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Human Bacille Calmette-Guérin Vaccination Elicits Trained Immunity Via the Hematopoietic Progenitor Compartment

47 Pages Posted: 23 Apr 2019 Last revised: 8 Jul 2019 Publication Status: Review Complete

See all articles by B. Cirovic

B. Cirovic

University of Bonn - Myeloid Cell Biology

L. C. J. de Bree

Radboud University Nijmegen - Department of Internal Medicine; Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI); Statens Serums Institut - Research Center for Vitamins and Vaccines; University of Southern Denmark - Odense Patient Data Explorative Network (OPEN)

L. Groh

Radboud University Nijmegen - Department of Internal Medicine; Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI)

B. A. Blok

Radboud University Nijmegen - Department of Internal Medicine; Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI); Statens Serums Institut - Research Center for Vitamins and Vaccines; University of Southern Denmark - Odense Patient Data Explorative Network (OPEN)

J. Chan

University of Melbourne - Department of Paediatrics; University of Melbourne - Murdoch Children's Research Institute

W.J.F.M. van der Velden

Radboud University Nijmegen - Department of Hematology

M. E. J. Bremmers

Radboud University Nijmegen - Department of Hematology

Reinout van Crevel

Radboud University Medical Center - Department of Internal Medicine and Radboud Center for Infectious Diseases

K. Händler

German Center for Neurodegenerative Diseases (DZNE) - Single Cell Genomics and Epigenomics Unit

S. Picelli

German Center for Neurodegenerative Diseases (DZNE) - Single Cell Genomics and Epigenomics Unit

J. Schulte-Schrepping

University of Bonn, Life and Medical Sciences Institute (LIMES), Genomics & Immunoregulation

K. Klee

University of Bonn, Life and Medical Sciences Institute (LIMES), Genomics & Immunoregulation

M. Oosting

Radboud University Nijmegen - Department of Internal Medicine; Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI)

Y. Li

University of Groningen - Department of Human Genetics

C. S. Benn

Statens Serums Institut - Research Center for Vitamins and Vaccines; University of Southern Denmark - Odense Patient Data Explorative Network (OPEN)

Joachim L. Schultze

University of Bonn - Life and Medical Sciences Institute (LIMES)

L. A. B. Joosten

Radboud University Nijmegen - Department of Internal Medicine; Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI)

N. Curtis

University of Melbourne - Department of Paediatrics; University of Melbourne - Murdoch Children's Research Institute

M. G. Netea

Radboud University Nijmegen - Department of Internal Medicine; Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI)

Andreas Schlitzer

University of Bonn - Department of Quantitative Systems Biology

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Abstract

Induction of trained immunity by Bacille-Calmette-Guérin (BCG) vaccination mediates beneficial heterologous effects, but the underlying mechanisms regulating the longevity and magnitude of such effects remain elusive. We show that BCG vaccination in humans induces the long-lasting activation of a transcriptional program connected to myeloid cell development and function within the hematopoietic stem and progenitor cell compartment in the bone marrow. As crucial regulators of this transcriptional shift we identify hepatic nuclear factor family members 1a and b. These findings are corroborated by higher granulocyte numbers in BCG- vaccinated infants, HNF1 SNP variants correlating with trained immunity, and elevated serum concentrations of the HNF1 target gene SERPINA1. In addition, transcriptomic HSPC remodelling was epigenetically conveyed to peripheral CD14+ monocytes, displaying an activated transcriptional signature 3 months after BCG vaccination. Taken together, transcriptomic, epigenomic and functional reprogramming of HSPCs and peripheral monocytes is pivotal in human in vivo BCG-induced trained immunity.

Suggested Citation

Cirovic, B. and de Bree, L. C. J. and Groh, L. and Blok, B. A. and Chan, J. and Velden, W.J.F.M. van der and Bremmers, M. E. J. and van Crevel, Reinout and Händler, K. and Picelli, S. and Schulte-Schrepping, J. and Klee, K. and Oosting, M. and Li, Y. and Benn, C. S. and Schultze, Joachim L. and Joosten, L. A. B. and Curtis, N. and Netea, M. G. and Schlitzer, Andreas, Human Bacille Calmette-Guérin Vaccination Elicits Trained Immunity Via the Hematopoietic Progenitor Compartment. Available at SSRN: https://ssrn.com/abstract=3376658 or http://dx.doi.org/10.2139/ssrn.3376658
This version of the paper has not been formally peer reviewed.

B. Cirovic

University of Bonn - Myeloid Cell Biology

Germany

L. C. J. De Bree

Radboud University Nijmegen - Department of Internal Medicine

Netherlands

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI)

Nijmegen
Netherlands

Statens Serums Institut - Research Center for Vitamins and Vaccines

Denmark

University of Southern Denmark - Odense Patient Data Explorative Network (OPEN)

Denmark

L. Groh

Radboud University Nijmegen - Department of Internal Medicine

Netherlands

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI)

Nijmegen
Netherlands

B. A. Blok

Radboud University Nijmegen - Department of Internal Medicine

Netherlands

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI)

Nijmegen
Netherlands

Statens Serums Institut - Research Center for Vitamins and Vaccines

Denmark

University of Southern Denmark - Odense Patient Data Explorative Network (OPEN)

Denmark

J. Chan

University of Melbourne - Department of Paediatrics

Australia

University of Melbourne - Murdoch Children's Research Institute

Parkville, Victoria
Australia

W.J.F.M. van der Velden

Radboud University Nijmegen - Department of Hematology

Netherlands

M. E. J. Bremmers

Radboud University Nijmegen - Department of Hematology

Netherlands

Reinout Van Crevel

Radboud University Medical Center - Department of Internal Medicine and Radboud Center for Infectious Diseases

Geert Grooteplein Zuid 10
Nijmegen
Netherlands

K. Händler

German Center for Neurodegenerative Diseases (DZNE) - Single Cell Genomics and Epigenomics Unit

Germany

S. Picelli

German Center for Neurodegenerative Diseases (DZNE) - Single Cell Genomics and Epigenomics Unit

Germany

J. Schulte-Schrepping

University of Bonn, Life and Medical Sciences Institute (LIMES), Genomics & Immunoregulation

Bonn
Germany

K. Klee

University of Bonn, Life and Medical Sciences Institute (LIMES), Genomics & Immunoregulation

Bonn
Germany

M. Oosting

Radboud University Nijmegen - Department of Internal Medicine

Netherlands

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI)

Nijmegen
Netherlands

Y. Li

University of Groningen - Department of Human Genetics

Hanzeplein 1, 9700 RB
Groningen
Netherlands

C. S. Benn

Statens Serums Institut - Research Center for Vitamins and Vaccines

Denmark

University of Southern Denmark - Odense Patient Data Explorative Network (OPEN)

Denmark

Joachim L. Schultze

University of Bonn - Life and Medical Sciences Institute (LIMES)

Bonn
Germany

L. A. B. Joosten

Radboud University Nijmegen - Department of Internal Medicine

Netherlands

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI)

Nijmegen
Netherlands

N. Curtis

University of Melbourne - Department of Paediatrics

Australia

University of Melbourne - Murdoch Children's Research Institute

Parkville, Victoria
Australia

M. G. Netea

Radboud University Nijmegen - Department of Internal Medicine

Netherlands

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI)

Nijmegen
Netherlands

Andreas Schlitzer (Contact Author)

University of Bonn - Department of Quantitative Systems Biology ( email )

Bonn
Germany