Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis
Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis
复制标题
DOI：
10.4161/auto.7.11.17660
复制
发表时间：
2011-11-01
期刊：
影响因子：
13.3
通讯作者：
Amer, Amal O.
中科院分区：
文献类型：
--
作者：
Abdulrahman, Basant A.;Abu Khweek, Arwa;Amer, Amal O.
囊性纤维化（CF）是白种人最常见的遗传性致死性疾病，可导致多器官功能障碍。然而，85%的死亡是由于肺部感染。结核分枝杆菌感染对CF患者是一种特别致命的威胁，因为它会引起严重和持续的肺部炎症，并且对几乎所有可用的抗生素都具有耐药性。在CFTR Delta F508 （Delta F508）小鼠巨噬细胞中，洋葱芽孢杆菌持续存在于不与溶酶体融合的空泡中，并介导IL-1 β的产生增加。据信，细胞内细菌的存活有助于细菌的持续存在。本研究首次发现，在野生型而非Delta F508巨噬细胞中，许多洋葱芽孢杆菌存在于感染后期与溶酶体融合的自噬体中。因此，CFTR-Delta F508巨噬细胞中洋葱芽孢杆菌的关联和细胞内存活率高于WT巨噬细胞。自噬体是一种吞噬无功能细胞器和部分细胞质的隔室，然后在饥饿或应激期间将它们传递给溶酶体降解以产生营养物质。此外，我们发现洋葱芽胞杆菌下调WT和Delta F508巨噬细胞的自噬基因。然而，自噬功能障碍在Delta F508巨噬细胞中更为明显，因为它们的自噬活性已经受损。我们证明了自噬刺激剂雷帕霉素通过诱导自噬增强对洋葱芽孢杆菌的清除，从而在体外显著降低洋葱芽孢杆菌感染。在体内，雷帕霉素可以减少CF小鼠肺部的细菌负荷，并显著减少肺部炎症的迹象。总之，我们的研究表明，如果有效激活，自噬可以控制洋葱芽胞杆菌感染并改善相关炎症。因此，自噬是CF患者控制洋葱芽胞杆菌感染及伴随炎症的新药开发的新靶点。
Cystic fibrosis (CF) is the most common inherited lethal disease in Caucasians which results in multiorgan 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 Delta F508 (Delta F508) mouse macrophages, B. cepacia persists in vacuoles that do not fuse with the lysosomes and mediates increased production of IL-1 beta. 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 but not in Delta F508 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-Delta F508 macrophages than in WT macrophages. An autophagosome is a compartment that engulfs nonfunctional 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 Delta F508 macrophages. However, autophagy dysfunction is more pronounced in Delta F508 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.