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β-hydroxybutyrate restores T cell metabolism and function in severe COVID-19

ABSTRACT: 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). 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). BHB promotes the survival and the production of Interferon-g 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 find that ketogenic diet (KD) reduced pulmonary fibrosis, a feature particular pronounced in COVID-19 ARDS and delivery of BHB as ketone ester drink reduces the mortality of SARS-CoV-2 infected mice. Altogether, our data suggest that impaired ketogenesis in patients with SARS-CoV-2 infection accounts, at least partially for disease progression and that supplementation ketone ester might represent an easy-to-implement treatment to improve the clinical outcome of COVID-19 patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207077 | GEO | 2022/07/01

REPOSITORIES: GEO

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