Single-cell transcriptomic profiles reveal changes associated with BCG-induced trained immunity and protective effects in circulating monocytes

Lingjia Kong; Simone J C F M Moorlag; Ariel Lefkovith; Bihua Li; Vasiliki Matzaraki; Liesbeth van Emst; Heather A Kang; Isabel Latorre; Martin Jaeger; Leo A B Joosten; Mihai G Netea; Ramnik J Xavier

doi:10.1016/j.celrep.2021.110028

Single-cell transcriptomic profiles reveal changes associated with BCG-induced trained immunity and protective effects in circulating monocytes

Cell Rep. 2021 Nov 16;37(7):110028. doi: 10.1016/j.celrep.2021.110028.

Authors

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
² Department of Internal Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Department of Internal Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
⁵ Center for Computational and Integrative Biology and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁶ Department of Internal Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Medical Genetics, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca 400000, Romania.
⁷ Department of Internal Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department for Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany. Electronic address: mihai.netea@radboudumc.nl.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: xavier@molbio.mgh.harvard.edu.

Abstract

Bacillus Calmette-Guérin (BCG) vaccine is one of the most widely used vaccines worldwide. In addition to protection against tuberculosis, BCG confers a degree of non-specific protection against other infections by enhancing secondary immune responses to heterologous pathogens, termed "trained immunity." To better understand BCG-induced immune reprogramming, we perform single-cell transcriptomic measurements before and after BCG vaccination using secondary immune stimulation with bacterial lipopolysaccharide (LPS). We find that BCG reduces systemic inflammation and identify 75 genes with altered LPS responses, including inflammatory mediators such as CCL3 and CCL4 that have a heightened response. Co-expression analysis reveals that gene modules containing these cytokines lose coordination after BCG. Other modules exhibit increased coordination, including several humanin nuclear isoforms that we confirm induce trained immunity in vitro. Our results link in vivo BCG administration to single-cell transcriptomic changes, validated in human genetics experiments, and highlight genes that are putatively responsible for non-specific protective effects of BCG.

Keywords: BCG vaccination; cytokines; humanin; monocytes; non-specific effects of vaccines; single-cell sequencing; trained immunity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
BCG Vaccine / genetics*
BCG Vaccine / immunology
Cytokines / immunology
Female
Gene Expression / genetics
Gene Expression Profiling / methods
Gene Expression Regulation / genetics
Healthy Volunteers
Humans
Immunity / genetics
Immunity, Innate / drug effects
Immunologic Memory / immunology
Inflammation
Inflammation Mediators / pharmacology
Male
Monocytes / immunology*
Monocytes / physiology
Transcriptome / genetics*
Vaccination

Substances

BCG Vaccine
Cytokines
Inflammation Mediators

Abstract

Publication types

MeSH terms

Substances

Grants and funding