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
Affiliations
Lingjia Kong
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
Simone J.C.F.M. Moorlag
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
Ariel Lefkovith
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Bihua Li
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
Vasiliki Matzaraki
Department of Internal Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands
Liesbeth van Emst
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
Heather A. Kang
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Isabel Latorre
Center for Computational and Integrative Biology and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Martin Jaeger
Department of Internal Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands
Leo A.B. Joosten
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
Mihai G. Netea
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; Corresponding author
Ramnik J. Xavier
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; Corresponding author
Summary: 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.
