Exertion intolerance and post-exertional malaise are defining features of ME/CFS. Work from our Center aims to uncover the molecular disruption that occurs during and around these features. Thus, through the lens of extracellular vesicles (EVs), a publication from co-lead authors Ludovic Giloteaux and Katherine Glass provides novel insights into these topics.
The study involved the isolation of EVs, membrane-bound non-replicating particles released from cells, from the plasma of 18 ME/CFS and 17 healthy control female participants. The cargo of EVs are relevant in that they provide signals that could uncover elements of dysfunction in ME/CFS. Specifically, protein cargo from EVs were examined in this publication before and after a cardiopulmonary exercise test (i.e., around the induction of PEM).
The EV proteome in response to exercise was clearly different in ME/CFS when compared to sedentary controls. These divergent responses were associated with different molecular pathways. Uncovered protein differences between the cohorts also point to contrasting tissues and cell types. Additionally, there were several proteins associated with a worsening of muscle pain (e.g., THBS1 and TPM4), PEM (e.g., NEXN), and fatigue (e.g., CLU) post exercise in ME/CFS. Although it is difficult to directly associate changes with the EV proteome to distinct cell types, this publication brings forth avenues to interrogate further.
If you are interested in more information regarding this publication, the entire paper is freely available in the Journal of Extracellular Vesicles.
The working group of the National Advisory Neurological Disorders and Stroke Council, part of the National Institutes of Health, recommended the development of research priorities for ME/CFS to help move the field towards translational research and clinical trials. The result led to creation of the ME/CFS Research Roadmap Working Group. The Group, co-led by Drs. Lucinda Bateman and Maureen Hanson, produced a series of eight webinars. A complete description of the webinar series can be found on the ME/CFS Research Roadmap website.
Our Center’s mission is to promote research to identify its cause(s), biomarkers, and pathophysiology in order to lead to prevention and effective treatments. With this focus, several Center investigators presented data to support the development of research priorities for ME/CFS. The talks from our Center are included below.
Maureen Hanson presented “ Immune cell-type approaches to identify mechanisms of ME/CFS” during the Immune System webinar. Her talk starts at 1:38:40.
Jessica Maya presented “Investigations and Consequences of Altered Metabolism in ME/CFS Immune Cells” during the Metabolism webinar. Her talk starts at 58:32.
Maureen Hanson presented “Chronic infection in ME/CFS: non-Herpes viruses” during the Chronic Infections webinar. Her talk starts at 1:01:25.
Ludovic Giloteaux presented “Extracellular vesicles” during the Physiology webinar. His talk starts at 3:15:10.
NIH held a hybrid online conference on the NIH campus on December 11-12, 2023. Center personnel attending in person were Claire McNally, Annie Gardella, David Iu, Jessica Maya, Tien Luyen (“Louis”) Vu, Katherine Glass, Arnaud Germain, Ludovic Giloteaux, Dawei Li, Andrew Grimson, and Maureen Hanson, as well as collaborator Nicholas Hampilos from Weill Cornell Medicine.
Both days of the conference are available online.
Jessica Maya’s presentation “Investigating T cell populations for immune cell dysfunction in ME/CFS” starts at 3:50:10.
Maureen Hanson’s presentation on “ME/CFS and long COVID: similarities and differences” starts at 1:03:00.
Andrew Grimson’s presentation on “Monocyte dysregulation in ME/CFS” starts at 1:37:35.
Nicholas Hampilos’ presentation on “Effect of Physical Exertion on CNS Oxidative Stress and Metabolism in ME/CFS” starts at 2:56:53.
NIH sponsored an early career researchers workshop on December 10, 2023 attended by Cornell graduate students Claire McNally Annie Gardella, and David Iu, postdoctoral associates Jessica Maya and Tien Luyen (“Louis”) Vu, and Research Associates Katherine Glass, Arnaud Germain and Ludovic Giloteaux. Drs. Glass and Maya helped organize the meeting.
David Iu: Epigenetic Reprogramming of CD8+ T cell Populations Drives Exhaustion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Tien Luyen Vu: Single-cell transcriptomics of ME/CFS circulating immune system before and after symptom provocation
Anne Gardella: Cell-free RNA signatures of myalgic encephalomyelitis/ chronic fatigue syndrome
Ludovic Giloteaux: Extracellular vesicle protein cargo in ME/CFS cases and controls following maximal exercise
Arnaud Germain: Proteomic adjustments following induction of post-exertional malaise
Claire McNally: Investigating the role of iNOS in endothelial dysfunction in ME/CFS
In an NIH-sponsored workshop featuring studies of long COVID, acute COVID19, HIV/AIDS, viral encephalitis, Epstein-Barr Virus, Ebola virus, Endogenous retroviruses, Maureen Hanson presented a talk entitled “Viruses, Immune Dysfunction, and ME/CFS”
A new open access publication in the Journal of Translational Medicine describes the work by Giloteaux et al. to uncover ways to detect the disease ME/CFS. Ludovic Giloteaux and Jiayin Li, joint first authors, took a collaborative approach to improve our understanding of ME/CFS. Giloteaux isolated extracellular vesicles from the plasma of 98 Chronic Fatigue Initiative individuals (49 ME/CFS and 49 controls) to study their signaling molecules (i.e., cytokines). Then he worked with Jiayin Li and David Ruppert, statisticians at Cornell, and using data generated by Columbia University investigators, the group combined plasma cytokine, EV cytokine, plasma proteomic, and demographic datasets to explore new ways to approach ME/CFS.
