The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection
Antibiotics are widely used in the treatment of bacterial infections. Although known for their microbicidal activity, antibiotics may also interfere with the host’s immune system. Here, we analyzed the effects of bedaquiline (BDQ), an inhibitor of the mycobacterial ATP synthase, on human macrophages...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/55692 |
| _version_ | 1811228058813726720 |
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| author | Alexandre Giraud-Gatineau Juan Manuel Coya Alexandra Maure Anne Biton Michael Thomson Elliott M Bernard Jade Marrec Maximiliano G Gutierrez Gérald Larrouy-Maumus Roland Brosch Brigitte Gicquel Ludovic Tailleux |
| author_facet | Alexandre Giraud-Gatineau Juan Manuel Coya Alexandra Maure Anne Biton Michael Thomson Elliott M Bernard Jade Marrec Maximiliano G Gutierrez Gérald Larrouy-Maumus Roland Brosch Brigitte Gicquel Ludovic Tailleux |
| author_sort | Alexandre Giraud-Gatineau |
| collection | DOAJ |
| description | Antibiotics are widely used in the treatment of bacterial infections. Although known for their microbicidal activity, antibiotics may also interfere with the host’s immune system. Here, we analyzed the effects of bedaquiline (BDQ), an inhibitor of the mycobacterial ATP synthase, on human macrophages. Genome-wide gene expression analysis revealed that BDQ reprogramed cells into potent bactericidal phagocytes. We found that 579 and 1,495 genes were respectively differentially expressed in naive- and M. tuberculosis-infected macrophages incubated with the drug, with an over-representation of lysosome-associated genes. BDQ treatment triggered a variety of antimicrobial defense mechanisms, including phagosome-lysosome fusion, and autophagy. These effects were associated with activation of transcription factor EB, involved in the transcription of lysosomal genes, resulting in enhanced intracellular killing of different bacterial species that were naturally insensitive to BDQ. Thus, BDQ could be used as a host-directed therapy against a wide range of bacterial infections. |
| first_indexed | 2024-04-12T09:52:08Z |
| format | Article |
| id | doaj.art-7742feb680244fcab351790b1c46fbe8 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:52:08Z |
| publishDate | 2020-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7742feb680244fcab351790b1c46fbe82022-12-22T03:37:48ZengeLife Sciences Publications LtdeLife2050-084X2020-05-01910.7554/eLife.55692The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infectionAlexandre Giraud-Gatineau0Juan Manuel Coya1Alexandra Maure2Anne Biton3Michael Thomson4Elliott M Bernard5Jade Marrec6Maximiliano G Gutierrez7https://orcid.org/0000-0003-3199-0337Gérald Larrouy-Maumus8Roland Brosch9Brigitte Gicquel10Ludovic Tailleux11https://orcid.org/0000-0003-3931-1052Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Institut Pasteur, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, FranceMycobacterial Genetics Unit, Institut Pasteur, Paris, FranceUnit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Institut Pasteur, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, FranceBioinformatics and Biostatistics, Department of Computational Biology, USR 3756 CNRS, Institut Pasteur, Paris, FranceMRC Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London, United KingdomHost-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United KingdomMycobacterial Genetics Unit, Institut Pasteur, Paris, FranceHost-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United KingdomMRC Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London, United KingdomUnit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Institut Pasteur, Paris, FranceMycobacterial Genetics Unit, Institut Pasteur, Paris, France; Department of Tuberculosis Control and Prevention, Shenzhen Nanshan Center for Chronic Disease Control, Shenzhen, ChinaUnit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Institut Pasteur, Paris, France; Mycobacterial Genetics Unit, Institut Pasteur, Paris, FranceAntibiotics are widely used in the treatment of bacterial infections. Although known for their microbicidal activity, antibiotics may also interfere with the host’s immune system. Here, we analyzed the effects of bedaquiline (BDQ), an inhibitor of the mycobacterial ATP synthase, on human macrophages. Genome-wide gene expression analysis revealed that BDQ reprogramed cells into potent bactericidal phagocytes. We found that 579 and 1,495 genes were respectively differentially expressed in naive- and M. tuberculosis-infected macrophages incubated with the drug, with an over-representation of lysosome-associated genes. BDQ treatment triggered a variety of antimicrobial defense mechanisms, including phagosome-lysosome fusion, and autophagy. These effects were associated with activation of transcription factor EB, involved in the transcription of lysosomal genes, resulting in enhanced intracellular killing of different bacterial species that were naturally insensitive to BDQ. Thus, BDQ could be used as a host-directed therapy against a wide range of bacterial infections.https://elifesciences.org/articles/55692host-pathogen interactioninnate immunitymacrophagestuberculosisantibiotics |
| spellingShingle | Alexandre Giraud-Gatineau Juan Manuel Coya Alexandra Maure Anne Biton Michael Thomson Elliott M Bernard Jade Marrec Maximiliano G Gutierrez Gérald Larrouy-Maumus Roland Brosch Brigitte Gicquel Ludovic Tailleux The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection eLife host-pathogen interaction innate immunity macrophages tuberculosis antibiotics |
| title | The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection |
| title_full | The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection |
| title_fullStr | The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection |
| title_full_unstemmed | The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection |
| title_short | The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection |
| title_sort | antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection |
| topic | host-pathogen interaction innate immunity macrophages tuberculosis antibiotics |
| url | https://elifesciences.org/articles/55692 |
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