Multi-omics analysis of innate and adaptive responses to BCG vaccination reveals epigenetic cell states that predict trained immunity

Simone J C F M Moorlag; Lukas Folkman; Rob Ter Horst; Thomas Krausgruber; Daniele Barreca; Linda C Schuster; Victoria Fife; Vasiliki Matzaraki; Wenchao Li; Stephan Reichl; Vera P Mourits; Valerie A C M Koeken; L Charlotte J de Bree; Helga Dijkstra; Heidi Lemmers; Bram van Cranenbroek; Esther van Rijssen; Hans J P M Koenen; Irma Joosten; Cheng-Jian Xu; Yang Li; Leo A B Joosten; Reinout van Crevel; Mihai G Netea; Christoph Bock

doi:10.1016/j.immuni.2023.12.005

Multi-omics analysis of innate and adaptive responses to BCG vaccination reveals epigenetic cell states that predict trained immunity

Immunity. 2024 Jan 9;57(1):171-187.e14. doi: 10.1016/j.immuni.2023.12.005.

Authors

Simone J C F M Moorlag¹, Lukas Folkman², Rob Ter Horst³, Thomas Krausgruber², Daniele Barreca³, Linda C Schuster³, Victoria Fife³, Vasiliki Matzaraki¹, Wenchao Li⁴, Stephan Reichl², Vera P Mourits¹, Valerie A C M Koeken¹, L Charlotte J de Bree⁵, Helga Dijkstra¹, Heidi Lemmers¹, Bram van Cranenbroek⁶, Esther van Rijssen⁶, Hans J P M Koenen⁶, Irma Joosten⁶, Cheng-Jian Xu⁷, Yang Li⁷, Leo A B Joosten⁸, Reinout van Crevel¹, Mihai G Netea⁹, Christoph Bock¹⁰

Affiliations

¹ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
² CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Medical University of Vienna, Institute of Artificial Intelligence, Center for Medical Data Science, Vienna, Austria.
³ CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
⁴ Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
⁵ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Bandim Health Project, OPEN, Institute of Clinical Research, University of Southern Denmark, Odense University Hospital, Odense, Denmark; Danish Institute for Advanced Study, University of Southern Denmark, Odense, Denmark.
⁶ Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, the Netherlands.
⁷ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
⁸ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
⁹ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department for Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. Electronic address: mihai.netea@radboudumc.nl.
¹⁰ CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Medical University of Vienna, Institute of Artificial Intelligence, Center for Medical Data Science, Vienna, Austria. Electronic address: cbock@cemm.oeaw.ac.at.

PMID: 38198850
DOI: 10.1016/j.immuni.2023.12.005

Abstract

Immune responses are tightly regulated yet highly variable between individuals. To investigate human population variation of trained immunity, we immunized healthy individuals with Bacillus Calmette-Guérin (BCG). This live-attenuated vaccine induces not only an adaptive immune response against tuberculosis but also triggers innate immune activation and memory that are indicative of trained immunity. We established personal immune profiles and chromatin accessibility maps over a 90-day time course of BCG vaccination in 323 individuals. Our analysis uncovered genetic and epigenetic predictors of baseline immunity and immune response. BCG vaccination enhanced the innate immune response specifically in individuals with a dormant immune state at baseline, rather than providing a general boost of innate immunity. This study advances our understanding of BCG's heterologous immune-stimulatory effects and trained immunity in humans. Furthermore, it highlights the value of epigenetic cell states for connecting immune function with genotype and the environment.

Keywords: BCG vaccination; bioinformatics; chromatin profiling; computational epigenomics; epigenetic cell states; genomics; systems immunology; trained immunity.

MeSH terms

BCG Vaccine*
Epigenesis, Genetic
Humans
Multiomics
Trained Immunity*
Vaccination

Substances

BCG Vaccine