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.
Keywords: COVID-19; inflammation; metabolites.
【저자키워드】 COVID-19, Inflammation, metabolites., 【초록키워드】 SARS-CoV-2, Coronavirus disease 2019, coronavirus, macrophages, Antiviral, IL-6, severity, interferons, metabolome, drug, molecular mechanism, type I interferon, serum, COVID-19 infection, mice, metabolites, metabolite, IFNs, cytokine production, Inflammatory cytokine, COVID-19 patients, NF-κB, NF-κB pathway, TNF, Tandem mass spectrometry, COVID-19 patient, putrescine, Proinflammatory cytokine, acute respiratory syndrome, Activation, stages, interferon regulatory factor, wildtype, systemic inflammatory responses, effector, strong immune response, IRFs, Administered, fibroblast, Effect, responsible, resulting, tested, caused, significantly, the disease, elevated, characterized, elicit, activate, changed, embryonic, exhibiting, alleviate, underlie, agmatine, circulating metabolite, IL-6 level, 【제목키워드】 serum, metabolite, Inflammatory response, identification,