extracellularvesicles – Cornell Center for Enervating NeuroImmune Disease

Extracellular Vesicle Study Sheds New Light on ME/CFS Biology

Researchers from the Center for Enervating Neuroimmune Disease have published a new study investigating extracellular vesicle (EV) proteins in ME/CFS. The research, published in Clinical and Translational Medicine, represents an important analysis of blood-derived EVs and their potential role in ME/CFS.

The study, led by Center Investigators Katherine Glass and Ludovic Giloteaux, analyzed plasma samples from 10 male ME/CFS patients and 12 age- and BMI-matched healthy sedentary male controls before, 15 minutes after, and 24 hours after a maximal exercise challenge, and is an extension of a prior study in an all-female cohort.

Graphical Abstract by Ludovic Giloteaux, Ph.D.

The researchers identified significant differences in EV protein cargo between ME/CFS patients and healthy controls at baseline. However, EV protein profiles in ME/CFS patients and controls showed the most pronounced differences 15 minutes post-exercise. ME/CFS subjects’ showed reduced EV protein levels related to energy metabolism, including the TCA cycle; immune overactivation, particularly in the complement system; and disruptions in protein homeostasis. Strikingly, changes in proteins involved in the endoplasmic reticulum (ER) stress response during the 24 hour recovery phase strongly correlated with post-exertional malaise (PEM) severity. We also observed dysregulation in protein homeostasis and ER stress response proteins in the female study. Notably, while EV protein dynamics in healthy controls correlated with exercise physiology metrics like VO₂ peak and ventilatory anaerobic threshold, these associations were absent in ME/CFS patients, suggesting a disruption in EV-mediated physiological adaptation. Together, these findings provide molecular insight into the mechanisms driving symptom exacerbation after exertion in ME/CFS.

This open access study, which represents an important step forward in understanding the molecular basis of ME/CFS, is freely available to read. The findings advance our understanding of how extracellular vesicles, important cellular messengers, may contribute to disease mechanisms in ME/CFS and suggest new directions for future research into diagnostic biomarkers and therapeutic targets.

To promote scientific collaboration and data transparency, the complete protein abundance data for each protein and subject has been made available through mapMECFS.

Dysregulation of EV protein cargo in ME/CFS females in response to maximal exercise

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).

Figure 1 from the publication provides an overview of the study’s experimental design

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.

New insights into ME/CFS using a multiomic approach

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.

Our first EV publication finds disturbances in cytokine networks

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.