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Bacille Calmette-Guérin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes
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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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“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 Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy (2021) · cites this paper as [40]
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LXR Activation Induces a Proinflammatory Trained Innate Immunity-Phenotype in Human Monocytes
Sohrabi, Y., Sonntag, G. V. H., Braun, L. C., Lagache, S. M. M., Liebmann, M., Klotz, L., Godfrey, R., Kahles, F., Waltenberger, J. L., & Findeisen, H. M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00353 · Cited by 80
“The induction of BCG-induced trained innate immunity is dependent on the activation of the NOD2-pathway (6).”
BackgroundBerghof, T. V. L., Parmentier, H. K., & Lammers, A. (2013) · Poultry Science · doi:10.3382/ps.2013-03177 · Cited by 80
“…of DNA nucleotide sequence in healthy individuals as often investigated in murine or human cells, for example to keep intestinal immune homeostasis, to generate oral tolerance, or to acquire trained immunity (Takahashi et al., 2009; Kleinnijenhuis et al., 2012; Martino and Prescott, 2013).”
BackgroundThe Elusive Anti-Candida Vaccine: Lessons From the Past and Opportunities for the Future
Tso, G. H. W., Reales‐Calderón, J. A., & Pavelka, N. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00897 · Cited by 80
“albicans infection through a T and B lymphocyte-independent mechanism (134).”
BackgroundThe impact of vaccines on heterologous adaptive immunity
Messina, N. L., Zimmermann, P., & Curtis, N. C. (2019) · Clinical Microbiology and Infection · doi:10.1016/j.cmi.2019.02.016 · Cited by 78
Innate immunity to malaria—The role of monocytes
Dobbs, K. R., Crabtree, J., & Dent, A. E. (2019) · Immunological Reviews · doi:10.1111/imr.12830 · Cited by 85
Accelerating research and development of new vaccines against tuberculosis: a global roadmap
Cobelens, F. G. J., Suri, R. K., Helinski, M. E. H., Makanga, M. M., Weinberg, A. L., Schaffmeister, B., Deege, F., & Hatherill, M. (2022) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(21)00810-0 · Cited by 81
The BCG replacement vaccine VPM1002: from drawing board to clinical trial
Kaufmann, S. H. E., Cotton, M. F., Eisele, B., Gengenbacher, M., Grode, L., Hesseling, A. C., & Walzl, G. (2014) · Expert Review of Vaccines · doi:10.1586/14760584.2014.905746 · Cited by 77
“Subsequent studies suggest that this policy may have increased the incidence of a wide variety of conditions, including atopic dermatitis [44,46].”
BackgroundA century of BCG: Impact on tuberculosis control and beyond
Ahmed, A., Rakshit, S., Adiga, V., Dias, M., Dwarkanath, P., D′Souza, G., & Vyakarnam, A. (2021) · Immunological Reviews · doi:10.1111/imr.12968 · Cited by 74
BCG turns 100: its nontraditional uses against viruses, cancer, and immunologic diseases
Singh, A. K., Netea, M. G., & Bishai, W. R. (2021) · Journal of Clinical Investigation · doi:10.1172/jci148291 · Cited by 79
Self-citationThe mineralocorticoid receptor as a modulator of innate immunity and atherosclerosis
van der Heijden, C. D. C. C., Deinum, J., Joosten, L. A. B., Netea, M. G., & Riksen, N. P. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy092 · Cited by 79
Self-citationThe role of trained immunity in COVID-19: Lessons for the next pandemic
Netea, M. G., Ziogas, A., Benn, C. S., Giamarellos‐Bourboulis, E. J., Joosten, L. A. B., Arditi, M., Chumakov, K., van Crevel, R., Gallo, R. C., Aaby, P., et al. (2023) · Cell Host & Microbe · doi:10.1016/j.chom.2023.05.004 · Cited by 79
Self-citationEpigenetics and Proteomics Join Transcriptomics in the Quest for Tuberculosis Biomarkers
Esterhuyse, M. M., Weiner, J. M., Caron, É., Loxton, A. G., Iannaccone, M., Wagman, C., Saikali, P., Stanley, K., Wolski, W., Mollenkopf, H., et al. (2015) · mBio · doi:10.1128/mbio.01187-15 · Cited by 75
“In particular, stable marks such as those derived from DNA methylation patterns are currently absent from studies of this kind, while more dynamic epigenetic marks (histone modifications) have uncovered matters relating to “trained immunity,” even in the case of recipients of the only current TB vaccine, M. tuberculos…”
Stensballe, L. G., Ravn, H., Birk, N. M., Kjærgaard, J., Nissen, T. N., Pihl, G. T., Thøstesen, L. M., Greisen, G. O., Jeppesen, D. L., Kofoed, P., et al. (2018) · Journal of the Pediatric Infectious Diseases Society · doi:10.1093/jpids/piy029 · Cited by 75
Guha, R., Mathioudaki, A., Doumbo, S., Doumtabé, D., Skinner, J., Arora, G., Siddiqui, S., Li, S., Kayentao, K., Ongoïba, A., et al. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009430 · Cited by 75
“Chromatin precipitation was performed using rabbit antihuman H3K4me3 IgG Ab (Active Motif) as described previously [50].”
