No abstract

Previous studies suggest a role for systemic reprogramming of host metabolism during viral pathogenesis to fuel rapidly expanding viral proliferation, for example by providing free amino acids and fatty acids as building blocks. In addition, general alterations in metabolism can provide key understanding of pathogenesis. However, little is known about the specific metabolic effects of SARS-COV-2 infection. The present study evaluated the serum metabolism of COVID-19 patients (n=33), identified by a positive nucleic acid test of a nasopharyngeal swab, as compared to COVID-19-negative control patients (n=16). Targeted and untargeted metabolomics analyses specifically identified alterations in the metabolism of tryptophan into the kynurenine pathway, which is wellknown to be involved in regulating inflammation and immunity. Indeed, the observed changes in tryptophan metabolism correlated with serum interleukin-6 (IL-6) levels. Metabolomics analysis also confirmed widespread dysregulation of nitrogen metabolism in infected patients, with decreased circulating levels of most amino acids, except for tryptophan metabolites in the kynurenine pathway, and increased markers of oxidant stress (e.g., methionine sulfoxide, cystine), proteolysis, and kidney dysfunction (e.g., creatine, creatinine, polyamines). Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis in COVID-19 patients.Metabolite levels in these pathways correlated with clinical laboratory markers of inflammation and disease severity (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen). In conclusion, this initial observational study of the metabolic consequences of COVID-19 infection in a clinical cohort identified amino acid metabolism (especially kynurenine and cysteine/taurine) and fatty acid metabolism as correlates of COVID-19, providing mechanistic insights, potential markers of clinical severity, and potential therapeutic targets.

Blood donor genetics and lifestyle affect the quality of red blood cell (RBC) storage. Heterozygotes for beta-thalassaemia (βThal+) constitute a non-negligible proportion of blood donors in the Mediterranean and other geographical areas. The unique haematological profile of βThal+ could affect capacity of enduring storage stress, however, the storability of βThal+ RBCs is largely unknown. In this study, RBCs from 18 βThal+ donors were stored in the cold and profiled for primary (haemolysis) and secondary (phosphatidylserine exposure, potassium leakage, oxidative stress) quality measures, and metabolomics, versus sex- and age-matched controls. The βThal+ units exhibited better levels of storage haemolysis and susceptibility to lysis following osmotic, oxidative and mechanical insults. Moreover, βThal+ RBCs had a lower percentage of surface removal signaling, reactive oxygen species and oxidative defects to membrane components at late stages of storage. Lower potassium accumulation and higher urate-dependent antioxidant capacity were noted in the βThal+ supernatant. Full metabolomics analyses revealed alterations in purine and arginine pathways at baseline, along with activation of pentose phosphate pathway and glycolysis upstream to pyruvate kinase in βThal+ RBCs. Upon storage, substantial changes were observed in arginine, purine and vitamin B6 metabolism, as well as in the hexosamine pathway. A high degree of glutamate generation in βThal+ RBCs was accompanied by low levels of purine oxidation products (IMP, hypoxanthine, allantoin). The βThal mutations impact the metabolism and the susceptibility to haemolysis of stored RBCs, suggesting good post-transfusion recovery. However, haemoglobin increment and other clinical outcomes of βThal+ RBC transfusion deserve elucidation by future studies.

As part of the ZOOMICS project, we set out to investigate common and diverging metabolic traits in the blood metabolome across various species by taking advantage of recent developments in high-throughput metabolomics. Here we provide the first comparative metabolomics analysis of fresh and stored human (n = 21, 10 males, 11 females), olive baboon (n = 20), and rhesus macaque (n = 20) red blood cells at baseline and upon 42 days of storage under blood bank conditions. The results indicated similarities and differences across species, which ultimately resulted in a differential propensity to undergo morphological alterations and lyse as a function of the duration of refrigerated storage. Focusing on purine oxidation, carboxylic acid, fatty acid, and arginine metabolism further highlighted species-specific metabolic wiring. For example, through a combination of steady state measurements and 13 C 6 15 N 4-arginine tracing experiments, we report an increase in arginine catabolism into ornithine in humans, suggestive of species-specific arginase 1 activity and nitric oxide synthesis-an observation that may impact the translatability of cardiovascular disease studies carried out in non-human primates (NHPs). Finally, we correlated metabolic measurements to storage-induced morphological alterations via scanning electron microscopy and hemolysis, which were significantly lower in human red cells compared to both NHPs.