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: 8512182
• 负责人: HERBERT P. SCHWEIZER
• 金额: $ 18.19万
• 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 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512182
• 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）：Burkholderia pseudomallei（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的频率越来越高。细菌会引起黑胶病，一种包括急性败血症到持久慢性表现的难以治疗感染的疾病。我们的 了解允许BP入侵，传播和生存在宿主中的因素的武库的知识充其量是基本的，几乎没有关于对细菌存活至关重要的铁采集途径的知识。以前假定该生物使用其他革兰氏阴性细菌病原体中常见的铁先电系统，但是我们的初步数据表明BP可以采用铁蛋白铁号采集途径。此处提出的研究旨在阐明这种新兴病原体的发病机理所需的关键途径。首先，我们将评估获得铁蛋白铁是否涉及的蛋白水解降解 铁蛋白支架。其次，我们将获得存在铁蛋白铁的存在的证据 通过识别铁蛋白铁运输中有缺陷的突变体来途径。第三，我们将使用细胞培养和小鼠模型研究铁蛋白铁获得基因的体内需求。这些研究的结果将大大改变我们当前对致病性革兰氏阴性细菌中铁采集机制的看法，并为BP感染的发病机理提供了更完整的图片。