MethodSpatiotemporal Adaptations of Macrophage and Dendritic Cell Development and Function
Roquilly, A., Mintern, J. D., & Villadangos, J. A. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101320-031931 · Cited by 81
Key advances in vaccine development for tuberculosis—success and challenges
Lai, R., Ogunsola, A. F., Rakib, T., & Behar, S. M. (2023) · npj Vaccines · doi:10.1038/s41541-023-00750-7 · Cited by 76
Innate immune memory in mammals
Hamon, M. A., & Quintin, J. (2016) · Seminars in Immunology · doi:10.1016/j.smim.2016.05.003 · Cited by 81
Self-citationImmunometabolism orchestrates training of innate immunity in atherosclerosis
van Tuijl, J., Joosten, L. A. B., Netea, M. G., Bekkering, S., & Riksen, N. P. (2019) · Cardiovascular Research · doi:10.1093/cvr/cvz107 · Cited by 77
“Atherosclerotic lesions grow through a combination of continuous recruitment of circulating monocytes60,61 as well as local macrophage proliferation.62 We previously hypothesized that trained circulating monocytes could therefore aggravate atherosclerotic lesion development.11 Interestingly, in humans in vivo, a train…”
BackgroundSelf-citationDallio, M., Sangineto, M., Romeo, M., Villani, R., Romano, A. D., Loguercio, C., Serviddio, G., & Federico, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22010436 · Cited by 77
The BCG Vaccine for COVID-19: First Verdict and Future Directions
González-Pérez, M., Sánchez-Tarjuelo, R., Shor, B., Nistal‐Villán, E., & Ochando, J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.632478 · Cited by 78
“The mechanisms by which BCG induces a cross-protection against other diseases and specifically respiratory tract infections, has been stablished during the last decade and suggests a critical role of the innate immune system (58).”
BackgroundThe Protective Role of Maternal Immunization in Early Life
Cinicola, B. L., Conti, M. G., Terrin, G., Sgrulletti, M., Elfeky, R., Carsetti, R., Salinas, A. F., Mortari, E. P., Brindisi, G., Curtis, M. D., et al. (2021) · Frontiers in Pediatrics · doi:10.3389/fped.2021.638871 · Cited by 79
Munawara, U., Catanzaro, M., Xu, W., Tan, C., Hirokawa, K., Bosco, N., Dumoulin, D., Khalil, A., Larbi, A., Lévesque, S., et al. (2021) · Immunity & Ageing · doi:10.1186/s12979-021-00236-x · Cited by 74
Weight cycling induces innate immune memory in adipose tissue macrophages
Caslin, H. L., Cottam, M. A., Pinon, J., Boney, L. Y., & Hasty, A. H. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.984859 · Cited by 80
“We next adopted a previously published cell culture model of innate immune memory with a 24-hour prime, 6-day washout, and 24-hour secondary activation (Figure 2A) (23, 24).”
BackgroundMethodInfluentialInnate Immune Modulation by GM-CSF and IL-3 in Health and Disease
Borriello, F., Galdiero, M. R., Varricchi, G., Loffredo, S., Spadaro, G., & Marone, G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20040834 · Cited by 77
DAMPs and Innate Immune Training
Jentho, E., & Weis, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.699563 · Cited by 73
Ferreira, A. V., Kostidis, S., Groh, L. A., Koeken, V. A. C. M., Bruno, M., Baydemir, İ., Kılıç, G., Bulut, O. P., Andriopoulou, T., Spanou, V. M., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112658 · Cited by 77
Hammer, Q., & Romagnani, C. (2016) · Advances in immunology · doi:10.1016/bs.ai.2016.10.001 · Cited by 72
The lncRNA Connection Between Cellular Metabolism and Epigenetics in Trained Immunity
Fok, E. T., Davignon, L., Fanucchi, S., & Mhlanga, M. M. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2018.03184 · Cited by 76
“BCG induces training by signaling through the NOD2 receptor and via the RIP2 pathway, to similarly elicit a NF-κB-mediated immune response (32, 33).”
BackgroundCole, J., Aberdein, J., Jubrail, J., & Dockrell, D. H. (2014) · Advances in microbial physiology/Advances in Microbial Physiology · doi:10.1016/bs.ampbs.2014.08.004 · Cited by 71
Arts, R. J. W., Blok, B. A., van Crevel, R., Joosten, L. A. B., Aaby, P., Benn, C. S., & Netea, M. G. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.6ab0914-416r · Cited by 71
“performed as described previously [15, 24].”
BackgroundInfluentialSelf-citationOxLDL-mediated immunologic memory in endothelial cells
Sohrabi, Y., Lagache, S. M. M., Voges, V. C., Semo, D., Sonntag, G., Hanemann, I., Kahles, F., Waltenberger, J. L., & Findeisen, H. M. (2020) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2020.07.006 · Cited by 69
Foster, M., Hill, P. C., Setiabudiawan, T. P., Koeken, V. A. C. M., Alisjahbana, B., & van Crevel, R. (2021) · Immunological Reviews · doi:10.1111/imr.12965 · Cited by 74
IL-1 family cytokines as drivers and inhibitors of trained immunity
Teufel, L. U., Arts, R. J. W., Netea, M. G., Dinarello, C. A., & Joosten, L. A. B. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155773 · Cited by 73
Self-citationInhibiting epigenetic enzymes to improve atherogenic macrophage functions
den Bossche, J. V., Neele, A. E., Hoeksema, M. A., de Heij, F., Boshuizen, M. C. S., van der Velden, S., de Boer, V. C. J., Reedquist, K. A., & de Winther, M. P. J. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.11.029 · Cited by 70
Correlates of immune exacerbations in leprosy
Geluk, A. (2018) · Seminars in Immunology · doi:10.1016/j.smim.2018.06.003 · Cited by 69
Metadata
- 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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