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Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19

酮发生 急性呼吸窘迫综合征 酮体 糖酵解 氧化磷酸化 生物能学 内科学 内分泌学 生物 化学 医学 新陈代谢 免疫学 生物化学 线粒体
作者
Fotios Karagiannis,Konrad Peukert,Laura Surace,Marcel Michla,Fabian Nikolka,Mario Fox,Patricia M. Weiss,Caroline Feuerborn,Paul Maier,Susanne Schulz,Burcu Al,Benjamin Seeliger,Tobias Welte,Sascha David,Inge Grondman,Aline de Nooijer,Peter Pickkers,Jan Lukas Kleiner,Marc Moritz Berger,Thorsten Brenner,Christian Putensen,Zeinab Abdullah,Eicke Latz,Susanne V. Schmidt,Gunther Hartmann,Hendrik Streeck,Beate M. Kümmerer,Hiroki Kato,Natalio Garbi,Mihai G. Netea,Karsten Hiller,Katarzyna Placek,Christian Bode,Christoph Wilhelm
出处
期刊:Nature [Nature Portfolio]
卷期号:609 (7928): 801-807 被引量:89
标识
DOI:10.1038/s41586-022-05128-8
摘要

Anorexia and fasting are host adaptations to acute infection, and induce a metabolic switch towards ketogenesis and the production of ketone bodies, including β-hydroxybutyrate (BHB)1-6. However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we show that the production of BHB is impaired in individuals with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not in those with influenza-induced ARDS. We found that BHB promotes both the survival of and the production of interferon-γ by CD4+ T cells. Applying a metabolic-tracing analysis, we established that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but could be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we show in mice that a ketogenic diet and the delivery of BHB as a ketone ester drink restores CD4+ T cell metabolism and function in severe respiratory infections, ultimately reducing the mortality of mice infected with SARS-CoV-2. Altogether, our data reveal that BHB is an alternative source of carbon that promotes T cell responses in pulmonary viral infections, and highlight impaired ketogenesis as a potential confounding factor in severe COVID-19.
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