Identification of Bacterial Genes that Disrupt Host Proteostasis

鉴定破坏宿主蛋白质稳态的细菌基因

• 批准号: 10041813
• 负责人: Daniel Milosz Czyz
• 金额: $ 7.46万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10041813
• 关键词: Affect; Aging; Alzheimer' s Disease; Amyloid; Amyotrophic Lateral Sclerosis; Antibiotics; Attenuated; Bacteria; Bacterial Genes; Bacterial Genome; Caenorhabditis elegans; Databases; Development; Disease; Environment; Genes; Goals; Human; Human Genome; Human Microbiome; Human body; Huntington Disease; Infection; Intestines; Klebsiella pneumoniae; Knock-out; Libraries; Link; Modeling; Muscle; Muscle function; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organ; Parkinson Disease; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Physiological; Play; Population; Process; Protein Conformation; Proteins; Pseudomonas aeruginosa; Regulation; Research; Role; Signaling Molecule; Source; Therapeutic; Tissues; commensal bacteria; dysbiosis; effective therapy; experimental study; genome wide screen; gut microbiota; mutant; neuron loss; pathogen; peptide hormone; polyglutamine; prophylactic; protein aggregation; protein biomarkers; protein folding; protein misfolding; proteostasis

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.

蛋白质构象疾病（PCD）的特征是神经元或肌肉的进行性丧失 由于蛋白质的错误折叠和聚集而发挥功能，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，或卢伽雷氏症。影响PCD的确切因素尚不清楚。最近 有证据显示细菌可能是这些神经退化疾病的致病因素。到 为了更好地了解细菌对蛋白质稳态的影响，我们正在研究 秀丽隐杆线虫肠道的细菌定殖对肠道和其他组织中蛋白质聚集的影响。 在对52种最常见的人类病原体细菌的筛选中，我们发现了两种革兰氏阴性菌， 种，铜绿假单胞菌和肺炎克雷伯菌，增强蛋白质聚集在 肠近五倍;这两个菌株也影响蛋白质聚集在肌肉中。这两个物种都是 是正常人体微生物组的一部分，是已知的机会致病菌。大量的 人类肠道内的这些细菌以前与神经退行性疾病的加速进展有关， 疾病总的来说，这些结果表明肠道细菌影响宿主的折叠环境;然而， 哪些细菌因子负责增强聚集仍然是未知的。因此我们 建议筛选铜绿假单胞菌和克雷伯菌的全基因组突变体文库。肺炎的基因，将废除 在C.线虫肠鉴定细菌 负责破坏宿主蛋白质稳态的基因和途径将提供新的机制， 对宿主-细菌相互作用的理解可以为药物的开发提供基础， 治疗剂和PCD的生物标志物。