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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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“In contrast, BCG-trained murine macrophages produced significantly higher concentrations of TNF in response to LPS when compared with non-trained cells, and this was reduced by addition of MTA (Figure 3B), which is consistent with previous reports demonstrating a role for histone methylation in BCG induced trained imm…”
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Diabetes propels the risk for cardiovascular disease: sweet monocytes becoming aggressive?
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“, the variation of innate reactivity in cells previously exposed to various stimuli, is a concept well known in invertebrates and also in vertebrates, which has been recently re-confirmed in higher vertebrates and humans (Kleinnijenhuis et al., 2012; Netea et al., 2016).”
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“For example, BCG reprogrammes monocytes through epigenetic changes to a more proinflammatory response; in animal models, this response reduces mortality from challenge to unrelated infections.(7) It would be indicated to conduct similar studies for OPV.”
Borriello, F., Iannone, R., Somma, S. D., Loffredo, S., Scamardella, E., Galdiero, M. R., Varricchi, G., Granata, F., Portella, G., & Marone, G. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00680 · Cited by 67
“Critically, in vivo evidence of trained immunity has also been obtained in humans (27).”
BackgroundNew Tuberculosis Vaccine Strategies: Taking Aim at Un-Natural Immunity
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“Trained immunity persists for at least 3 months after vaccination (Kleinnijenhuis et al., 2012), at which time BCG has been eliminated from the local injection site, and the transcriptional and immunological profile can be considered to be due to the memory-like response induced by trained immunity.”
BackgroundSelf-citationThe Epigenetic Memory of Monocytes and Macrophages as a Novel Drug Target in Atherosclerosis
Bekkering, S., Joosten, L. A. B., van der Meer, J. W. M., Netea, M. G., & Riksen, N. P. (2015) · Clinical Therapeutics · doi:10.1016/j.clinthera.2015.01.008 · Cited by 65
Self-citationDevelopment of BCG Scar and Subsequent Morbidity and Mortality in Rural Guinea-Bissau
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“Recent immunologic studies have shown that BCG induces epigenetic modulations in monocytes and increased responsiveness against unrelated stimuli, thus providing a plausible immunological mechanism behind the beneficial nonspecific effects [14, 15].”
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“45,47,51 Epigenetic control denotes the regulation of gene transcription without altering the nucleotide sequence of the DNA by the modification of the chromatin structure.”
Self-citationBCG and protection against inflammatory and auto-immune diseases
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“…it is now well established that innate immune cells have the capacity for metabolic, epigenetic, and functional reprogramming that leads to long-lasting increases in host resistance to infection ( Netea et al., 2020 ; Kleinnijenhuis et al., 2012 ; Quintin et al., 2012 ; Saeed et al., 2014 ).”
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“Impressively, this vaccine was also capable of reprograming mononuclear phagocytes by using nucleotide-binding oligomerisation domain-containing protein2 (NOD2) to introduce epigenetic modifications at the level of histone H3 trimethyl lysine4 (H3K4me3) [213].”
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Sharrock, J., & Sun, J. C.-Y. (2020) · Current Opinion in Immunology · doi:10.1016/j.coi.2019.12.001 · Cited by 65
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“In vitro studies with purified monocytes and in vivo studies with severe combined immunodeficient (SCID) mice indicate T and B cells are not required for development of trained immunity (1).”
BackgroundInfluentialBCG scarring and improved child survival: a combined analysis of studies of BCG scarring
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BackgroundBCG Therapy for Type 1 Diabetes: Restoration of Balanced Immunity and Metabolism
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“The self-adjuvanted BCG vaccine, live attenuated Mycobacterium bovis, activates multiple TLRs and nucleotide-binding oligomerization domain 2, triggers trained immunity (27,39), and is associated with reduced all cause mortality, largely due to infections other than tuberculosis, in the first month of life (40).”
