Ketone body metabolism activates the immune response against Staphylococcus aureus infection by fueling the tricarboxylic acid cycle and affecting histone β-hydroxybutyrylation.

Staphylococcus aureus (S. aureus) is a prominent human pathogen that causes persistent inflammation and is notoriously difficult to treat. Fasting is one of host adaptations to infection, and the induction of ketogenesis and ketolysis is a well-described host metabolic adaptation in response to fasting. However, more information about the energy substrates required to meet the immune response to S. aureus infection demands is needed. This study shows that the production of β-hydroxybutyrate (BHB) is enhanced in individuals with S. aureus, and BHB levels correlate with inflammatory cytokines and fibrotic biomarkers. We found that treatment with BHB or a ketogenic diet promotes the production of interferon and inflammatory cytokines, protecting mice from S. aureus infection and disease. Further studies demonstrated that ketogenesis and ketolysis were required for immune responses to S. aureus infection. Mechanistically, ketone bodies, including BHB and acetoacetate, fuel the tricarboxylic acid cycle. On the other hand, BHB also regulates immune response via effects on histone β-hydroxybutyrylation. These findings suggest ketogenesis and ketolysis are metabolic and epigenetic drivers of immune responses during S. aureus infection.