AUTHOR=Ceballos Francisco C., Virseda-Berdices Ana, Resino Salvador, Ryan Pablo, Martínez-González Oscar, Peréz-García Felipe, Martin-Vicente María, Brochado-Kith Oscar, Blancas Rafael, Bartolome-Sánchez Sofía, Vidal-Alcántara Erick Joan, Albóniga-Díez Oihane Elena, Cuadros-González Juan, Blanca-López Natalia, Martínez Isidoro, Martinez-Acitores Ignacio Ramirez, Barbas Coral, Fernández-Rodríguez Amanda, Jiménez-Sousa María Ángeles TITLE=Metabolic Profiling at COVID-19 Onset Shows Disease Severity and Sex-Specific Dysregulation JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/articles/10.3389/fimmu.2022.925558 DOI=10.3389/fimmu.2022.925558 ISSN=1664-3224 ABSTRACT=Backgroundmetabolic changes through SARS-CoV-2 infection has been reported but not fully comprehended. This metabolic dysregulation affects multiple organs during COVID-19 and its early detection can be used as a prognosis marker of severity. Therefore, we aimed to characterize metabolic and cytokine profile at COVID-19 onset and its relationship with disease severity to identify metabolic profiles predicting disease progression.Material and Methodswe performed a retrospective cross-sectional study in 123 COVID-19 patients which were stratified as asymptomatic/mild, moderate and severe according to the highest COVID-19 severity status, and a group of healthy controls. We performed an untargeted plasma metabolic profiling (gas chromatography and capillary electrophoresis-mass spectrometry (GC and CE-MS)) and cytokine evaluation.ResultsAfter data filtering and identification we observed 105 metabolites dysregulated (66 GC-MS and 40 CE-MS) which shown different expression patterns for each COVID-19 severity status. These metabolites belonged to different metabolic pathways including amino acid, energy, and nitrogen metabolism among others. Severity-specific metabolic dysregulation was observed, as an increased transformation of L-tryptophan into L-kynurenine. Thus, metabolic profiling at hospital admission differentiate between severe and moderate patients in the later phase of worse evolution. Several plasma pro-inflammatory biomarkers showed significant correlation with deregulated metabolites, specially with L-kynurenine and L-tryptophan. Finally, we describe a strong sex-related dysregulation of metabolites, cytokines and chemokines between severe and moderate patients. In conclusion, metabolic profiling of COVID-19 patients at disease onset is a powerful tool to unravel the SARS-CoV-2 molecular pathogenesis.ConclusionsThis technique makes it possible to identify metabolic phenoconversion that predicts disease progression and explains the pronounced pathogenesis differences between sexes.