Pseudomonas aeruginosa infection liberates transmissible, cytotoxic prion amyloids
Pseudomonas aeruginosa infection liberates transmissible, cytotoxic prion amyloids
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DOI：
10.1096/fj.201601042rr
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发表时间：
2017-07-01
期刊：
影响因子：
4.8
通讯作者：
Stevens, Troy
中科院分区：
文献类型：
--
作者：
Balczon, Ron;Morrow, K. Adam;Stevens, Troy
从肺炎中康复的患者出院后由于继发性器官损伤的死亡率升高，但其原因尚不清楚。我们使用铜绿假单胞菌（医院获得性肺炎的常见原因）作为研究这种现象的模型。我们发现，铜绿假单胞菌感染肺内皮细胞会诱导产生和释放具有朊病毒特征的细胞毒性淀粉样蛋白分子，包括对各种核酸酶和蛋白酶的抗性。这种细胞毒素是自我繁殖的，被抗淀粉样蛋白抗体中和，并诱导内皮细胞和神经元死亡。此外，细胞毒素引起离体肺水肿。通过刺激与朊病毒蛋白相关的信号转导途径，保护内皮细胞和分离的肺免受细胞毒素诱导的死亡。对从铜绿假单胞菌肺炎患者身上收集的支气管肺泡灌洗液进行的分析显示出细胞毒性活性，灌洗液中含有淀粉样蛋白分子，包括寡聚-r 和 AI3。假单胞菌感染后长效细胞毒剂的证明可能与肺炎康复后几个月内终末器官损伤导致的高死亡率建立分子联系，而与朊病毒蛋白相关的信号转导途径的调节可能提供一种干预机制。
Patients who recover from pneumonia subsequently have elevated rates of death after hospital discharge as a result of secondary organ damage, the causes of which are unknown. We used the bacterium Pseudomonas aeruginosa, a common cause of hospital-acquired pneumonia, as a model for investigating this phenomenon. We show that infection of pulmonary endothelial cells by P. aeruginosa induces production and release of a cytotoxic amyloid molecule with prion characteristics, including resistance to various nucleases and proteases. This cytotoxin was self-propagating, was neutralized by anti-amyloid Abs, and induced death of endothelial cells and neurons. Moreover, the cytotoxin induced edema in isolated lungs. Endothelial cells and isolated lungs were protected from cytotoxin-induced death by stimulation of signal transduction pathways that are linked to prion protein. Analysis of bronchoalveolar lavage fluid collected from human patients with P. aeruginosa pneumonia demonstrated cytotoxic activity, and lavage fluid contained amyloid molecules, including oligomeric-r and AI3. Demonstration of long-lived cytotoxic agents after Pseudomonas infection may establish a molecular link to the high rates of death as a result of end-organ damage in the months after recovery from pneumonia, and modulation of signal transduction pathways that have been linked to prion protein may provide a mechanism for intervention.