Identification of Bacterial Genes that Disrupt Host Proteostasis

蛋白质构象疾病(PCD)的特征是神经元或肌肉的进行性丧失。 由于蛋白质错误折叠和聚集而起作用，这是阿尔茨海默氏症等疾病的共同特征， 帕金森氏症、亨廷顿氏症或卢·格里克病。影响PCDS的确切因素尚不清楚。近期 有证据表明，细菌可能与这些神经退行性疾病的发病机制有关。至 为了更好地了解细菌对蛋白质稳态的影响，我们正在研究 秀丽线虫肠道细菌定植对肠道和其他组织蛋白质聚集的影响。 在对52种最常见的人类致病共生菌的筛查中，我们发现了两种革兰氏阴性菌 铜绿假单胞菌和肺炎克雷伯氏菌，它们促进了蛋白质在 这两种菌株还会影响肌肉中的蛋白质聚集。这两个物种都是 是正常人类微生物群的一部分，是已知的机会性病原体。……丰度的增加 人类肠道中的这些细菌以前与神经退行性变的加速进展有关 疾病。总而言之，这些结果表明肠道细菌影响宿主折叠环境；然而， 目前尚不清楚哪些细菌因素对聚集性的增强负责。因此，我们 建议筛选铜绿假单胞菌和肺炎克雷伯菌全基因组突变文库，以寻找将废除 线虫肠道定植时蛋白质聚集的增强。细菌的鉴定 负责破坏宿主蛋白平衡的基因和途径将提供一种新的机制 对宿主-细菌相互作用的了解可以为预防药物的开发提供基础， 治疗学和多囊疾病的生物标记物。

Protein conformational diseases (PCDs) are characterized by a progressive loss of neuronal or muscle function due to protein misfolding and aggregation, a common feature among diseases such as Alzheimer's, Parkinson's, Huntington's, or Lou Gehrig's disease. The exact factors that influence PCDs are not known. Recent evidence suggests that bacteria may contribute to the pathogenesis of these neurodegenerative diseases. To better understand the influence of bacteria on protein homeostasis (proteostasis), we are studying the effect of bacterial colonization of the Caenorhabditis elegans gut on protein aggregation in the intestine and other tissues. In a screen of 52 of the most common human pathogenic-commensal bacteria, we found two Gram-negative species, Pseudomonas aeruginosa and Klebsiella pneumoniae, that enhanced protein aggregation in the intestine by nearly five-fold; these two strains also affect protein aggregation in the muscle. Both species are part of the normal human microbiome and are known opportunistic pathogens. An increase in the abundance of these bacteria within the human gut was previously linked with the enhanced progression of neurodegenerative diseases. Collectively, these results suggest that intestinal bacteria affect the host folding environment; however, which bacterial factors are responsible for the enhancement of aggregation remains unknown. As such, we propose to screen genome-wide mutant libraries of P. aeruginosa and K. pneumoniae for genes that will abolish the enhancement of protein aggregation upon colonization of the C. elegans intestine. Identification of bacterial genes and pathways that are responsible for disruption of host proteostasis will provide a new mechanistic understanding of host-bacteria interaction that can provide a basis for the development of prophylactics, therapeutics, and biomarkers for PCDs.