Immunopathology Unit, Institute of Clinical Chemistry and Clinical Pharmacology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.
Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Bonn, Germany.
Nature. 2022 Sep;609(7928):801-807. doi: 10.1038/s41586-022-05128-8. Epub 2022 Jul 28.
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). 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.
厌食症和禁食是宿主对急性感染的适应，导致代谢向酮体生成和酮体（包括β-羟丁酸（BHB））的产生转变。然而，酮体生成是否会在肺部感染中对免疫反应产生代谢影响尚不清楚。在这里，我们表明，在由 SARS-CoV-2 引起的急性呼吸窘迫综合征（ARDS）患者中，BHB 的产生受损，但在由流感引起的 ARDS 患者中没有受损。我们发现 BHB 促进 CD4 T 细胞的存活和干扰素-γ的产生。通过代谢追踪分析，我们确定 BHB 为氧化磷酸化（OXPHOS）和生物能氨基酸和谷胱甘肽的产生提供了替代碳源，这对于维持氧化还原平衡很重要。来自 SARS-CoV-2 引起的 ARDS 患者的 T 细胞衰竭并偏向于糖酵解，但可以通过 BHB 进行代谢重编程以进行 OXPHOS，从而提高其功能。最后，我们在小鼠中表明，生酮饮食和 BHB 作为酮酯饮料的递送可恢复严重呼吸道感染中 CD4 T 细胞的代谢和功能，最终降低感染 SARS-CoV-2 的小鼠的死亡率。总而言之，我们的数据表明，BHB 是一种替代碳源，可促进肺部病毒感染中的 T 细胞反应，并强调酮体生成受损可能是严重 COVID-19 的一个潜在混杂因素。
