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

Alexandre Giraud-Gatineau (1, 2) , Juan Manuel Coya (3) , Alexandra Maure (1, 2) , Anne Biton (4) , Michael Thomson (5) , Elliott Bernard (6) , Jade Marrec (3) , Maximiliano Gutierrez (6) , Gérald Larrouy-Maumus (5) , Roland Brosch (1) , Brigitte Gicquel (3, 7) , Ludovic Tailleux (3, 1)

1 Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics
2 Cellule Pasteur UPMC
3 Génétique mycobactérienne - Mycobacterial genetics
4 Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB
5 MRC CMBI - Medical Research Council Centre for Molecular Bacteriology and Infection [Londres, Royaume-Uni]
6 Host-Pathogen Interactions in Tuberculosis Laboratory [London]
7 ShenZhenCDC - Shenzhen Nanshan Center for Chronic Disease Control [Shenzhen, China]

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.

Mots clés: innate immunity; macrophages; microbiology; tuberculosis; antibiotics; host-pathogen interaction; human; immunology; infectious disease; inflammation

Domaines: Sciences du Vivant [q-bio]; Immunologie; Immunité innée; Microbiologie et Parasitologie; Médecine humaine et pathologie; Maladies infectieuses

Alexandre Giraud-Gatineau, Juan Manuel Coya, Alexandra Maure, Anne Biton, Michael Thomson, et al.. The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection. eLife, 2020, 9, pp.e55692. ⟨10.7554/eLife.55692⟩. ⟨pasteur-02876140⟩