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“Although individual innate immune cells have a very limited lifespan [247], long-term trained innate immunity effects (often several months up to years) have been observed in many instances [248,249].”
BackgroundA single-cell view on host immune transcriptional response to in vivo BCG-induced trained immunity
Li, W., Moorlag, S. J. C. F. M., Koeken, V. A. C. M., Röring, R. J., de Bree, L. C. J., Mourits, V. P., Gupta, M. K., Zhang, B., Fu, J., Zhang, Z., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112487 · Cited by 56
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“Long-lasting heightened capacity to produce pro-inflammatory cytokines (IL-1β, IL-6, TNF) and chemokines (CCL2, CCL5) usually accompanies the phenotypic modifications 126,131,133 .”
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Self-citationSystemic administration of β-glucan induces immune training in microglia
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“inflammatory ↑IL-1b ↑Th1 T cells downregulate trained immunity Protection against infection (5)”
BackgroundInfluentialThe influence of the gut microbiome on BCG-induced trained immunity
Stražar, M., Mourits, V. P., Koeken, V. A. C. M., de Bree, L. C. J., Moorlag, S. J. C. F. M., Joosten, L. A. B., van Crevel, R., Vlamakis, H. C., Netea, M. G., & Xavier, R. J. (2021) · Genome biology · doi:10.1186/s13059-021-02482-0 · Cited by 60
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“This idea that innate cells can retain some memory of past immunological insults, allowing for enhanced cellular responses to secondary infections, is well documented in the case of microbial stimuli [86,87] and endogenous molecules [88,89] but has only recently been demonstrated for exogenous molecules [90,91].”
BackgroundFunctional and Genomic Architecture of Borrelia burgdorferi -Induced Cytokine Responses in Humans
Oosting, M., Kerstholt, M., ter Horst, R., Li, Y., Deelen, P., Smeekens, S. P., Jaeger, M., Lachmandas, E., Vrijmoeth, H. D., Lupșe, M. S., et al. (2016) · Cell Host & Microbe · doi:10.1016/j.chom.2016.10.006 · Cited by 60
“…observation, as Mtb and Borrelia are both recognized by a combination of both membrane-bound (TLR2) and intracellular (NOD2) receptors, while the extracellular bacteria are largely recognized by membrane-bound receptors only (Kleinnijenhuis et al., 2011, 2012; Oosting et al., 2010, 2011a).”
BackgroundSelf-citationPostinfectious Epigenetic Immune Modifications — A Double-Edged Sword
DiNardo, A. R., Netea, M. G., & Musher, D. M. (2021) · New England Journal of Medicine · doi:10.1056/nejmra2028358 · Cited by 58
Self-citationTrained Immunity: Linking Obesity and Cardiovascular Disease across the Life-Course?
Bekkering, S., Saner, C. C. S., Riksen, N. P., Netea, M. G., Sabin, M. A., Saffery, R., Stienstra, R., & Burgner, D. P. (2020) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2020.01.008 · Cited by 60
Self-citationCopland, A., Diogo, G. R., Hart, P. J., Harris, S., Tran, A. C., Paul, M. J., Singh, M., Cutting, S. M., & Reljić, R. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00346 · Cited by 62
“While its efficacy in many demographics is modest, there are accumulating data indicating that BCG may protect against non-TB diseases by training the innate immune system to respond non-specifically to diverse microbial threats (7, 8).”
BackgroundJayaraman, K., Adhisivam, B., Nallasivan, S., Krishnan, R. G., Kamalarathnam, C. N., Bharathi, M., McSharry, B., Namachivayam, S. P., Shann, F. A., Boopalan, S. I., et al. (2018) · The Pediatric Infectious Disease Journal · doi:10.1097/inf.0000000000002198 · Cited by 58
Targeting immunometabolism in host defence against Mycobacterium tuberculosis
Sheedy, F. J., & Divangahi, M. (2020) · Immunology · doi:10.1111/imm.13276 · Cited by 62
Bacillus Calmette–Guérin Immunotherapy for Cancer
Cardillo, F., Bonfim, M., Sousa-Vasconcelos, P. D. S., Mengel, J., Castello-Branco, L. R. R., & Pinho, R. T. (2021) · Vaccines · doi:10.3390/vaccines9050439 · Cited by 59
“BCG also induced human monocyte epigenetic reprogramming NOD2-dependent modifications [123].”
