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.
The publication is open access so see the website for more information. Additionally, the EV cytokine data is available on mapMECFS.
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.
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.
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.
When we started this project, our goal was to ask which components of the immune system are most altered in ME/CFS (and which are not). If we could answer this question, we hoped that it would give us a clear path towards understanding some of the molecular underpinnings of ME/CFS, which is likely to be an essential step towards therapies. We used a technique called single-cell RNA sequencing to answer this question, an approach that looks at the genes expressed in thousands of individual cells from each ME/CFS individual (and control). When we look at the data (which in aggregate contains about 0.5 million immune cells found in peripheral blood, sampled from 30 ME/CFS individuals and 28 controls), the strongest signal of dysregulation is found in classical monocytes, a type of innate immune cell with diverse roles. There are three fundamental observations we can make about monocytes in ME/CFS. First, within individuals with ME/CFS, the proportion of monocytes that are dysregulated is variable, with a mixture of relatively normal cells and those that are altered. Second, comparing between individuals, the proportion of altered monocytes is also variable, with individuals with a higher fraction of altered monocytes tending to have more serious cases of ME/CFS. Third, by looking at the genes mis-expressed in altered monocytes, we can find patterns that suggest what might be different about the biology of the altered monocytes. In essence, what we see is that monocytes in individuals with ME/CFS appear to be triggered to migrate to tissues, where they become macrophages. This migration and differentiation pathway is a normal function of monocytes – we think the pathway is more active in ME/CFS, and this increased activity could contribute to many of the symptoms of ME/CFS. This work sets up lots of questions that motivate our work now – where are the monocytes going in ME/CFS individuals, what is causing them to be dysregulated, and ultimately, can we reverse this dysregulation?
This manuscript takes a look at 4,790 circulating plasma proteins from 20 ME/CFS women compared to 20 healthy women, over an unprecedented range, for ME/CFS, of 9 orders of magnitude.
Pathway analysis uncovered disrupted cell-to-cell communication, specifically in the ephrin-Eph signaling pathway. This pathway is crucial for many aspects of our body’s homeostasis, including development, physiology, and disease regulation.
Additionally, the paper outlines promising results for the development of a diagnostic test using protein ratios.
First author, Arnaud Germain, PhD, outlines these findings in a video abstract below.
Our MECFSnet collaborator, RTI, which operates the Data Management and Coordinating Center (DMCC) for the NIH ME/CFS Centers, has officially launched two research tools – mapMECFS and searchMECFS.
With mapMECFS, the Cornell ME/CFS Collaborative Research Center has worked promptly to submit data to the network. A total of 8 datasets are available. Below lists the publications from which the datasets have been uploaded.
Center investigator Dr. Ludovic Giloteaux is lead author of a new publication out in the Journal of Translational Medicine. The paper describes cytokine profiling in extracellular vesicles (EVs) in ME/CFS. The study specifically looks at EVs from the plasma of 70 participants, 35 of which are diagnosed with ME/CFS and compared with 35 healthy controls. Both female and male participants were included in this work. Dr. Jesus Castro-Marrero visited our lab from Spain on a fellowship to contribute to the project.
One key finding of the study is the noted disturbances in cytokine networks.. Disturbances in these cytokine networks were seen in both plasma and EVs, and provides further evidence of immune dysregulation in ME/CFS. We are using information from this work to inform our further studies on EVs from blood collected before and after an exercise challenge. Stay tuned for future publications from our Center on this topic.
Center Director Dr. Maureen Hanson will be presenting current scientific research on ME/CFS during a panel session hosted by New York State Department of Health (NYS DOH). The session titled “Scientific Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in the Age of COVID-19” will be moderated by Dr. Charles Gonzalez. Dr. Ian Lipkin (Columbia University) and Dr. Avindra Nath (NIH) will be joining Hanson as panel presenters.
UPDATE: In case you missed the panel discussion, NYS DOH released a recording along with each presenter’s slides. Direct links to the recording and Dr. Hanson’s slides are below. Visit the NYS DOH ME/CFS website for more information.