Immunometabolic Pathways in BCG-Induced Trained Immunity

• DOI: 10.1016/j.celrep.2016.11.011
• Publication Date: 2016-12-06T18:15:54Z
• Authors: Rob J.W. Arts; Agostinho Carvalho; Claudia La Rocca; Carla Palma; Fernando Rodrigues; Ricardo Silvestre; Johanneke Kleinni...; Ekta Lachmandas; Luís G. Gonçalves; Ana Belinha; Cristina Cunha; Marije Oosting; Leo A.B. Joosten; Giuseppe Matarese; Reinout van Crevel; Mihai G. Netea
• Keywords: 0301 basic medicine; immunometabolism; Article; Monocytes; Epigenesis, Genetic; trained immunity; Mice; 03 medical and health sciences; BCG; epigenetics; glycolysis; immunometabolism; monocytes; trained immunity; Animals; Humans; Tuberculosis; BCG; Radboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences; epigenetics; glycolysis; Radboudumc 9: Rare cancers RIMLS: Radboud Institute for Molecular Life Sciences; Chromatin Assembly and Disassembly; Immunity, Innate; 3. Good health; Histone Code; BCG Vaccine; Radboudumc 4: lnfectious Diseases and Global Health RIHS: Radboud Institute for Health Sciences; monocytes; Glycolysis; Immunologic Memory

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.