Abstract
More than 65 million individuals worldwide are estimated to have Long COVID (LC), a complex multisystemic condition, wherein patients of all ages report fatigue, post-exertional malaise, and other symptoms resembling myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). With no current treatments or reliable diagnostic markers, there is an urgent need to define the molecular underpinnings of these conditions. By studying bioenergetic characteristics of peripheral blood lymphocytes in over 16 healthy controls, 15 ME/CFS, and 15 LC donors, we find both ME/CFS and LC donors exhibit signs of elevated oxidative stress, relative to healthy controls, especially in the memory subset. Using a combination of flow cytometry, bulk RNA-seq analysis, mass spectrometry, and systems chemistry analysis, we observed gender-specific aberrations in ROS clearance and damage pathways. While ME/CFS females exhibit higher total ROS and mitochondrial calcium levels, ME/CFS males have normal ROS levels, but larger changes in lipid oxidative damage. The higher ROS levels correlate with hyperproliferation of T cells and can be attenuated by metformin, suggesting this FDA-approved drug may be an effective treatment. Thus, we report that both ME/CFS and LC are mechanistically related and can be diagnosed with quantitative blood cell measurements. We also suggest that effective, patient tailored drugs might be discovered using standard lymphocyte stimulation assays.