BackgroundTrained Immunity: An Overview and the Impact on COVID-19
Brueggeman, J., Zhao, J., Schank, M., Yao, Z. Q., & Moorman, J. P. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.837524 · Cited by 58
“Currently, the data suggests that BCG-trained immune responses are present 3 months post BCGtreatment (24); thus, further research should be conducted to evaluate the cellular response of BCG-trained cells for longer times to determine the maximal duration of memory response and protection.”
BackgroundInfluentialvan Puffelen, J. H., Novakovic, B., van Emst, L., Kooper, D., Zuiverloon, T. C. M., Oldenhof, U. T. H., Witjes, J. A., Galesloot, T. E., Vrieling, A., Aben, K. K. H., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-005518 · Cited by 58
Self-citationTraining vs. Tolerance: The Yin/Yang of the Innate Immune System
Lajqi, T., Köstlin‐Gille, N., Bauer, R., Zarogiannis, S. G., Lajqi, E., Ajeti, V., Dietz, S., Kranig, S. A., Rühle, J., Demaj, A., et al. (2023) · Biomedicines · doi:10.3390/biomedicines11030766 · Cited by 60
“Kleinnijenhuis and colleagues provided firm evidence that BCG promotes the non-specific long-term boosting of innate immune system, trained immunity, mediated by a NOD2-dependent regulation of epigenetic marks such as histone H3 at lysine 4 (H3K4) trimethylation [77,78].”
BackgroundTiwari, V., Prajapati, B., Asare, Y., Damkou, A., Ji, H., Liu, L., Naser, N., Gouna, G., Leszczyńska, K. B., Mieczkowski, J., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.07.001 · Cited by 58
The microbiome and immune memory formation
McCoy, K. D., Burkhard, R., & Geuking, M. B. (2019) · Immunology and Cell Biology · doi:10.1111/imcb.12273 · Cited by 62
“Trained immunity can also be induced in myeloid cells following infection with Candida albicans or stimulation with b-glucan(65) and BCG vaccination.(66,67) Indeed, the ability of several live vaccines, such as BCG, to provide protection from infections other than that targeted by the vaccine suggests an important rol…”
BackgroundBickett, T. E., McLean, J., Creissen, E., Izzo, L. S., Hagan, C. E., Izzo, A. J., Angulo, F. S., & Izzo, A. A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01202 · Cited by 57
“Furthermore, at the protein level, production of TNF-α, IL-1β, IL-6, and IL-10 were similar between the two culture conditions (Figure 5D), reinforcing the fact that non-replicating BCG was a good as replicating BCG in producing key cytokines.”
BackgroundInfluentialLibraty, D. H., Zhang, L., Woda, M., Acosta, L. P., Obcena, A., Brion, J. D., & Capeding, R. Z. (2013) · Trials in Vaccinology · doi:10.1016/j.trivac.2013.11.004 · Cited by 56
“In one report, BCG vaccination increased in vitro PBMC IFN-γ release to unrelated pathogens (Staphylococcus aureus and Candida albicans) for up to 3 months [13].”
