A single-cell view on host immune transcriptional response to in vivo BCG-induced trained immunity

Wenchao Li; Simone J C F M Moorlag; Valerie A C M Koeken; Rutger J Röring; L Charlotte J de Bree; Vera P Mourits; Manoj K Gupta; Bowen Zhang; Jianbo Fu; Zhenhua Zhang; Inge Grondman; Krista E van Meijgaarden; Liang Zhou; Ahmed Alaswad; Leo A B Joosten; Reinout van Crevel; Cheng-Jian Xu; Mihai G Netea; Yang Li

doi:10.1016/j.celrep.2023.112487

A single-cell view on host immune transcriptional response to in vivo BCG-induced trained immunity

Cell Rep. 2023 May 30;42(5):112487. doi: 10.1016/j.celrep.2023.112487. Epub 2023 May 7.

Authors

Wenchao Li¹, Simone J C F M Moorlag², Valerie A C M Koeken³, Rutger J Röring², L Charlotte J de Bree², Vera P Mourits², Manoj K Gupta¹, Bowen Zhang¹, Jianbo Fu¹, Zhenhua Zhang¹, Inge Grondman², Krista E van Meijgaarden⁴, Liang Zhou¹, Ahmed Alaswad¹, Leo A B Joosten⁵, Reinout van Crevel², Cheng-Jian Xu³, Mihai G Netea⁶, Yang Li⁷

Affiliations

¹ Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Lower Saxony, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Lower Saxony, Germany.
² Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
³ Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Lower Saxony, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Lower Saxony, Germany; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
⁴ Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands.
⁵ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
⁶ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.
⁷ Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Lower Saxony, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Lower Saxony, Germany; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. Electronic address: yang.li@helmholtz-hzi.de.

Abstract

Bacillus Calmette-Guérin (BCG) vaccination is a prototype model for the study of trained immunity (TI) in humans, and results in a more effective response of innate immune cells upon stimulation with heterologous stimuli. Here, we investigate the heterogeneity of TI induction by single-cell RNA sequencing of immune cells collected from 156 samples. We observe that both monocytes and CD8⁺ T cells show heterologous transcriptional responses to lipopolysaccharide, with an active crosstalk between these two cell types. Furthermore, the interferon-γ pathway is crucial in BCG-induced TI, and it is upregulated in functional high responders. Data-driven analyses and functional experiments reveal STAT1 to be one of the important transcription factors for TI shared in all identified monocyte subpopulations. Finally, we report the role of type I interferon-related and neutrophil-related TI transcriptional programs in patients with sepsis. These findings provide comprehensive insights into the importance of monocyte heterogeneity during TI in humans.

Keywords: BCG; CP: Immunology; IFN-γ; STAT1; in vivo training; monocyte heterogeneity; single-cell RNA-seq; trained immunity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

BCG Vaccine
CD8-Positive T-Lymphocytes
Humans
Immunity, Innate
Interferon-gamma / metabolism
Mycobacterium bovis* / metabolism
Trained Immunity

Substances

BCG Vaccine
Interferon-gamma