A project summary as written by Isabel Barao-Silvestre, Ruben Dagda, and Victor Darley-Usmar:
Natural Killer (NK) lymphocytes are a critical first defense against viruses and cancer. NK cell dysfunction is a pathological hallmark in chronic fatigue syndrome (CFS). CFS patients have difficulties controlling EBV, HHV6, HCMV, HSV-1 and -2 chronic viral infections and many develop non-Hodgkin’s lymphoma. Mitochondrial metabolism is critical for immune cell function. Although many triggers of NK cell activation and subsequent NK cell effector responses have been well characterized, the metabolic requirements to drive NK cell functional responses are not well known. Mitochondrial dysfunction has been reported in CFS. However, the extent by which the metabolic profiles of lymphocytes is associated with immune dysfunction remainsto be elucidated. More importantly, there is currently no diagnostic test or cure for CFS. Variations in the bioenergetic function of the patient’s immune cells can reflect both metabolic stress and the mutable role of these cells in patient’s immunity and disease pathogenesis. The Bioenergetic Health Index (BHI) of immune cells is a measure of mitochondrial metabolism with prognostic and diagnostic value. Our project has two aims to test whether the three energy-generating mitochondrial pathways, oxidative phosphorylation (OXPHOS), glycolysis, and fatty acid oxidation (FAO) are deregulated in CFS NK cells and affect their function. In aim 1, we propose to define the bioenergetic status of NK cells in CFS patients and determine the ability of NK cells to utilize different nutrients. In addition, we plan to develop a BHI of NK cells as a surrogate biomarker for severity of disease and immune dysfunction. In aim 2, we will take other cellular approaches, evaluating phenotype and function of NK cells derived from CFS patients. A significant correlation of alterations in the metabolic profiles of NK cells with CFS pathology will be interpreted as evidence that the bioenergetic status of NK cells is a disease-determining factor. This will be the first comprehensive metabolic assessment of NK cells in CFS that will lead to the development of a BHI as potential new diagnostic tool for CFS. The results derived from this pilot study can pave the way for a more efficient diagnosis for CFS and clinical trials that test new NK cell and mitochondrial-based therapies to CFS.