Gechang Zhong

Trained immunity refers to the long-term memory of the innate immune cells. However, little is known about how environmental nutrient availability influences trained immunity. This study finds that physiologic carbon sources impact glucose contribution to the tricarboxylic acid (TCA) cycle and enhance cytokine production of trained monocytes. Our experiments demonstrate that trained monocytes preferentially employe lactate over glucose as a TCA cycle substrate, and lactate metabolism is required for trained immune cell responses to bacterial and fungal infection. Except for the contribution to the TCA cycle, endogenous lactate or exogenous lactate also supports trained immunity by regulating histone lactylation. Further transcriptome analysis, ATAC-seq, and CUT&Tag-seq demonstrate that lactate enhance chromatin accessibility in a manner dependent histone lactylation. Inhibiting lactate-dependent metabolism by silencing lactate dehydrogenase A (LDHA) impairs both lactate fueled the TCA cycle and histone lactylation. These findings suggest that lactate is the hub of immunometabolic and epigenetic programs in trained immunity. Here, Cai et al. demonstrate that environmental metabolite availability directly impacts glucose utilization and function in trained immunity - trained monocytes prefer lactate over glucose as a physiologic fuel, and lactate regulates trained immunity by altering histone lactylation.

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. • BHB is enhanced in individuals with S. aureus. • Ketone bodies is preferred over glucose for fueling the TCA cycle • Ketogenesis and ketolysis are required for S. aureus -induced immune responses • S. aureus regulates histone β-hydroxybutyrylation via ketone body metabolism

Our previous studies have shown that major vault protein (MVP) is a virus-induced host factor that participates in the innate immune response. However, little is known about the role of MVP in Influenza A virus (IAV)- induced ferroptosis. In this study, the expression of MVP was found to positively correlate with that of interferon regulatory factor 1 (IRF1) and ferroptosis suppressor protein 1 (FSP1), but not with glutathione peroxidase 4 (GPX4), in peripheral blood mononuclear cells from patients with IAV. In vitro and in vivo evidence indicate that MVP is a potent factor in ferroptosis resistance during IAV infection. Upon investigating the mechanisms underlying this event, MVP was found to sequester IRF1 from tumor necrosis factor receptor-associated factor 6 (TRAF6), thereby suppressing its polyubiquitination and nuclear localization. Therefore, the transcription inhibition of IRF1 on the FSP1 promoter was removed, thereby enhancing FSP1 expression. A second wave of MVP regulation for IAV-induced ferroptosis also occurs. In the presence of the MVP, transcriptionally induced FSP1 is released from IRF1, leading to its ubiquitination and myristoylation, which enable its recruitment to the plasma membrane, where it functions as an oxidoreductase. These findings define a ferroptosis suppression pathway during IAV infection.