BackgroundMalgorzata-Miller, G., Heinbockel, L., Brandenburg, K., van der Meer, J. W. M., Netea, M. G., & Joosten, L. A. B. (2016) · Scientific Reports · doi:10.1038/srep34221 · Cited by 55
Self-citationNonspecific Effects of Oral Polio Vaccine on Diarrheal Burden and Etiology Among Bangladeshi Infants
Upfill-Brown, A. M., Taniuchi, M., Platts-Mills, J. A., Kirkpatrick, B. D., Burgess, S. L., Oberste, M. S., Weldon, W. C., Houpt, E. R., Haque, R., Zaman, K., et al. (2017) · Clinical Infectious Diseases · doi:10.1093/cid/cix354 · Cited by 57
“Nonspecific Effects of Oral Polio Vaccine • CID 2017:65 (1 August) • 415 [10, 11].”
BackgroundGut microbiome communication with bone marrow regulates susceptibility to amebiasis
Burgess, S. L., Leslie, J. L., Uddin, M. J., Oakland, D. N., Gilchrist, C. A., Moreau, G. B., Watanabe, K., Saleh, M., Simpson, M. D., Thompson, B. A., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci133605 · Cited by 57
Yitbarek, K., Abraham, G., Girma, T., Tilahun, T., & Woldie, M. K. (2020) · Vaccine · doi:10.1016/j.vaccine.2020.08.018 · Cited by 62
“, 2012 [36] People between 20 and 36 years of age Induction of trained immunity and non-specific protection from”
InfluentialMicroglial innate memory and epigenetic reprogramming in neurological disorders
Martins-Ferreira, R., Leal, B., Costa, P., & Ballestar, E. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101971 · Cited by 55
Gu, H., Zeng, X., Peng, L., Xiang, C., Zhou, Y., Zhang, X., Zhang, J., Wang, N., Guo, G. F., Li, Y., et al. (2021) · eLife · doi:10.7554/elife.69951 · Cited by 54
The WHO Review of the Possible Nonspecific Effects of Diphtheria-Tetanus-Pertussis Vaccine
Aaby, P., Ravn, H., & Benn, C. S. (2016) · The Pediatric Infectious Disease Journal · doi:10.1097/inf.0000000000001269 · Cited by 55
Kjærgaard, J., Birk, N. M., Nissen, T. N., Thøstesen, L. M., Pihl, G. T., Benn, C. S., Jeppesen, D. L., Pryds, O. A., Kofoed, P., Aaby, P., et al. (2016) · Pediatric Research · doi:10.1038/pr.2016.142 · Cited by 55
The phenotype and function of preterm infant monocytes: implications for susceptibility to infection
de Jong, E., Strunk, T., Burgner, D. P., Lavoie, P. M., & Currie, A. J. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.4ru0317-111r · Cited by 55
“Although the concept of immune training has been validated in human adults following Bacille Calmette-Guerin (BCG) vaccination [103], further studies are needed in neonates to determine how pre- or postnatal exposure to microbes may affect preterm infants’ tolerance to subsequent infections.”
BackgroundBCG vaccination induces cross-protective immunity against pathogenic microorganisms
Soto, J. A., Gálvez, N. M. S., Andrade, C. A., Ramírez, M. A., Riedel, C. A., Kalergis, A. M., & Bueno, S. M. (2022) · Trends in Immunology · doi:10.1016/j.it.2021.12.006 · Cited by 54
Trained Immunity Contribution to Autoimmune and Inflammatory Disorders
Funes, S. C., Ríos, M., Fernández‐Fierro, A., Genaro, M. S. D., & Kalergis, A. M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.868343 · Cited by 53
“Thus is induced the proteolytic activation of caspase 1 or 11 and the cleavage and subsequent release of bioactive IL-1b, a key molecule of inflammation and innate immunity (115).”
