The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection

Autor: Alexandre Giraud-Gatineau, Brigitte Gicquel, Juan Manuel Coya, Roland Brosch, Gerald Larrouy-Maumus, Elliott M. Bernard, Alexandra Maure, Anne Biton, Michael Thomson, Jade Marrec, Ludovic Tailleux, Maximiliano G. Gutierrez
Přispěvatelé: Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Cellule Pasteur UPMC, Institut Pasteur [Paris] (IP)-Sorbonne Université (SU), Génétique mycobactérienne - Mycobacterial genetics, Institut Pasteur [Paris] (IP), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Medical Research Council Centre for Molecular Bacteriology and Infection [Londres, Royaume-Uni] (MRC CMBI), Imperial College London, Host-Pathogen Interactions in Tuberculosis Laboratory [London], The Francis Crick Institute [London], Shenzhen Nanshan Center for Chronic Disease Control [Shenzhen, China] (ShenZhenCDC), European Commission (604237) (Brigitte Gicquel), Institut Pasteur (Roland Brosch, Brigitte Gicquel, Ludovic Tailleux), Francis Crick Institute (Maximiliano G Gutierrez), Cancer Research UK (FC001092) (Maximiliano G Gutierrez), Medical Research Council (FC001092) (Maximiliano G Gutierrez), Wellcome (FC001092) (Maximiliano G Gutierrez), Engineering and Physical Sciences Research Council (EP/M027007/1) (Gérald Larrouy-Maumus), Fondation pour la Recherche Médicale (FDM201806006250) (Alexandra Maure), Agence Nationale de la Recherche (ANR-10-LABX-62-IBEID) (Roland Brosch), We thank Olivier Neyrolles and Howard E Takiff for reading the manuscript and helpful discussion. We gratefully acknowledge the UTechS Cytometry and Biomarkers and the UTechS Photonic BioImaging (Imagopole) Citech of Institut Pasteur (Paris, France) as well as the France–BioImaging infrastructure network supported by the French National Research Agency (ANR-10–INSB–04, Investments for the Future) for support in conducting this study, in particular PH. Commere for help with flow cytometry. We also thank Charles Privé (CHU Sainte-Justine Integrated Centre for Pediatric Clinical Genomics, Montreal, Canada) and Mickael Orgeur (Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur) for their technical support., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 604237,EC:FP7:NMP,FP7-NMP-2013-LARGE-7,NAREB(2014), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Sorbonne Université (SU), Institut Pasteur [Paris]
Jazyk: angličtina
Rok vydání: 2020
Předmět:
[SDV]Life Sciences [q-bio]
Antibiotics
host-pathogen interaction
0601 Biochemistry and Cell Biology
[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity
antibiotics
immunology
chemistry.chemical_compound
0302 clinical medicine
Immunology and Inflammation
[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Biology (General)
Diarylquinolines
innate immunity
0303 health sciences
Microbiology and Infectious Disease
Phagocytes
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
General Neuroscience
General Medicine
3. Good health
Anti-Bacterial Agents
macrophages
[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology
tuberculosis
Host-Pathogen Interactions
Medicine
[SDV.IMM]Life Sciences [q-bio]/Immunology
Research Article
Modern medicine
Tuberculosis
QH301-705.5
medicine.drug_class
Science
Host–pathogen interaction
infectious disease
Biology
General Biochemistry
Genetics and Molecular Biology
Microbiology
03 medical and health sciences
Immune system
Immunity
medicine
Autophagy
Humans
Calcium Signaling
human
030304 developmental biology
Innate immune system
General Immunology and Microbiology
microbiology
Mycobacterium tuberculosis
Macrophage Activation
medicine.disease
Immunity
Innate
HEK293 Cells
chemistry
inflammation
Other
Bedaquiline
Lysosomes
030217 neurology & neurosurgery
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Zdroj: eLife
eLife, 2020, 9, pp.e55692. ⟨10.7554/eLife.55692⟩
eLife, eLife Sciences Publication, 2020, 9, pp.e55692. ⟨10.7554/eLife.55692⟩
eLife, Vol 9 (2020)
ISSN: 2050-084X
DOI: 10.7554/eLife.55692⟩
Popis: 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.
eLife digest The discovery of antibiotic drugs, which treat diseases caused by bacteria, has been a hugely valuable advance in modern medicine. They work by targeting specific cellular processes in bacteria, ultimately stopping them from multiplying or killing them outright. Antibiotics sometimes also affect their human hosts and can cause side-effects, such as gut problems or skin reactions. Recent evidence suggests that antibiotics also have an impact on the human immune system. This may happen either indirectly, by affecting ‘friendly’ bacteria normally present in the body, or through direct effects on immune cells. In turn, this could change the effectiveness of drug treatments. For example, if an antibiotic weakens immune cells, the body could have difficulty fighting off the existing infection – or become more vulnerable to new ones. However, even though new drugs are being introduced to combat the worldwide rise of antibiotic-resistant bacteria, their effects on immunity are still not well understood. For example, bedaquiline is an antibiotic recently developed to treat tuberculosis infections that are resistant to several drugs. Giraud-Gatineau et al. wanted to determine if bedaquiline altered the human immune response to bacterial infection independently from its direct anti-microbial effects. Macrophages engulf foreign particles like bacteria and break them down using enzymes stored within small internal compartments, or ‘lysosomes’. Initial experiments using human macrophages, grown both with and without bedaquiline, showed that the drug did not harm the cells and that they grew normally. A combination of microscope imaging and genetic analysis revealed that exposure to bedaquiline not only increased the number of lysosomes within macrophage cells, but also the activity of genes and proteins that increase lysosomes’ ability to break down foreign particles. These results suggested that bedaquiline treatment might make macrophages better at fighting infection, even if the drug itself had no direct effect on bacterial cells. Further studies, where macrophages were first treated with bedaquiline and then exposed to different types of bacteria known to be resistant to the drug, confirmed this hypothesis: in every case, the treated macrophages became efficient bacterial killers. In contrast, older anti-tuberculosis drugs did not have any such potentiating effect on the macrophages. This work sheds new light on our how antibiotic drugs can interact with the cells of the human immune system, and can sometimes even boost our innate defences. Such immune-boosting effects could one day be exploited to make more effective treatments against bacterial infections.
Databáze: OpenAIRE
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