Deciphering the role of monocytes in Chronic Fatigue Syndrome

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is a complex disease with many potential unknown triggers. Immune and metabolic alterations are the most common features in ME/CFS patients. The development of innovative systems biology approaches over the last decade has helped us understand many unknown aspects of the disease at the single-cell level. However, the common belief that permanent characteristic alterations in ME patients at genetic and epigenetic levels can be quantified at the molecular level has not led to any findings that can be translated to clinics. In 2018, our group, for the first time, showed that genes are not only up or down-regulated. They are also switched on and off under specific physiological requirements. I hypothesize that this dynamic nature of genes and pathways defines ME/CFS. Cell-specific and stimulus-specific variations in pathways also add more complexities to the patient’s response to external stimuli like infection, exercise, food, temperature etc. As a proof-of-concept study, we have gathered strong evidence suggesting a potential role of monocytes in modulating immune response in ME patients under various stimuli like extracellular ATP and viral infection. We have identified key alterations in pathways that explain the altered behavior of platelets and mast cells in a significant subset of ME patients, paving the way to a potentially successful treatment strategy. However, the use of peripheral blood-derived immune cells has certain limitations. Important categories of immune cells, like macrophages and dendritic cells, are challenging to capture in sufficient numbers to study the dynamic behavior of these immune cells. Therefore, in this study, I propose differentiating monocytes into various types of macrophages and monocyte-derived dendritic cells under experimental conditions and testing their response to stimuli like extracellular ATP and viral infections. This study will decipher the dynamic differences in monocyte/macrophage behavior in ME patients.