Abstract
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by a strong production of inflammatory cytokines such as TNF and IL-6, which underlie the severity of the disease. However, the molecular mechanisms responsible for such a strong immune response remains unclear. Here, utilizing targeted tandem mass spectrometry to analyze serum metabolome and lipidome in COVID-19 patients at different temporal stages, we identified that 611 metabolites (of 1,039) were significantly altered in COVID-19 patients. Among them, two metabolites, agmatine and putrescine, were prominently elevated in the serum of patients; and 2-quinolinecarboxylate was changed in a biphasic manner, elevated during early COVID-19 infection but levelled off. When tested in mouse embryonic fibroblasts (MEFs) and macrophages, these 3 metabolites were found to activate the NF-κB pathway that plays a pivotal role in governing cytokine production. Importantly, these metabolites were each able to cause strong increase of TNF and IL-6 levels when administered to wildtype mice, but not in the mice lacking NF-κB. Intriguingly, these metabolites have little effects on the activation of interferon regulatory factors (IRFs) for the production of type I interferons (IFNs) for antiviral defenses. These data suggest that circulating metabolites resulting from COVID-19 infection may act as effectors to elicit the peculiar systemic inflammatory responses, exhibiting severely strong proinflammatory cytokine production with limited induction of the interferons. Our study may provide a rationale for development of drugs to alleviate inflammation in COVID-19 patients.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (31922034, 82088102, 91854208, 92057204, 31730058, 82072777), Science and Technology Program of Fujian Provincial Health Commission (2021ZD02006), Xiamen Science and Technology Major Project (3502Z2020YJ05), Xiamen Municipal Bureau of Science and Technology (3502Z20209005), Fundamental Research Funds for the Central Universities (20720200014, 20720200069, 20720190084), and Program of Introducing Talents of Discipline to Universities (BP2018017). We acknowledge all health care workers involved in the diagnosis and treatment of patients in the First Affiliated Hospital of Xiamen University, and all the patients, supporters, and their families for their confidence in our work. We also thank Dr. Menno de Winther (Academic Medical Center, Universiteit Utrecht) for providing p105/p50-/- mice (Jackson Laboratory, #006097).
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11427_2021_2099_MOESM3_ESM.xlsx
Table S2 Full list of metabolites identified in this study. See Sheets 1 and 2 for polar metabolites, and Sheets 3 and 4 for lipids; also included are P values for each metabolite changed during the COVID-19
11427_2021_2099_MOESM4_ESM.xlsx
Table S3 List of polar metabolites significantly changed in COVID-19, and their effects on NF-κB signaling. See Sheet 1 for those increased, Sheet 2 for those decreased, and Sheet 3 for those fluctuated metabolites in COVID-19. See also supplier information, and the concentrations of each metabolite used in screening assays.
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Zhang, CS., Zhang, B., Li, M. et al. Identification of serum metabolites enhancing inflammatory responses in COVID-19. Sci. China Life Sci. 65, 1971–1984 (2022). https://doi.org/10.1007/s11427-021-2099-7
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DOI: https://doi.org/10.1007/s11427-021-2099-7