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BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity.
Cell Host Microbe. 2018 Jan 10; 23(1):89-100.e5.CH

Abstract

The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections. The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain. Epigenetic reprogramming was accompanied by functional changes indicative of trained immunity. Reduction of viremia was highly correlated with the upregulation of IL-1β, a heterologous cytokine associated with the induction of trained immunity, but not with the specific IFNγ response. The importance of IL-1β for the induction of trained immunity was validated through genetic, epigenetic, and immunological studies. In conclusion, BCG induces epigenetic reprogramming in human monocytes in vivo, followed by functional reprogramming and protection against non-related viral infections, with a key role for IL-1β as a mediator of trained immunity responses.

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Authors+Show Affiliations

Arts RJW
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
Moorlag SJCFM
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
Novakovic B
Department of Molecular Biology, Radboud University, Nijmegen, the Netherlands.
Li Y
Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.
Wang SY
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
Oosting M
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
Kumar V
Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.
Xavier RJ
Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard School of Medicine, Boston, MA, USA; Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
Wijmenga C
Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.
Joosten LAB
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
Reusken CBEM
Department Viroscience, WHO Collaborating Centre for Arboviruses and Viral Hemorrhagic Fever Reference and Research, Erasmus University Medical Center, Rotterdam, the Netherlands.
Benn CS
Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; OPEN, Institute of Clinical Research, University of Southern Denmark/Odense University Hospital, Odense, Denmark.
Aaby P
Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; OPEN, Institute of Clinical Research, University of Southern Denmark/Odense University Hospital, Odense, Denmark.
Koopmans MP
Department Viroscience, WHO Collaborating Centre for Arboviruses and Viral Hemorrhagic Fever Reference and Research, Erasmus University Medical Center, Rotterdam, the Netherlands.
Stunnenberg HG
Department of Molecular Biology, Radboud University, Nijmegen, the Netherlands.
van Crevel R
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
Netea MG
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany. Electronic address: mihai.netea@radboudumc.nl.

MeSH

AdultBCG VaccineCellular ReprogrammingEpigenesis, GeneticHumansInterferon-gammaInterleukin-1betaMaleMonocytesMycobacterium bovisPolymorphism, Single NucleotideVaccinationViremiaVirus DiseasesYellow FeverYellow fever virusYoung Adult

Pub Type(s)

Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

29324233

Clinical Trial Links

BCG Vaccine for Health Care Workers as Defense Against COVID 19
Performance Evaluation of BCG Vaccination in Healthcare Personnel to Reduce the Severity of SARS-COV-2 Infection
Using BCG Vaccine to Protect Health Care Workers in the COVID-19 Pandemic

Citation

Arts, Rob J W., et al. "BCG Vaccination Protects Against Experimental Viral Infection in Humans Through the Induction of Cytokines Associated With Trained Immunity." Cell Host & Microbe, vol. 23, no. 1, 2018, pp. 89-100.e5.
Arts RJW, Moorlag SJCFM, Novakovic B, et al. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe. 2018;23(1):89-100.e5.
Arts, R. J. W., Moorlag, S. J. C. F. M., Novakovic, B., Li, Y., Wang, S. Y., Oosting, M., Kumar, V., Xavier, R. J., Wijmenga, C., Joosten, L. A. B., Reusken, C. B. E. M., Benn, C. S., Aaby, P., Koopmans, M. P., Stunnenberg, H. G., van Crevel, R., & Netea, M. G. (2018). BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host & Microbe, 23(1), 89-e5. https://doi.org/10.1016/j.chom.2017.12.010
Arts RJW, et al. BCG Vaccination Protects Against Experimental Viral Infection in Humans Through the Induction of Cytokines Associated With Trained Immunity. Cell Host Microbe. 2018 Jan 10;23(1):89-100.e5. PubMed PMID: 29324233.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. AU - Arts,Rob J W, AU - Moorlag,Simone J C F M, AU - Novakovic,Boris, AU - Li,Yang, AU - Wang,Shuang-Yin, AU - Oosting,Marije, AU - Kumar,Vinod, AU - Xavier,Ramnik J, AU - Wijmenga,Cisca, AU - Joosten,Leo A B, AU - Reusken,Chantal B E M, AU - Benn,Christine S, AU - Aaby,Peter, AU - Koopmans,Marion P, AU - Stunnenberg,Hendrik G, AU - van Crevel,Reinout, AU - Netea,Mihai G, PY - 2017/04/18/received PY - 2017/09/25/revised PY - 2017/12/19/accepted PY - 2018/1/12/entrez PY - 2018/1/13/pubmed PY - 2018/8/17/medline KW - BCG KW - IL-1 KW - epigenetics KW - innate immune memory KW - monocytes KW - non-specific effects of vaccines KW - trained immunity KW - yellow fever vaccine SP - 89 EP - 100.e5 JF - Cell host & microbe JO - Cell Host Microbe VL - 23 IS - 1 N2 - The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections. The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain. Epigenetic reprogramming was accompanied by functional changes indicative of trained immunity. Reduction of viremia was highly correlated with the upregulation of IL-1β, a heterologous cytokine associated with the induction of trained immunity, but not with the specific IFNγ response. The importance of IL-1β for the induction of trained immunity was validated through genetic, epigenetic, and immunological studies. In conclusion, BCG induces epigenetic reprogramming in human monocytes in vivo, followed by functional reprogramming and protection against non-related viral infections, with a key role for IL-1β as a mediator of trained immunity responses. SN - 1934-6069 UR - https://www.unboundmedicine.com/medline/citation/29324233/full_citation L2 - https://linkinghub.elsevier.com/retrieve/pii/S1931-3128(17)30546-2 DB - PRIME DP - Unbound Medicine ER -