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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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BackgroundThe Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma
McBride, M. A., Owen, A. M., Stothers, C. L., Hernandez, A., Luan, L., Burelbach, K. R., Patil, T. K., Bohannon, J. K., Sherwood, E. R., & Patil, N. K. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01043 · Cited by 120
Optimize Prime/Boost Vaccine Strategies: Trained Immunity as a New Player in the Game
Palgen, J., Feraoun, Y., Dzangué-Tchoupou, G., Joly, C., Martinon, F., Grand, R. L., & Beignon, A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.612747 · Cited by 117
“Trained Immunity-Inducing Vaccines In the last decade, trained immunity has been abundantly reported following BCG vaccination, in humans and mice, and after b-glucan injection in mice (29, 31, 34, 46, 56, 69, 70).”
BackgroundMethodLong, Q., Zheng, P., Zheng, X. W., Li, W., Hua, L., Yang, Z., Huang, W., & Ma, Y. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114321 · Cited by 114
Progress and challenges in TB vaccine development
Voss, G., Casimiro, D. R., Neyrolles, O., Williams, A., Kaufmann, S. H. E., McShane, H., Hatherill, M., & Fletcher, H. A. (2018) · F1000Research · doi:10.12688/f1000research.13588.1 · Cited by 114
Microglial Priming as Trained Immunity in the Brain
Haley, M. J., Brough, D., Quintin, J., & Allan, S. M. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2017.12.039 · Cited by 104
“The initial priming stimuli and secondary challenge may be temporally separated, for example inflammatory challenge in utero can lead to alterations in microglial reactivity later in life for offspring (Knuesel et al., 2014).”
BackgroundSelf-citationChild survival and BCG vaccination: a community based prospective cohort study in Uganda
for the PROMISE- EBF Study Group, Nankabirwa, V., Tumwine, J. K., Mugaba, P. M., Tylleskär, T., & Sommerfelt, H. (2015) · BMC Public Health · doi:10.1186/s12889-015-1497-8 · Cited by 113
“It is posited that the BCG vaccine induces its non-specific effects via epigenetic reprogramming of the innate immune cells [12].”
BackgroundTuberculosis Vaccine Development: Progress in Clinical Evaluation
Sable, S. B., Posey, J. E., & Scriba, T. J. (2019) · Clinical Microbiology Reviews · doi:10.1128/cmr.00100-19 · Cited by 120
Aaby, P., Martins, C. L., Garly, M., Andersen, A., Fisker, A. B., Claësson, M. H., Ravn, H., Rodrigues, A., Whittle, H. C., & Benn, C. S. (2014) · Clinical Infectious Diseases · doi:10.1093/cid/ciu354 · Cited by 112
“Last, recent studies have shown that BCG induces epigenetic changes that reprogram monocytes to enhanced response to unrelated infections [33].”
Innate immune memory: Implications for host responses to damage‐associated molecular patterns
Crișan, T. O., Netea, M. G., & Joosten, L. A. B. (2016) · European Journal of Immunology · doi:10.1002/eji.201545497 · Cited by 118
Self-citationRegulating trained immunity with nanomedicine
van Leent, M. M. T., Priem, B., Schrijver, D. P., de Dreu, A., Hofstraat, S. R. J., Zwolsman, R. C., Beldman, T. J., Netea, M. G., & Mulder, W. J. M. (2022) · Nature Reviews Materials · doi:10.1038/s41578-021-00413-w · Cited by 117
Self-citationThe role of neutrophils in trained immunity
Kalafati, L., Hatzioannou, A., Hajishengallis, G., & Chavakis, T. (2022) · Immunological Reviews · doi:10.1111/imr.13142 · Cited by 117
Trained immunity in organ transplantation
Ochando, J., Fayad, Z. A., Madsen, J. C., Netea, M. G., & Mulder, W. J. M. (2019) · American Journal of Transplantation · doi:10.1111/ajt.15620 · Cited by 113
“42 Trained macrophages were shown to increase the trimethylation of histone H3 at lysine (H3K4me3) at the IL‐6 and TNF α promoters, which were associated with an increased secretion of these pro‐inflammatory cytokines.”
Self-citationAndersen, A., Fisker, A. B., Rodrigues, A., Martins, C. L., Ravn, H., Lund, N., Biering-Sørensen, S. R., Benn, C. S., & Aaby, P. (2018) · Frontiers in Public Health · doi:10.3389/fpubh.2018.00013 · Cited by 109
“For instance, BCG reprograms monocytes through epigenetic changes to a more pro-inflammatory response; in animal models, this translates into reduced mortality from challenge to unrelated infections (3).”
BackgroundHeterologous Effects of Infant BCG Vaccination: Potential Mechanisms of Immunity
Butkevičiūtė, E., Jones, C. E., & Smith, S. G. (2018) · Future Microbiology · doi:10.2217/fmb-2018-0026 · Cited by 109
Immunosenescence is both functional/adaptive and dysfunctional/maladaptive
Fülöp, T., Larbi, A., Hirokawa, K., Cohen, A. A., & Witkowski, J. M. (2020) · Seminars in Immunopathology · doi:10.1007/s00281-020-00818-9 · Cited by 106
Scriba, T. J., Netea, M. G., & Ginsberg, A. M. (2020) · Seminars in Immunology · doi:10.1016/j.smim.2020.101431 · Cited by 116
Self-citationBrandi, P., Conejero, L., Cueto, F. J., Martínez-Cano, S., Dunphy, G., Gómez, M. J., Relaño‐Rupérez, C., Saz-Leal, P., Enamorado, M., Quintas, A., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2021.110184 · Cited by 112
Impact of virus genetic variability and host immunity for the success of COVID-19 vaccines
dos Santos, W. G. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111272 · Cited by 108
“Additionally, transcriptional, epigenetic and metabolic reprograming were observed in myeloid cells of vaccinated individuals [163,164].”
