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Cell Rep. 2016 Dec 6;17(10):2562-2571. doi: 10.1016/j.celrep.2016.11.011.

Immunometabolic Pathways in BCG-Induced Trained Immunity.

Author information

1
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
2
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.
3
Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy.
4
Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, 00161 Roma, Italy.
5
Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal.
6
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.
7
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.

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.

KEYWORDS:

BCG; epigenetics; glycolysis; immunometabolism; monocytes; trained immunity

PMID:
27926861
PMCID:
PMC5177620
DOI:
10.1016/j.celrep.2016.11.011
[Indexed for MEDLINE]
Free PMC Article

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