Publications – Cornell Center for Enervating NeuroImmune Disease

Uncovering Protein Signatures of Post-Exertional Malaise in ME/CFS

Graphical abstract by Arnaud Germain, Ph.D.

Post-exertional malaise (PEM) is the hallmark symptom of ME/CFS: an exacerbation of symptoms triggered by physical or mental exertion that is often disproportionate to the activity. While PEM has long been recognized as central to ME/CFS, the molecular mechanisms underlying this debilitating response have remained largely unknown.

A recent paper from the Center, published in Molecular & Cellular Proteomics, provides a comprehensive look at what happens at the protein level when people with ME/CFS experience PEM. The work was led by first author and Center investigator Arnaud Germain, a postdoctoral research associate in the Hanson Lab. The paper has also been featured in an article on Medscape.

What Was Done

The study used a powerful aptamer-based proteomic assay (the SomaScan 7K) to measure 6,361 unique plasma proteins in 132 individuals (79 ME/CFS cases, 53 age/BMI-matched sedentary controls). The design included two maximal cardiopulmonary exercise tests (CPET) separated by 24 h, enabling the investigators to chart the molecular aftermath of exertion and recovery.

By comparing ME/CFS to sedentary controls rather than healthy active individuals, the team could distinguish disease-specific alterations from changes simply due to physical deconditioning, a key approach that differentiates this study from others.

Key Findings

Our analysis revealed widespread proteomic changes following exertion, with the most dramatic alterations occurring in ME/CFS participants during the 24-hour recovery period—precisely when PEM symptoms typically emerge.

Immune System Dysfunction:

Suppression of T and B cell signaling
Reduced IL17 and cell-cell communication pathways

Metabolic Disruption:

Up-regulation of glycolysis/gluconeogenesis pathways, consistent with mitochondrial stress and impaired immune recovery
Disrupted associations between protein levels and physiological performance (VO₂max, ventilatory anaerobic threshold) in ME/CFS compared to controls

Clinical Correlations:

Correlations between immune-related proteins and symptom severity, including muscle pain, recurrent sore throat, and lymph node tenderness

Sex Differences:

Sex-stratified analyses revealed distinct molecular responses in females and males, emphasizing the critical importance of considering sex as a biological variable in future research

Key Insights

For Patients: This research provides molecular validation for what ME/CFS patients have long known—that their bodies respond abnormally to exertion. The recovery phase in ME/CFS is characterized by prolonged, maladaptive molecular responses rather than a healthy return to baseline. This data provides scientific backing for clinical recommendations around pacing and avoiding activities that trigger PEM.

For Researchers: The findings reveal that immune, metabolic, and neuromuscular pathways remain dysregulated in ME/CFS long after exertion ends. The study also demonstrates that women and men with ME/CFS may exhibit different molecular pathophysiology, emphasizing the need to account for sex differences in future studies.

For the Field: This work provides a rich molecular dataset and a foundation for mechanistic follow-up. The longitudinal dynamic profiling approach may also serve as a model for investigating other disorders featuring exertion intolerance (e.g., Long COVID).

Access the Research

The full manuscript is now available in Molecular & Cellular Proteomics:

Germain A, Glass KA, Eckert MA, Giloteaux L, Hanson MR. Temporal dynamics of the plasma proteomic landscape reveals maladaptation in ME/CFS following exertion. Molecular & Cellular Proteomics (2025). doi: https://doi.org/10.1016/j.mcpro.2025.101467

The associated dataset can be accessed on the journal’s website and on mapMECFS.

Cell-free RNA may help us understand and diagnose ME/CFS

Great work by Center member and lead author Anne Gardella (doctoral student, De Vlaminck Lab) on demonstrating how cell-free RNA (cfRNA) in blood could help us understand—and possibly diagnose—ME/CFS. This Center-led project highlights our cross-lab collaboration, with cfRNA expertise from the De Vlaminck Lab, guidance and materials from our Center’s Administrative Core, and immune profiling resources from our Center’s Grimson Lab.

What the study did:

Our team analyzed cfRNA from plasma samples from 93 people with ME/CFS and 75 sedentary healthy controls, drawn from our Center’s prior cardiopulmonary exercise testing (CPET) study.

What the study found:

Using a machine-learning approach, the study uncovered 21 cfRNA signals that, together, identified ME/CFS cases versus controls with 0.81 AUC and 77% accuracy in a held-out test set. This is promising research, but not yet a clinical test.

By using an immune cell “atlas” from our Center’s Grimson Lab, the team estimated where the cfRNA signals likely came from. They found differences in the relative contributions of several cell types, including plasmacytoid dendritic cells, monocytes, naive CD8 T cells, MAIT cells, and platelets.

Gene-level analyses in ME/CFS point to broad changes in immune function, extracellular matrix organization, and mitochondrial function, consistent with prior studies.

When looking at circulating viral signals, the study did not find a significant difference in overall viral burden between groups.

