Alaridah Nader, Lutay Nataliya, Tenland Erik, Rönnholm Anna, Hallgren Oskar, Puthia Manoj, Westergren-Thorsson Gunilla, Godaly Gabriela
Division of Laboratory Medicine, Department of MIG, Lund University, Lund, Sweden.
J Innate Immun. 2017;9(3):318-329. doi: 10.1159/000453454. Epub 2016 Dec 24.
Mycobacterium bovis bacille Calmette-Guérin (BCG) is currently the only approved vaccine against tuberculosis (TB). BCG mimics M. tuberculosis (Mtb) in its persistence in the body and is used as a benchmark to compare new vaccine candidates. BCG was originally designed for mucosal vaccination, but comprehensive knowledge about its interaction with epithelium is currently lacking. We used primary airway epithelial cells (AECs) and a murine model to investigate the initial events of mucosal BCG interactions. Furthermore, we analysed the impact of the G-protein-coupled receptors (GPCRs), CXCR1 and CXCR2, in this process, as these receptors were previously shown to be important during TB infection. BCG infection of AECs induced GPCR-dependent Rac1 up-regulation, resulting in actin redistribution. The altered distribution of the actin cytoskeleton involved the MAPK signalling pathway. Blocking of the CXCR1 or CXCR2 prior to infection decreased Rac1 expression, and increased epithelial transcriptional activity and epithelial cytokine production. BCG infection did not result in epithelial cell death as measured by p53 phosphorylation and annexin. This study demonstrated that BCG infection of AECs manipulated the GPCRs to suppress epithelial signalling pathways. Future vaccine strategies could thus be improved by targeting GPCRs.
牛分枝杆菌卡介苗（BCG）是目前唯一被批准用于预防结核病（TB）的疫苗。BCG在体内的持久性与结核分枝杆菌（Mtb）相似，被用作比较新候选疫苗的基准。BCG最初设计用于黏膜疫苗接种，但目前缺乏关于其与上皮细胞相互作用的全面知识。我们使用原代气道上皮细胞（AECs）和小鼠模型来研究黏膜BCG相互作用的初始事件。此外，我们分析了G蛋白偶联受体（GPCRs）CXCR1和CXCR2在此过程中的影响，因为这些受体先前已被证明在结核感染期间很重要。AECs感染BCG会诱导GPCR依赖的Rac1上调，导致肌动蛋白重新分布。肌动蛋白细胞骨架分布的改变涉及MAPK信号通路。感染前阻断CXCR1或CXCR2会降低Rac1表达，并增加上皮转录活性和上皮细胞因子产生。通过p53磷酸化和膜联蛋白检测发现，BCG感染并未导致上皮细胞死亡。这项研究表明，AECs感染BCG会操纵GPCRs来抑制上皮信号通路。因此，未来的疫苗策略可以通过靶向GPCRs来改进。
