The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection
The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection
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DOI：
10.7554/elife.55692
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发表时间：
2020-05-04
期刊：
影响因子：
7.7
通讯作者：
Tailleux, Ludovic
中科院分区：
文献类型：
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作者：
Giraud-Gatineau, Alexandre;Coya, Juan Manuel;Tailleux, Ludovic
抗生素广泛用于治疗细菌感染。尽管抗生素以其杀微生物活性而闻名，但它也可能干扰宿主的免疫系统。在这里，我们分析了结核分枝杆菌ATP合成酶抑制剂贝达喹啉（BDQ）对人巨噬细胞的影响。全基因组基因表达分析显示，BDQ将细胞重编程为有效的杀菌吞噬细胞。我们发现，579和1,495基因分别在幼稚和M。结核感染的巨噬细胞与药物一起孵育，溶酶体相关基因过度表达。BDQ处理触发了多种抗菌防御机制，包括吞噬体-溶酶体融合和自噬。这些效应与转录因子EB的激活有关，参与溶酶体基因的转录，导致对天然对BDQ不敏感的不同细菌物种的细胞内杀伤增强。因此，BDQ可用作针对广泛的细菌感染的宿主导向疗法。
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.