Bacille Calmette-Guérin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes
Open accessAbstract
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.
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NOD2 stimulation by MDP and its analogs can alter host immunity through multiple pathways, including macrophage activation for tumor clearance, epigenetic reprogramming of monocytes, generation of conventional type 1 dendritic cells, and dendritic cell priming for cross-presentation to CD8+ T cells.
“our findings corroborate a wealth of emerging evidence that NOD2 stimulation by MDP and its analogs can alter host immunity through multiple pathways including the direct activation of macrophages for tumor cell clearance (39), epigenetic reprogramming of monocytes (40, 41), generation of conventional type 1 dendritic cells (42), and priming of dendritic cells for cross-presentation to CD8+ T cell”
From <i>Enterococcus</i> peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy (2021) · cites this paper as [40]
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- Authors
- Kleinnijenhuis, J., Quintin, J., Preijers, F., Joosten, L. A. B., Ifrim, D. C., Saeed, S., Jacobs, C., van Loenhout, J., de Jong, D., Stunnenberg, H. G., Xavier, R. J., van der Meer, J. W. M., van Crevel, R., & Netea, M. G.
- Affiliations
- Radboud University Medical Center (NL)
- Department of Medicine,
- Radboud University Nijmegen (NL)
- Public Health Office GGD, Nijmegen, The Netherlands;
- Department of Gastroenterology, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands;
- Broad Institute (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-09-17
- Volume
- 109
- Issue
- 43
- Pages
- 17537-17542
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3491454
- OpenAlex
- W2059403792
- Cited by
- 1,728
- References
- 35
- Citations by year
- 2026: 139 · 2025: 174 · 2024: 127 · 2023: 150 · 2022: 170 · 2021: 226 · 2020: 204 · 2019: 118 · 2018: 119 · 2017: 79 · 2016: 74 · 2015: 68 · 2014: 51 · 2013: 25 · 2012: 2
- FWCI
- 20.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- HAL (submittedVersion)
- Funders
- Leona M. and Harry B. Helmsley Charitable Trust
- Higher Education Commision, Pakistan
- National Institutes of Health (DK 043351)
- National Institute of Allergy and Infectious Diseases (AI 062773, R01AI062773)
- National Institute of Diabetes and Digestive and Kidney Diseases ((DK043351, R01DK083756, DK 83756, P30DK043351)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- BCG vaccine, trained immunity, NOD2, epigenetic reprogramming, histone H3 lysine 4 trimethylation, monocytes, innate immunity, interferon-gamma, TNF-α, IL-1β, TLR4, CD11b, candidiasis, BCG vaccination, SCID mice
- MeSH terms
- Adult, B-Lymphocytes, Base Sequence, BCG Vaccine, Histones, Humans, Methylation, Monocytes, T-Lymphocytes, Polymerase Chain Reaction, DNA Primers, Epigenesis, Genetic, Chromatin Immunoprecipitation, Nod2 Signaling Adaptor Protein
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