BackgroundInfluentialInnate immune memory in cardiometabolic disease
Bahrar, H., Bekkering, S., Stienstra, R., Netea, M. G., & Riksen, N. P. (2023) · Cardiovascular Research · doi:10.1093/cvr/cvad030 · Cited by 53
Self-citationTrained immunity: a new avenue for tuberculosis vaccine development
Lerm, M., & Netea, M. G. (2015) · Journal of Internal Medicine · doi:10.1111/joim.12449 · Cited by 54
Self-citationMTBVAC from discovery to clinical trials in tuberculosis-endemic countries
Marinova, D., Gonzalo‐Asensio, J., Aguiló, N., & Martı́n, C. (2017) · Expert Review of Vaccines · doi:10.1080/14760584.2017.1324303 · Cited by 58
“(T- and B-cell dependent) to pathogens via epigenetic reprogramming of monocytes [28].”
BackgroundNardini, C., Moreau, J., Gensous, N., Ravaioli, F., Garagnani, P., & Bacalini, M. G. (2018) · Seminars in Immunology · doi:10.1016/j.smim.2018.10.009 · Cited by 54
An integrative genomics approach identifies KDM4 as a modulator of trained immunity
Moorlag, S. J. C. F. M., Matzaraki, V., van Puffelen, J. H., van der Heijden, C. D. C. C., Keating, S., Groh, L. A., Röring, R. J., Bakker, O. B., Mourits, V. P., Koeken, V. A. C. M., et al. (2021) · European Journal of Immunology · doi:10.1002/eji.202149577 · Cited by 56
Self-citationA molecular atlas of innate immunity to adjuvanted and live attenuated vaccines, in mice
Lee, A. W. Q., Scott, M. K. D., Wimmers, F., Arunachalam, P. S., Luo, W., Fox, C. B., Tomai, M. A., Khatri, P., & Pulendran, B. (2022) · Nature Communications · doi:10.1038/s41467-022-28197-9 · Cited by 52
Trained immunity: A Yin‐Yang balance
Hu, Z., Lu, S., Lowrie, D. B., & Fan, X. (2022) · MedComm · doi:10.1002/mco2.121 · Cited by 55
Innate Immune Memory: The Latest Frontier of Adjuvanticity
Töpfer, E., Boraschi, D., & Italiani, P. (2015) · Journal of Immunology Research · doi:10.1155/2015/478408 · Cited by 53
“, CD14dimCD16+, CD14CD16), a topic that has not yet been fully investigated [15]; an increased expression of PRRs on the cell membrane following BCG vaccination [17, 53]; and the role of soluble mediators, such as inflammatory cytokines.”
BackgroundInfluentialIntracellular signalling pathways: targets to reverse immunosenescence
Fülöp, T., Witkowski, J. M., Page, A. Y. L., Fortin, C. F., Pawelec, G., & Larbi, A. (2016) · Clinical & Experimental Immunology · doi:10.1111/cei.12836 · Cited by 54
Hypothesis: stimulation of trained immunity as adjunctive immunotherapy in cancer
Netea, M. G., Joosten, L. A. B., & van der Meer, J. W. M. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.5ri0217-064rr · Cited by 53
“components [such as fungal b-1,3-(D)-glucan (b-glucan)], and bacterial peptidoglycans/muramyl dipeptide (MDP), and the oxidized low-density lipoproteins [50, 51, 53].”
BackgroundSelf-citationStroma: the forgotten cells of innate immune memory
Crowley, T., Buckley, C. D., & Clark, A. R. (2018) · Clinical & Experimental Immunology · doi:10.1111/cei.13149 · Cited by 55
Martı́n, C., Aguiló, N., Marinova, D., & Gonzalo‐Asensio, J. (2020) · Applied Sciences · doi:10.3390/app10072632 · Cited by 57
“In addition, there is emerging evidence that BCG may induce nonspecific resistance (T- and B-cell dependent) to other pathogens [20], which should be taken into consideration for AMR TB.”
BackgroundBerendsen, M. L., Gijzel, S. W. L. V., Smits, J. P. J. M., de Mast, Q., Aaby, P., Benn, C. S., Netea, M. G., & van der Ven, A. J. (2019) · BMJ Global Health · doi:10.1136/bmjgh-2019-001862 · Cited by 52
Self-citation
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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