Center for Microbial Interface Biology, Department of Microbial Infection, Ohio State University, Columbus, OH, USA.
Autophagy. 2011 Nov;7(11):1359-70. doi: 10.4161/auto.7.11.17660. Epub 2011 Nov 1.
Cystic fibrosis (CF) is the most common inherited lethal disease of Caucasians which results in multi organ dysfunction. However, 85% of the deaths are due to pulmonary infections. Infection by Burkholderia cenocepacia (B. cepacia) is a particularly lethal threat to CF patients because it causes severe and persistent lung inflammation and is resistant to nearly all available antibiotics. In CFTR ΔF508 mouse macrophages, B. cepacia persists in vacuoles that do not fuse with the lysosomes and mediates increased production of IL-1β. It is believed that intracellular bacterial survival contributes to the persistence of the bacterium. Here we show for the first time that in wild-type macrophages but not in ΔF508 macrophages, many B. cepacia reside in autophagosomes that fuse with lysosomes at later stages of infection. Accordingly, association and intracellular survival of B. cepacia are higher in CFTR-ΔF508 (ΔF508) macrophages than in WT macrophages. An autophagosome is a compartment that engulfs non-functional organelles and parts of the cytoplasm then delivers them to the lysosome for degradation to produce nutrients during periods of starvation or stress. Furthermore, we show that B. cepacia downregulates autophagy genes in WT and ΔF508 macrophages. However, autophagy dysfunction is more pronounced in ΔF508 macrophages since they already have compromised autophagy activity. We demonstrate that the autophagy-stimulating agent, rapamycin markedly decreases B. cepacia infection in vitro by enhancing the clearance of B. cepacia via induced autophagy. In vivo, Rapamycin decreases bacterial burden in the lungs of CF mice and drastically reduces signs of lung inflammation. Together, our studies reveal that if efficiently activated, autophagy can control B. cepacia infection and ameliorate the associated inflammation. Therefore, autophagy is a novel target for new drug development for CF patients to control B. cepacia infection and accompanying inflammation.
囊性纤维化（CF）是白种人最常见的遗传性致命疾病，可导致多器官功能障碍。然而，85%的死亡是由于肺部感染。伯克霍尔德菌（B. cepacia）的感染对 CF 患者是一个特别致命的威胁，因为它会导致严重和持续的肺部炎症，并且几乎对所有可用的抗生素都有耐药性。在 CFTR ΔF508 小鼠巨噬细胞中，B. cepacia 存在于不与溶酶体融合的空泡中，并介导 IL-1β 的产生增加。人们认为，细胞内细菌的存活有助于细菌的持续存在。在这里，我们首次表明，在野生型巨噬细胞中，但不在 CFTR ΔF508 巨噬细胞中，许多 B. cepacia 存在于自噬体中，这些自噬体在感染后期与溶酶体融合。因此，CFTR-ΔF508（ΔF508）巨噬细胞中 B. cepacia 的关联和细胞内存活高于 WT 巨噬细胞。自噬体是一种吞噬无功能细胞器和细胞质部分的隔室，然后将它们递送到溶酶体进行降解，以在饥饿或应激期间产生营养物质。此外，我们还表明，B. cepacia 下调 WT 和 ΔF508 巨噬细胞中的自噬基因。然而，自噬功能障碍在 ΔF508 巨噬细胞中更为明显，因为它们已经存在自噬功能受损。我们证明，自噬刺激剂雷帕霉素通过诱导自噬增强 B. cepacia 的清除，显著降低体外 B. cepacia 的感染。在体内，雷帕霉素降低 CF 小鼠肺部的细菌负荷，并大大减少肺部炎症的迹象。总之，我们的研究表明，如果能有效地激活，自噬可以控制 B. cepacia 的感染，并改善相关的炎症。因此，自噬是为 CF 患者开发新药物控制 B. cepacia 感染和伴随炎症的新靶点。
