Pseudomonas toxin pyocyanin triggers autophagy: Implications for pathoadaptive mutations
Pseudomonas toxin pyocyanin triggers autophagy: Implications for pathoadaptive mutations
复制标题
假单胞菌毒素绿脓素触发自噬：对病理适应性突变的影响
DOI：
10.1080/15548627.2016.1170256
复制
发表时间：
2016-01-01
期刊：
影响因子：
13.3
通讯作者：
Zou, Cheng-Gang
中科院分区：
文献类型：
--
作者：
Yang, Zhong-Shan;Ma, Lan-Qing;Zou, Cheng-Gang
摘要铜绿假单胞菌可通过产生基因功能丧失突变，增强细菌在气道中的适应性，从而在囊性纤维化患者中建立终身慢性感染。然而，病理适应性突变在慢性气道感染中持续存在的确切作用在很大程度上仍然未知。在这里，我们证明，绿脓菌素，一个众所周知的铜绿假单胞菌毒力因子，在初始感染中起着重要作用，促进支气管上皮细胞的自噬。破坏绿脓菌素生物合成所需的phzM，导致Beas-2B细胞和肺组织中自噬的显著减少。绿脓菌素诱导的自噬由EIF 2AK 4/GCN 2-EIF 2S 1/eIF 2 α-ATF 4途径介导。有趣的是，在慢性铜绿假单胞菌感染期间，与感染野生型（WT）铜绿假单胞菌PA 14菌株的大鼠相比，感染phzMΔ突变菌株的大鼠具有较高的死亡率和菌落形成单位数。此外，在大鼠的肺气道中，phzMΔ突变株比WT株诱导更广泛的肺泡壁增厚。由于自噬在抑制细菌负荷方面起着至关重要的作用，我们的研究结果提供了一个详细的了解，为什么在慢性气道感染中铜绿假单胞菌中绿脓菌素产生的减少与更好的宿主适应和更差的囊性纤维化结果有关。
ABSTRACT Pseudomonas aeruginosa can establish life-long chronic infection in patients with cystic fibrosis by generating genetic loss-of-function mutations, which enhance fitness of the bacterium in the airways. However, the precise role of the pathoadaptive mutations in persistence in chronic airways infection remains largely unknown. Here we demonstrate that pyocyanin, a well-described P. aeruginosa virulence factor that plays an important role in the initial infection, promotes autophagy in bronchial epithelial cells. Disruption of phzM, which is required for pyocyanin biosynthesis, leads to a significant reduction in autophagy in Beas-2B cells and lung tissues. Pyocyanin-induced autophagy is mediated by the EIF2AK4/GCN2-EIF2S1/eIF2α-ATF4 pathway. Interestingly, rats infected with the phzMΔ mutant strain have high mortality rate and numbers of colony-forming units, compared to those infected with wild-type (WT) P. aeruginosa PA14 strain, during chronic P. aeruginosa infection. In addition, the phzMΔ mutant strain induces more extensive alveolar wall thickening than the WT strain in the pulmonary airways of rats. As autophagy plays an essential role in suppressing bacterial burden, our findings provide a detailed understanding of why reduction of pyocyanin production in P. aeruginosa in chronic airways infections has been associated with better host adaptation and worse outcomes in cystic fibrosis.