Anorexia and fasting are host adaptations to acute infection, inducing 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 report impaired production of BHB in humans with SARS-CoV-2-induced but not influenza-induced acute respiratory distress syndrome (ARDS). CD4+ T cell function is impaired in COVID-19 and BHB promotes both survival and production of Interferon-γ from CD4⁺ T cells. Using metabolic tracing analysis, we uncovered 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 can be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we demonstrate that ketogenic diet (KD) and delivery of BHB as ketone ester drink restores CD4+ T cell metabolism and function in respiratory infections, ultimately reducing the mortality of SARS-CoV-2 infected mice. Altogether, our data reveal BHB as alternative carbon source promoting T cell responses in pulmonary viral infections, highlighting impaired ketogenesis as a potential confounder of severe COVID-19.

厌食和禁食是宿主对急性感染的适应，诱导代谢转变为生酮和酮体的产生，包括 β-羟基丁酸 (BHB) ^1-6。然而，生酮是否在代谢上影响肺部感染的免疫反应仍不清楚。在这里，我们报告了由 SARS-CoV-2 引起但不是由流感引起的急性呼吸窘迫综合征 (ARDS) 的人体内 BHB 的产生受损。^{CD4+ T 细胞功能在 COVID-19 中受损，BHB 促进 CD4 +}的存活和干扰素-γ 的产生T 细胞。使用代谢追踪分析，我们发现 BHB 提供了一种替代碳源来促进氧化磷酸化 (OXPHOS) 以及生物能氨基酸和谷胱甘肽的产生，这对于维持氧化还原平衡很重要。来自 SARS-CoV-2 诱发的 ARDS 患者的 T 细胞已经耗尽并倾向于糖酵解，但可以通过 BHB 进行代谢重新编程以执行 OXPHOS，从而增加它们的功能。最后，我们证明生酮饮食 (KD) 和以酮酯饮料形式提供 BHB 可以恢复 CD4+ T 细胞的代谢和在呼吸道感染中的功能，最终降低 SARS-CoV-2 感染小鼠的死亡率。总之，我们的数据显示 BHB 作为替代碳源促进肺病毒感染中的 T 细胞反应，