title: Immunometabolic Pathways in BCG-Induced Trained Immunity.
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.
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Rob J W
authors.initials: RJW
authors.lastname: Arts
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Agostinho
authors.initials: A
authors.lastname: Carvalho
authors.affiliation: Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: La Rocca
authors.affiliation: Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, 00161 Roma, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Palma
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodrigues
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Silvestre
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Johanneke
authors.initials: J
authors.lastname: Kleinnijenhuis
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Ekta
authors.initials: E
authors.lastname: Lachmandas
authors.affiliation: Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal.
authors.forename: Luís G
authors.initials: LG
authors.lastname: Gonçalves
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Belinha
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cunha
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Oosting
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Leo A B
authors.initials: LAB
authors.lastname: Joosten
authors.affiliation: Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, 80131 Napoli, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matarese
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Reinout
authors.initials: R
authors.lastname: van Crevel
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: mihai.netea@radboudumc.nl.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000276:immunology*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics / Q000276:immunology; D044127:Epigenesis, Genetic / Q000276:immunology; D006019:Glycolysis / Q000276:immunology; D042421:Histone Code / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate; D007156:Immunologic Memory / Q000235:genetics*; D051379:Mice; D009000:Monocytes / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control
chemical_list: D001500:BCG Vaccine
keywords: BCG; epigenetics; glycolysis; immunometabolism; monocytes; trained immunity