Mechanisms of Ferritin-iron Acquisition and Burkholderia pseudomallei Infection.

铁蛋白-铁获取和类鼻疽伯克霍尔德氏菌感染的机制。

• 批准号: 8605839
• 负责人: HERBERT P. SCHWEIZER
• 金额: $ 3.59万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-16 至 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605839
• 关键词: Acute; Address; Animals; Antibiotics; Australia; Bacteria; Biochemical Genetics; Burkholderia pseudomallei; Cell Culture Techniques; Cells; Chronic; Chronic Disease; Communities; Critical Pathways; Data; Diagnosis; Disease; Elements; Ferritin; Frequencies; Genes; Goals; Gram-Negative Bacteria; Growth; Health; Human; Infection; International; Invaded; Investigation; Iron; Knowledge; Laboratories; Melioidosis; Nutrient; Organism; Pathogenesis; Pathway interactions; Peptide Hydrolases; Process; Proteins; Research; Resistance; Risk; Role; Sepsis; Siderophores; Southeastern Asia; System; Thailand; Therapeutic Intervention; United States; Virulence Factors; in vivo; mortality; mouse model; mutant; pathogen; scaffold; tool

DESCRIPTION (provided by applicant): Burkholderia pseudomallei (Bp) is an emerging Gram-negative bacterial pathogen that is found with increasing frequency in tropical and subtropical regions of the world. The bacterium causes melioidosis, a disease comprising difficult-to-treat infections ranging from acute sepsis to long-lasting chronic manifestations. Our knowledge of the arsenal of factors that allow Bp to invade, spread and survive in the host is stil rudimentary at best, and virtually nothing is known about iron acquisition pathways crucial for bacterial survival. Previously it was assumed that the organism employs iron-acquisition systems commonly found in other Gram-negative bacterial pathogens, but our preliminary data indicate that Bp may employ a ferritin-iron acquisition pathway. The studies proposed here are intended to elucidate a critical pathway required for the pathogenesis of this emerging pathogen. First, we will assess whether access to ferritin-iron involves proteolytic degradation of the ferritin scaffold. Second, we will obtain evidence for existence of a ferritin-iron acquisition pathway by identifying mutants defective in ferritin-iron transport. Third, we will investigate in vivo requirements for ferritin-iron acquisition genes using cell culture and mouse models. Results from these investigations will substantially alter our current view of iron acquisition mechanisms in pathogenic Gram-negative bacteria and also provide a more complete picture of the pathogenesis of infection with Bp.

描述（由申请人提供）：类鼻疽伯克霍尔德氏菌（Bp）是一种新兴的革兰氏阴性细菌病原体，在世界热带和亚热带地区发现的频率越来越高。这种细菌会引起类鼻疽，这是一种包括难以治疗的感染的疾病，范围从急性败血症到长期慢性表现。我们的 对于允许 Bp 侵入、传播和在宿主中生存的因素的了解最多仍然是初级的，并且实际上对细菌生存至关重要的铁获取途径一无所知。此前，人们认为该生物体采用了其他革兰氏阴性细菌病原体中常见的铁获取系统，但我们的初步数据表明，Bp 可能采用铁蛋白-铁获取途径。这里提出的研究旨在阐明这种新兴病原体发病机制所需的关键途径。首先，我们将评估铁蛋白-铁的获取是否涉及铁蛋白的蛋白水解降解。 铁蛋白支架。其次，我们将获得铁蛋白-铁收购存在的证据 通过识别铁蛋白-铁转运缺陷的突变体来探索途径。第三，我们将使用细胞培养和小鼠模型研究铁蛋白-铁获取基因的体内需求。这些研究的结果将极大地改变我们目前对致病性革兰氏阴性菌铁获取机制的看法，并为 Bp 感染的发病机制提供更完整的认识。