title: Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes.
abstract: Adaptive features of innate immunity, recently described as "trained immunity," have been documented in plants, invertebrate animals, and mice, but not yet in humans. Here we show that bacille Calmette-Guérin (BCG) vaccination in healthy volunteers led not only to a four- to sevenfold increase in the production of IFN-γ, but also to a twofold enhanced release of monocyte-derived cytokines, such as TNF and IL-1β, in response to unrelated bacterial and fungal pathogens. The enhanced function of circulating monocytes persisted for at least 3 mo after vaccination and was accompanied by increased expression of activation markers such as CD11b and Toll-like receptor 4. These training effects were induced through the NOD2 receptor and mediated by increased histone 3 lysine 4 trimethylation. In experimental studies, BCG vaccination induced T- and B-lymphocyte-independent protection of severe combined immunodeficiency SCID mice from disseminated candidiasis (100% survival in BCG-vaccinated mice vs. 30% in control mice). In conclusion, BCG induces trained immunity and nonspecific protection from infections through epigenetic reprogramming of innate immune cells.
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
authors.forename: Johanneke
authors.initials: J
authors.lastname: Kleinnijenhuis
authors.forename: Jessica
authors.initials: J
authors.lastname: Quintin
authors.forename: Frank
authors.initials: F
authors.lastname: Preijers
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Daniela C
authors.initials: DC
authors.lastname: Ifrim
authors.forename: Sadia
authors.initials: S
authors.lastname: Saeed
authors.forename: Cor
authors.initials: C
authors.lastname: Jacobs
authors.forename: Joke
authors.initials: J
authors.lastname: van Loenhout
authors.forename: Dirk
authors.initials: D
authors.lastname: de Jong
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Reinout
authors.initials: R
authors.lastname: van Crevel
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology; D001500:BCG Vaccine / Q000276:immunology*; D001483:Base Sequence; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D009000:Monocytes / Q000276:immunology*; D053473:Nod2 Signaling Adaptor Protein / Q000276:immunology*; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D001500:BCG Vaccine; D017931:DNA Primers; D006657:Histones; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein