotypic peptides employing an efficient membrane protein extraction method for natural killer cells 

Sasso EM, Thapaliya K, Barnden L, Maksoud R, Weigel B, Rudd PA, Herrero LJ and Marshall-Gradisnik S.  

Front. Physiol. 13:947723. 


Introduction: Mutations and misfolding of membrane proteins are associated with various disorders, hence they make suitable targets in proteomic studies. However, extraction of membrane proteins is challenging due to their low abundance, stability, and susceptibility to protease degradation.  

Given the limitations in existing protocols for membrane protein extraction, the aim of this investigation was to develop a protocol for a high yield of membrane proteins for isolated Natural Killer (NK) cells.  

This will facilitate genetic analysis of membrane proteins known as transient receptor potential melastatin 3 (TRPM3) ion channels in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) research. 

Methods: Two protocols, internally identified as Protocol 1 and 2, were adapted and optimized for high yield protein extraction. Protocol 1 utilized ultrasonic and salt precipitation, while Protocol 2 implemented a detergent and chloroform/methanol approach.  

Protein concentrations were determined by the Pierce Bicinchoninic Acid (BCA) and the Bio-Rad DC (detergent compatible) protein assays according to manufacturer’s recommendation. Using Protocol 2, protein samples were extracted from NK cells of n = 6 healthy controls (HC) and n = 4 ME/CFS patients. In silico tryptic digest and enhanced signature peptide (ESP) predictor were used to predict high-responding TRPM3 tryptic peptides.  

Trypsin in-gel digestion was performed on protein samples loaded on SDS-PAGE gels (excised at 150–200 kDa). A liquid chromatography-multiple reaction monitoring (LC-MRM) method was optimized and used to evaluate the detectability of TRPM3 n = 5 proteotypic peptides in extracted protein samples. 

Results: The detergent-based protocol protein yield was significantly higher (p < 0.05) compared with the ultrasonic-based protocol. The Pierce BCA protein assay showed more reproducibility and compatibility compared to the Bio-Rad DC protein assay.  

Two high-responding tryptic peptides (GANASAPDQLSLALAWNR and QAILFPNEEPSWK) for TRPM3 were detectable in n = 10 extracted protein samples from NK cells isolated from HC and ME/CFS patients. 

Conclusion: A method was optimized for high yield protein extraction from human NK cells and for the first time TRPM3 proteotypic peptides were detected using LC-MRM.  

This new method provides for future research to assess membrane protein structural and functional relationships, particularly to facilitate proteomic investigation of TRPM3 ion channel isoforms in NK cells in both health and disease states, such as ME/CFS. 

Long-COVID Research References  

  1. Sleep symptoms are essential features of long-COVID – Comparing healthy controls with COVID-19 cases of different severity in the international COVID sleep study (ICOSS-II) 
  1. The Neurobiology of Long COVID 
  1. Pathophysiology of Post-COVID syndromes: a new perspective 
  1. Plasma cytokine levels reveal deficiencies in IL-8 and gamma interferon in Long-COVID 
  1. Kynurenine serves as useful biomarker in acute, Long- and Post-COVID-19 diagnostics 
  1. Acute COVID-19 Syndrome Predicts Severe Long COVID-19: An Observational Study 
  1. Newonset neuropsychiatric sequelae and ‘longCOVID’ syndrome (Review) 
  1. Protocol for a systematic review of interventions targeting mental health, cognition or psychological well-being among individuals with long COVID 
  1. Support amid uncertainty: Long COVID illness experiences and the role of online communities 
  1. Antioxidants and Long Covid 
  1. Post-Viral Fatigue in COVID-19: A Review of Symptom Assessment Methods, Mental, Cognitive, and Physical Impairment 
  1. Preliminary Guidelines for the Clinical Evaluation and Management of Long COVID 
  1. Long COVID: defining the role of rheumatology in care and research 
  1. Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021 
  1. Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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