You are here

Proc Natl Acad Sci U S A DOI:10.1073/pnas.1202870109

Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes.

Publication TypeJournal Article
Year of Publication2012
AuthorsKleinnijenhuis, J, Quintin, J, Preijers, F, Joosten, LAB, Ifrim, DC, Saeed, S, Jacobs, C, van Loenhout, J, de Jong, D, Stunnenberg, HG, Xavier, RJ, van der Meer, JWM, van Crevel, R, Netea, MG
JournalProc Natl Acad Sci U S A
Date Published2012 Oct 23
KeywordsAdult, B-Lymphocytes, Base Sequence, BCG Vaccine, Chromatin Immunoprecipitation, DNA Primers, Epigenesis, Genetic, Histones, Humans, Methylation, Monocytes, Nod2 Signaling Adaptor Protein, Polymerase Chain Reaction, T-Lymphocytes

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.


Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID22988082
PubMed Central IDPMC3491454
Grant ListP30 DK043351 / DK / NIDDK NIH HHS / United States
R01 AI062773 / AI / NIAID NIH HHS / United States
DK 83756 / DK / NIDDK NIH HHS / United States
AI 062773 / AI / NIAID NIH HHS / United States
DK 043351 / DK / NIDDK NIH HHS / United States
R01 DK083756 / DK / NIDDK NIH HHS / United States