Myalgic Encephalomyelitis and Chronic Fatigue Syndrome (ME/CFS) is a debilitating and mysterious chronic illness caused by diverse environmental triggers. Severe disruptions in several immune system components have been described and proposed as drivers of disease pathogenesis and symptoms. However, there is no consensus on the immunological basis for ME/CFS development and sustenance. The two major barriers to progress are the significant patient heterogeneity in symptomatology and disease progression, combined with the lack of quantitative tools to stratify patients and probe the molecular immune underpinnings of disease. The ability to stratify heterogeneous patient groups using reliable, clinically accessible immunological biomarkers would transform efforts to manage ME/CFS clinically and investigate the disease mechanistically. Development of robust multi-parameter biomarker sets would also impact efforts to develop personalized treatment options for ME/CFS patients. The present proposal outlines a multi-disciplinary, systems-biology approach to investigate the immune mechanisms of ME/CFS and to develop ME/CFS-patient specific immune signatures from blood-derived immune cells. The guiding hypothesis is that immune perturbations, particularly to the effector functions of T cell and innate cell (natural killer and myeloid) subsets, contribute to pathogenesis of ME/CFS and that these immune signatures can be used as predictive biomarkers. We will address this hypothesis using a cutting-edge immunogenomics approach based on integrated, high-resolution functional and transcriptomic profiling of immune cell subsets within the blood samples of a large, clinically characterized ME/CFS patient cohort and healthy controls. We will then examine the transcriptional alterations associated with ME/CFS within T and innate cell subsets, with a focus on long non?coding RNAs, owing to their high cell- type-specificity and impact on immune cell development.
Our Specific Aims are: 1) To determine the frequencies of immune cell subsets in the blood of a clinically defined ME/CFS patient cohort; 2) To assess functional capacity of memory T cells, innate cells and the differentiation potential of naive T cells during ME/CFS; and 3) To determine the T cell and innate cell subset?specific gene and lncRNA transcripts in ME/CFS patient blood samples. Our goal is to develop a detailed functional and genetic immunological framework that can be used to i) decode the mechanisms of ME/CFS and ii) to develop robust, quantitative immune-biomarker sets for predicting disease susceptibility, stratifying patients and guiding treatment strategies. We have assembled a unique team of experts in human immunology, clinical ME/CFS biology for well-defined patient samples, non-coding RNAs, transcriptomics and bioinformatics, together will contribute to the deep and complimentary expertise necessary to bring about this goal.

Public Health Relevance

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating illness that causes major burden on millions of people in the United States and around the world. ME/CFS patients are also heterogeneous and the causes that lead to symptoms remain unclear. There is also no known cure for ME/CFS. This proposed research aims to understand abnormalities of immune system in ME/CFS patients, to understand the disease mechanisms and to develop novel, predictive diagnostic tests.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI121920-01A1
Application #
9178459
Study Section
Special Emphasis Panel (ZRG1-CFS-M (80))
Program Officer
Gondre-Lewis, Timothy A
Project Start
2016-06-01
Project End
2021-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
1
Fiscal Year
2016
Total Cost
$652,055
Indirect Cost
$267,111
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Tastan, Cihan; Karhan, Ece; Zhou, Wei et al. (2018) Tuning of human MAIT cell activation by commensal bacteria species and MR1-dependent T-cell presentation. Mucosal Immunol 11:1591-1605
Chen, Xin; Kozhaya, Lina; Tastan, Cihan et al. (2018) Functional Interrogation of Primary Human T Cells via CRISPR Genetic Editing. J Immunol 201:1586-1598