1 Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, and.
2 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, University of Dublin, Dublin, Ireland; and.
Am J Respir Cell Mol Biol. 2018 Nov;59(5):548-556. doi: 10.1165/rcmb.2017-0382OC.
Vitamin A deficiency strongly predicts the risk of developing tuberculosis (TB) in individuals exposed to Mycobacterium tuberculosis (Mtb). The burden of antibiotic-resistant TB is increasing globally; therefore, there is an urgent need to develop host-directed adjunctive therapies to treat TB. Alveolar macrophages, the niche cell for Mtb, metabolize vitamin A to all-trans retinoic acid (atRA), which influences host immune responses. We sought to determine the mechanistic effects of atRA on the host immune response to intracellular bacterial infection in primary human and murine macrophages. In this study, atRA promoted autophagy resulting in a reduced bacterial burden in human macrophages infected with Mtb and Bordetella pertussis, but not bacillus Calmette-Guérin (BCG). Autophagy is induced by cytosolic sensing of double-stranded DNA via the STING/TBK1/IRF3 axis; however, BCG is known to evade cytosolic DNA sensors. atRA enhanced colocalization of Mtb, but not BCG, with autophagic vesicles and acidified lysosomes. This enhancement was inhibited by blocking TBK1. Our data indicate that atRA augments the autophagy of intracellular bacteria that trigger cytosolic DNA-sensing pathways but does not affect bacteria that evade these sensors. The finding that BCG evades the beneficial effects of atRA has implications for vaccine design and global health nutritional supplementation strategies. The ability of atRA to promote autophagy and aid bacterial clearance of Mtb and B. pertussis highlights a potential role for atRA as a host-directed adjunctive therapy.
维生素 A 缺乏强烈预测了暴露于结核分枝杆菌（Mtb）的个体发生结核病（TB）的风险。全球范围内抗生素耐药性结核病的负担正在增加；因此，迫切需要开发针对宿主的辅助治疗方法来治疗结核病。肺泡巨噬细胞是 Mtb 的生态位细胞，可将维生素 A 代谢为全反式视黄酸（atRA），这会影响宿主的免疫反应。我们试图确定 atRA 对原发性人源和鼠源巨噬细胞中细胞内细菌感染的宿主免疫反应的机制影响。在这项研究中，atRA 促进了自噬，从而减少了感染 Mtb 和百日咳博德特氏菌但不感染卡介苗（BCG）的人巨噬细胞中的细菌负担。自噬是通过 STING/TBK1/IRF3 轴感应细胞质中的双链 DNA 而诱导的；然而，BCG 已知可逃避细胞质 DNA 传感器。atRA 增强了 Mtb 与自噬小泡和酸化溶酶体的共定位，但不增强 BCG。这种增强作用可通过阻断 TBK1 来抑制。我们的数据表明，atRA 增强了触发细胞质 DNA 感应途径的细胞内细菌的自噬，但不影响逃避这些传感器的细菌。BCG 逃避 atRA 的有益作用的发现对疫苗设计和全球健康营养补充策略具有重要意义。atRA 促进自噬并有助于清除 Mtb 和 B. pertussis 的能力突出了 atRA 作为针对宿主的辅助治疗方法的潜在作用。
