Immunometabolic Pathways in BCG-Induced Trained Immunity

TLDR

BCG’s protective effects against unrelated infections are believed to arise from long‑term metabolic changes and chromatin remodeling in innate immune cells, a process known as trained immunity. The study aims to identify metabolic pathways that could guide the design of vaccines combining immunological and metabolic stimulation. The authors modulated key glycolysis enzymes pharmacologically and genetically, showing that inhibition of these enzymes blocks trained immunity and alters histone marks H3K4me3 and H3K9me3. BCG‑induced trained immunity in monocytes is driven by a pronounced shift toward glycolysis, with glutamine metabolism playing a lesser role, and this metabolic reprogramming is essential for the histone modifications and functional changes observed in vitro, mice, and humans.

Abstract

The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity. Here, we show that BCG induction of trained immunity in monocytes is accompanied by a strong increase in glycolysis and, to a lesser extent, glutamine metabolism, both in an in-vitro model and after vaccination of mice and humans. Pharmacological and genetic modulation of rate-limiting glycolysis enzymes inhibits trained immunity, changes that are reflected by the effects on the histone marks (H3K4me3 and H3K9me3) underlying BCG-induced trained immunity. These data demonstrate that a shift of the glucose metabolism toward glycolysis is crucial for the induction of the histone modifications and functional changes underlying BCG-induced trained immunity. The identification of these pathways may be a first step toward vaccines that combine immunological and metabolic stimulation.