Cellular Metabolic Signatures of Long COVID-19

Background/Objectives: Long COVID-19 (LC-19), also known as Post-Acute COVID-19 Syndrome (PACS), is a chronic condition some people experience after an initial SARS-CoV-2 infection. The etiology of this complex, multifactorial disease remains largely unknown, although various theories have been propounded. This study aims to profile and compare the metabolic activity of cells of normal and LC-19 patients. Methods: A cohort of 20 individuals, 10 with LC-19 and 10 without LC-19, was selected based on their post-COVID-19 symptomatology. Saliva was tested for opportunistic viruses like Epstein–Barr virus (EBV) and Human Herpesvirus 6 (HHV-6). Lymphoblastoid cell lines derived from blood were analyzed using the Biolog Phenotype Mammalian Microarrays (PM-M1, PM-M6, and PM-M7) to assess metabolic activity across a wide array of growth substrates and effector molecules. Results: Unique metabolic profiles emerged across the controls and LC-19 groups. The SARS-CoV-2 infection causes an over two-fold enhanced utilization of glycolytic and anaerobic substrates and a reduced response to growth factors and effectors. The increased energy source utilization assessed in PM-M1 is unsustainable, and the LC-19 groups demonstrate this with a clear correlation with the number of LC-19 symptoms, demonstrating a trend consistent with metabolic reprogramming. The infection also results in a reduced response to growth factors and effectors, assessed in PM-M6 and PM-M7, with the level of reduction commensurate with the symptom burden. Conclusions: The data from the patient groups were analyzed and compared to construct a metabolic profile unique to individuals who developed LC-19, which could, in the future, be used for diagnosis and to identify targets for therapeutic intervention. Our study identified an LC-19-specific metabolic profile indicative of adaptive responses to stress, cellular dysfunction, and prolonged inflammation, leading to the reprogramming of bioenergetic pathways.