What We Do

The CfS for ME/CFS is designed to rapidly adapt to the insights and opportunities that are continuously emerging in the field of ME/CFS research. Accordingly, we are a center without walls—we recruit new investigators nationally and internationally based on their commitment and expertise rather than their institutional affiliation.

Our funding during the first two years of the Collaborative Center Program will be used to mine the rich data and sample sets established with the support of the NIH, the Hutchins Family Foundation, and the Microbe Discovery Project. This work is inspired by discoveries in our laboratory and others pointing to the importance of the microbiome, the virome, and the fungome as determinants of health. We will look for immune responses that may persist long after an infectious agent has either been cleared from the body or become dormant, and for autoantibodies. We will also profile metabolites in plasma and gene expression in white blood cells.

Clinical research studies will connect with the laboratory studies. We will examine the impact of physical activity on the microbiome, the metabolome, and the transcriptome for clues to understanding the basis of persistent fatigue, cognitive dysfunction, and other symptoms after exercise. We will design a mobile app and mine existing datasets for insights into clinical features, comorbidities, and sub-types that could refine laboratory analyses and enhance care.

We are hoping to find additional resources for epigenetic studies that could explain how genes are turned on or off in response to exercise. Clinical trials are not part of our current mandate. However, we are aware of the urgency and need for progress in clinical care. Each of our projects has been prioritized for its potential to lead to solutions for ME/CFS through the development of animal models of ME/CFS or clinical trials of antibiotics, pre- and probiotics, antifungals, antivirals, or immunomodulatory treatments.

Learn more information about each of the three main projects supported by the NIH award below.

Project 1: Molecular correlates of symptom severity in ME/CFS

The symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) typically wax and wane. Our objective in this project is to identify biomarkers that correlate with fluctuations in clinical status and have the potential to yield insights into pathogenesis that enable interventions.

Sixty people with ME/CFS followed in a large New York City practice and 60 healthy controls matched +/- 5 years for age, sex, and socioeconomic status, will use a smartphone application to regularly report the severity of their symptoms, and whether they are having a particularly good or bad day. Immediately after a person enters data, the information will be sent to the study server and (on good and bad days) to a study coordinator/phlebotomist who will contact the individual to visit the subject’s location to obtain blood, saliva, and feces within 24 hours. We will pursue biomarker discovery on good and bad days.

We will profile multiple cytokines previously found to be abnormal in ME/CFS; quantitate the prevalence and abundance of microbial sequences in plasma, saliva, and feces using capture sequencing; assay levels of antibodies to specific target epitopes using a state-of-the-art phage display system; and perform single cell RNASeq analyses of B cells, T cells, dendritic cells, NK cells and the recently discovered Kir+CD8+ regulatory T cells.

Metabolomic and lipidomic studies will be conducted in plasma, saliva, and feces to determine if abnormalities, that we and others have previously identified, improve on good days and worsen on bad days. These include evidence of peroxisomal dysfunction (decreased levels of plasmalogens, unsaturated phospholipid ethers and carnitines and increased levels of polyunsaturated long-chain triacylglycerides); consistently reduced plasma levels of prostaglandin F2 alpha, the oxylipin resolvin D1 and phosphatidylcholines (PCs); significant elevations in α-ketoglutarate (α-KG) and succinate (TCA cycle intermediates). Collectively, these changes may contribute to mitochondrial dysfunction/impaired ATP generation and the pro-inflammatory state that have been found in ME/CFS. Fecal metabolomics allow measurement of very short chain fatty acids, a clear indicator of differences in fermentative energy metabolism, and measurement of physiologically relevant microbial products that impact carbohydrate metabolism and immune function.

Project 2: Genotypic analyses in ME/CFS

The epidemiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) indicates a significant relationship in the population for both close (first or second cousins) and distant (third cousins) relatives. Our objective is to identify DNA differences that distinguish people with ME/CFS from healthy controls. We will use a well-established, well-powered, genome-wide association study (GWAS) design that has a demonstrated ability to identify genes, as well as novel molecular and cellular pathways, contributing to susceptibility for other complex diseases. GWAS have shown that about 10-times more cases will be needed to be well-powered.

We will obtain saliva DNA from a minimum of 5,000 individuals meeting Institute of Medicine/National Academy of Medicine (IOM/NAM) and/or Canadian Consensus Criteria (CCC) for ME/CFS. ME/CFS subjects will be recruited via a questionnaire created by the Solve ME/CFS Initiative (Solve ME) and will utilize a smartphone application designed by Care Evolution. Genotyping data from these US-based ME/CFS cases will be compared to data from 400,000 healthy controls genotyped by the Kaiser Permanente Research Bank (KPRB) using the Axiom Precision Medicine Diversity v2 Plus Array. Once data from US-based cases is obtained (Solve ME and KPRB), it will be used in a US case-control GWAS, before being trans-ancestry meta-analyzed with UK cohort data from the DecodeME Study and the UK Biobank (UKB).

The two cohorts are complementary by providing opportunities for replicating associated loci and for using diverse genetic ancestries to enhance predictive power. We anticipate that genetic associations will provide the evidence base necessary to improve the perception of ME/CFS among health care professionals and the general public and yield insights into risk and pathogenesis that have the potential to result in interventions.

Project 3: Pathogen discovery through longitudinal serological surveillance in ME/CFS.

Many people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) report that the illness begins with an “infectious-like” prodrome—typically, respiratory and gastrointestinal symptoms, fever, lymphadenopathy, and myalgias. Evidence of immune dysregulation consistent with infection has been reported in blood and cerebrospinal fluid (CSF) by several research groups. Proteomic studies of plasma and CSF revealed evidence of antigen-driven clonal B cell expansion. Up to 40% of patients are reported to respond to intravenous infusions of the Toll-like receptor 3 agonist, Ampligen, a double-stranded RNA analogue stabilized with uridine that is proposed to inhibit viral replication. Others report responses to antiviral drugs specific for herpesviruses, pre- and probiotics, or fecal transplantation.

The observation that SARS-CoV-2 infection can lead to chronic disability with clinical features consistent with ME/CFS underscores the importance of exploring the role of infection in the pathogenesis of ME/CFS. Our hypothesis is that some individuals with ME/CFS may experience the onset or worsening of the disease due to an infectious trigger and that previous attempts to implicate infection may have been hindered by suboptimal sampling methods, with respect to the type of samples collected, the timing of collection, and/or limitations in the performance of the assays used. To address this hypothesis, we will shift from efforts during the first cycle of the Center for Solutions for ME/CFS that focused on direct detection of potential microbial triggers to a search for serological evidence of exposure prior to onset of illness using the unique resource of the Department of Defense Serum Repository (DoDSR).

The DoDSR comprises >62 million samples collected since 1989 from active and reserve personnel of the Army, Navy, and Air Force linked to a clinical database that can be used to retrieve sera from individuals with specific diagnoses. More than 75% of individuals are represented by multiple specimens collected at annual intervals. Samples collected from people with ME/CFS, before and after diagnosis, and from matched controls, will be interrogated using a high-density short-peptide phage display system that enables quantitation and characterization of antiviral responses indicative of ongoing and past infections, as well as reactivation. We will also test for evidence of immune dysregulation by measuring the levels of cytokines/chemokines using a CLIA-approved Luminex assay. Finally, we will use results of phage display to develop more practical and less expensive diagnostic assays that can be used to facilitate timely identification of microbial triggers that may be associated with the onset and/or exacerbation of ME/CFS.