One of the key findings from the publication is the 86% accuracy in differentiating between people with ME/CFS and health controls. Giloteaux et al. leveraged multiple datasets to achieve this goal. The paper also outlines interesting correlations between various biological molecules and clinical surveys that measure disease severity. For example, higher levels of pro-inflammatory molecules (e.g., CSF2 & TNFa) were correlated with greater physical and fatigue symptoms in people with ME/CFS.
Announced April 11, 2023, the ENID Center has successfully competed for a 5-year U54 award from the National Institutes of Health. The U54 award provides funding for a multidisciplinary, multicomponent collaborative research center. The award will fund exciting research to explore topics such as endothelium function, cell-free RNA, immune cell dysfunction, extracellular vesicles, and more.
The new research award includes a subject participation component. We will soon provide information on how interested people can get involved. Check back here later, or stay tuned to the Center’s tweets and Facebook posts for updates.
The new funding is partly an extension of previous work. Specifically, we plan to utilize previous and future data, highlighted in the figure below, to perform multiomic analyses. Multiomics uses sophisticated computation approaches to incorporate multiple datasets, which can provide an enhanced and holistic perspective.
The Cornell Chronicle first announced the U54 award. Check out the press release for more information.
Cardiopulmonary exercise testing (CPET) was an integral part of our NIH-funded collaborative research center (CRC). The Cornell CRC used the CPET as a way to interrogate the hallmark symptom of ME/CFS—post-exertional malaise (PEM). CPET-associated samples are being analyzed to uncover the molecular basis of PEM. This molecular work gave us the opportunity to explore other aspects of PEM such as recovery following exertion.
Dr. Geoffrey Moore, M.D., Cornell CRC Clinical Core Co-director, led an effort to describe CPET recovery in ME/CFS. This work is now available in the journal Medicina under the title Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The paper documents a significant difference in recovery between sedentary controls (~2 days) and people with ME/CFS (~13 days). Moore et al. studied 84 people with ME/CFS and 60 controls using a self-reported symptom severity questionnaire. Both female and male participants from three different test sites across the United States were included in the study. The publication is open access so check it out for more information.
We have a new study published today that compares metabolite levels in urine of ME/CFS patients and sedentary controls before and after cardiopulmonary exercise testing (CPET).
Katie Glass is lead author of Urine Metabolomics Exposes Anomalous Recovery after Maximal Exertion in Female ME/CFS Patients. The study is available online in the International Journal of Molecular Sciences and full text is open access.
As shown in the graphical abstract above and explained in the video abstract below, we found a large number of metabolites at increased concentrations in the urine of controls 24 hours after CPET compared to baseline. However, we did not find significant changes in levels of any metabolites in the urine of ME/CFS patients after CPET.
When we looked at which metabolites were changing differently in ME/CFS patients and controls after exercise, we found the most compounds in the amino acid and lipid metabolic superpathways.
Overall, our data suggests that the metabolisms of sedentary controls undergo major changes that allow them to recover from exertion, while ME/CFS patients fail to make similar adaptive responses. This dysfunctional metabolic excretion could be contributing to exercise intolerance in ME/CFS patients.
Check out the paper to see many more results, including individual compounds that are significantly different between patients and controls and altered correlations between urine and plasma metabolites.
A new publication from the Center on fatty acid oxidation in immune cells has appeared today. Jessica Maya is the lead author of Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome published in the International Journal of Molecular Sciences.
As discussed in the paper, there is more evidence for abnormal immunometabolism in ME/CFS. Maya utilized her expertise in flow cytometry and Seahorse flux analysis to demonstrate this dysfunction. She isolated natural killer (NK), helper T (CD4), and cytotoxic T (CD8) cell populations from both healthy donors and people with ME/CFS. These immune cell populations were studied in their circulating state and after stimulation. The stimulation process aims to mimic an immune response. Maya’s findings showed that all three of the cell types have an increased use of fats to power their activities when compared to healthy donors. Her results show that ME/CFS immune cells have a greater reliance on fats for energy when they are stimulated. Overall, these findings support the presence of an altered metabolic state in certain immune cells in individuals with ME/CFS.
Maya outlines these findings in her graphical and video abstracts inserted below.