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PLoS Pathog. 2014 Oct 30;10(10):e1004485. doi: 10.1371/journal.ppat.1004485. eCollection 2014 Oct.

Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer.

Author information

1
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
2
The Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America; Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
3
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
4
Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
5
Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.
6
Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, The Netherlands.
7
Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, The Netherlands; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
8
Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands; Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, The Netherlands.
9
Department of Medicine, University of Crete, Heraklion, Crete, Greece.

Abstract

The anti-tuberculosis-vaccine Bacillus Calmette-Guérin (BCG) is the most widely used vaccine in the world. In addition to its effects against tuberculosis, BCG vaccination also induces non-specific beneficial effects against certain forms of malignancy and against infections with unrelated pathogens. It has been recently proposed that the non-specific effects of BCG are mediated through epigenetic reprogramming of monocytes, a process called trained immunity. In the present study we demonstrate that autophagy contributes to trained immunity induced by BCG. Pharmacologic inhibition of autophagy blocked trained immunity induced in vitro by stimuli such as β-glucans or BCG. Single nucleotide polymorphisms (SNPs) in the autophagy genes ATG2B (rs3759601) and ATG5 (rs2245214) influenced both the in vitro and in vivo training effect of BCG upon restimulation with unrelated bacterial or fungal stimuli. Furthermore, pharmacologic or genetic inhibition of autophagy blocked epigenetic reprogramming of monocytes at the level of H3K4 trimethylation. Finally, we demonstrate that rs3759601 in ATG2B correlates with progression and recurrence of bladder cancer after BCG intravesical instillation therapy. These findings identify a key role of autophagy for the nonspecific protective effects of BCG.

PMID:
25356988
PMCID:
PMC4214925
DOI:
10.1371/journal.ppat.1004485
[Indexed for MEDLINE]
Free PMC Article

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