Zhang, B., Moorlag, S. J. C. F. M., Dominguez-Andres, J., Bulut, O. P., Kilic, G., Liu, Z., van Crevel, R., Xu, C.-J., Joosten, L. A. B., Netea, M. G., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci147719 · Cited by 111
“TI is characterized by enhanced responses of TI signature markers upon restimulation as compared with untrained cells (7, 8).”
BackgroundSelf-citationBukhbinder, A. S., Ling, Y., Hasan, O., Jiang, X., Kim, Y., Phelps, K. N., Schmandt, R. E., Amran, A., Coburn, R. P., Ramesh, S., et al. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220361 · Cited by 111
“The molecular mechanisms driving the changes in cytokine signaling and PRR expression following vaccination include “epigenetic reprogramming” [47] of immune cells through processes such as DNA methylation, histone modification, or post-transcriptional miRNA targeting of regulatory sequences related to cytokine or PRR…”
BackgroundTuberculosis vaccines: Opportunities and challenges
Zhu, B., Dockrell, H. M., Ottenhoff, T. H. M., Evans, T. G., & Zhang, Y. (2018) · Respirology · doi:10.1111/resp.13245 · Cited by 116
Uthayakumar, D., Paris, S., Chapat, L., Freyburger, L., Poulet, H., & Luca, K. D. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02869 · Cited by 105
“was previously described to upregulate pro-inflammatory genes (Figure 1B) (25, 46).”
BackgroundInfluentialIngle, H., Lee, S., Ai, T. L., Orvedahl, A., Rodgers, R., Zhao, G., Sullender, M. E., Peterson, S. T., Locke, M. C., Liu, T., et al. (2019) · Nature Microbiology · doi:10.1038/s41564-019-0416-7 · Cited by 109
Could BCG Vaccination Induce Protective Trained Immunity for SARS-CoV-2?
Covián, C., Retamal-Díaz, A. R., Bueno, S. M., & Kalergis, A. M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00970 · Cited by 104
“This antigen-unspecific immune “memory” induced by trained innate immune cells can last for up to 3 months postvaccination (13).”
BackgroundInfluentialTrained immunity in chronic inflammatory diseases and cancer
Hajishengallis, G., Netea, M. G., & Chavakis, T. (2025) · Nature reviews. Immunology · doi:10.1038/s41577-025-01132-x · Cited by 113
“…are consistent with studies showing the potent induction of TRIM in clinical trials in which BCG vaccination induced protection against heterologous infections 52 , as well as experimental models in which BCG protected against heterologous infections in the absence of functional lymphocytes 25 .”
Self-citationImmunomodulating Effects of Fungal Beta-Glucans: From Traditional Use to Medicine
van Steenwijk, H. P., Bast, A., & de Boer, A. (2021) · Nutrients · doi:10.3390/nu13041333 · Cited by 103
“MDP is derived from various sources and is present in human peripheral blood [97,98].”
BackgroundInfluentialSingh, A. K., Praharaj, M., Lombardo, K. A., Yoshida, T., Matoso, A., Baras, A. S., Zhao, L., Srikrishna, G., Huang, J., Prasad, P., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28509-z · Cited by 106
RetractedInnate Immune Memory: Time for Adopting a Correct Terminology
Boraschi, D., & Italiani, P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00799 · Cited by 108
“Recently, the phenomenon of vertebrate innate memory has experienced a renewed interest (19, 24).”
BackgroundCOVID-19 Pandemic and Vaccines Update on Challenges and Resolutions
Khan, W. H., Hashmi, Z., Goel, A., Ahmad, R., Gupta, K., Khan, N., Alam, I., Ahmed, F., & Ansari, M. A. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.690621 · Cited by 105
“…Variable Immune Response BCG vaccination in healthy volunteers increases IFN-g; enhances monocyte-derived cytokines TNF and IL-1b release; and elevates activation markers CD11b and PRRs such as Toll-like receptor-4, CD-14, and scavenger receptors (Kleinnijenhuis et al., 2012; Goswami et al., 2020).”
BackgroundFlanagan, K. L., van Crevel, R., Curtis, N. C., Shann, F. A., Levy, O., & for the Optimmunize Network (2013) · Clinical Infectious Diseases · doi:10.1093/cid/cit209 · Cited by 101
Tuberculosis Infectiousness and Host Susceptibility
Turner, R. D., Chiu, C., Churchyard, G., Esmail, H., Lewinsohn, D. M., Gandhi, N. R., & Fennelly, K. P. (2017) · The Journal of Infectious Diseases · doi:10.1093/infdis/jix361 · Cited by 111
“Indeed, it has been proposed that this might be one way in which BCG vaccine can confer protection against nonmycobacterial diseases [76].”
BackgroundAbnormal Epigenetic Regulation of Immune System during Aging
Jasiulionis, M. G. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00197 · Cited by 103
“For example, metabolic changes in monocytes activated by β-glucan from Candida are associated with increased levels of the active histone marks, H3K4 trimethylation, and H3K27 acetylation, leading to increased production of IL-6 and TNF cytokines, inflammation, and “trained immunity” (155).”
Background
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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