Why this matters:

This work advances our understanding of the biology of ME/CFS and supports the search for blood-based biomarkers. It is part of our NIH-funded U54 research program.

What’s next:

We are now studying cfRNA before and after CPET to better understand post-exertional malaise, and we are exploring how cfRNA patterns may relate to muscle and cellular function. Stay tuned for updates.

Want to read more?

The Cornell Chronicle has published a press release about this study. The full paper appears in PNAS. The Chronicle article provides background, explains the approach, and highlights key findings.

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.

New Study Explores Autoantibody Profiles in ME/CFS Using Advanced Screening Technologies

Researchers from the Cornell Center for Enervating Neuroimmune Disease, Fred Hutchinson Cancer Center, Yale School of Medicine, and Augmenta Bioworks have published a study investigating autoantibody patterns in ME/CFS. The research, published in the International Journal of Molecular Sciences, represents an in-depth look at the involvement of autoimmunity in ME/CFS.

The study examined blood samples from a substantial cohort of 172 participants who were evaluated at multiple sites across the US. All ME/CFS patients met the Canadian Consensus Criteria for diagnosis and developed their condition prior to 2020, ensuring their illness was not related to the COVID-19 pandemic.

Using two sophisticated platforms – a 1,134 autoantibody Luminex panel and Rapid Extracellular Antigen Profiling (REAP) – researchers examined over 7,500 antibody-antigen interactions. Unlike previous studies, this comprehensive analysis found no significant differences in autoantibody reactivities between ME/CFS patients and controls. This includes previously reported targets such as β-adrenergic receptors and other G protein-coupled receptors. The results indicate that the role of autoantibodies in ME/CFS needs further investigation.

The paper is available through open access, and we encourage those interested to read the full publication for more detailed information.

New Research Links T Cell Exhaustion to ME/CFS

A new study from our Center, recently published in the Proceedings of the National Academy of Sciences (PNAS), has revealed important insights into how ME/CFS affects the immune system. The research team, led by Associate Director Andrew Grimson, discovered that patients with ME/CFS show signs of T cell exhaustion, a condition where immune cells become less effective at fighting infections. This finding helps to better understand the chronic nature of the disease and may open new paths for treatment approaches.

Fig. 5 *Model of proposed ME T cell mechanism of action via exhaustion.*
Source: PNAS publication

The Cornell Chronicle has published an accompanying article about this research, offering a detailed look at the study’s implications for ME/CFS patients. The article explains how the research team conducted their investigation and what these findings might mean for future treatment strategies. You can read the full Cornell Chronicle coverage to learn more about this significant development in ME/CFS research.

Comparing IACCs is essential to make progress on all

Peluso, Hanson, and Deeks present a compelling Viewpoint in Science Translational Medicine, exploring infection-associated chronic conditions (IACCs). The article begins by addressing the complexities of studying IACCs. It then delves into a notable historical account of chronic conditions linked to infections, emphasizing the lessons these histories offer for advancing Long Covid research. The authors highlight the importance of avoiding past mistakes and adopting a measured, objective approach.

One key recommendation is to use what we already know about IACCs, such as ME/CFS, to inform Long Covid research. The authors also emphasize the importance of recognizing disease subtypes and accounting for sex differences in research.

Distinguishing between IACCs can be particularly challenging when the underlying cause is unknown. The authors propose using well-characterized patient populations from various IACCs and studying them under the same protocol to identify both overlaps and differences. Such comprehensive studies could clarify how these conditions relate to one another.

In addition to research, the authors stress the urgent need for clinical treatments for IACCs. They outline ongoing clinical trials and suggest focusing on approaches that consider viral persistence, immune dysfunction, and combination therapies.

Large CPET publication describes the physiological component of post-exertional malaise in ME/CFS

Out in the Journal of Translational Medicine, Betsy Keller et al. describes results from the Center’s large multi-site 2-day CPET study. The publication analyzes cardiopulmonary exercise testing (CPET) data collected over two days from 84 individuals with ME/CFS and 71 sedentary controls. Within this population, 55 sex, age, and fitness-matched pairs were also compared. This is the largest 2-day CPET study of ME/CFS to date.

The article provides robust documentation of impaired recovery in people with ME/CFS following exertion (i.e., post-exertional malaise), something that is not seen in the control population. The study also recruited sedentary controls and used sex, age, and fitness-matched pairs to validate that fitness level does not predispose someone with ME/CFS to exertion intolerance. Keller et al. highlights that the autonomic nervous system is, at least partly, associated with ME/CFS due to the disrupted hemodynamic and ventilatory responses to exertion. Additionally, the worsening of CPET parameters over the two-day protocol led to increased clinical impairment status in ME/CFS whereas controls remain relatively the same.

Overall, the manuscript provides a detailed look at the physiological component of post-exertional malaise in ME/CFS. The paper is open access. Individuals interested in the topic should check out the full publication for more information.

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.

Recovery from two-day CPET in ME/CFS

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.

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