Mechanisms of Ferritin-iron Acquisition and Burkholderia pseudomallei Infection.

描述(申请人提供)：假鼻疽伯克霍尔德氏菌(BP)是一种新出现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病，这是一种由从急性败血症到长期慢性表现的难以治疗的感染组成的疾病。我们的 关于允许BP入侵、传播和在宿主中生存的各种因素的知识充其量仍然是初级的，对于细菌生存至关重要的铁获取途径几乎一无所知。以前，人们假设该生物体使用在其他革兰氏阴性细菌中常见的铁获取系统，但我们的初步数据表明，BP可能使用铁蛋白-铁获取途径。这里提出的研究旨在阐明这种新出现的病原体的发病机制所需的关键途径。首先，我们将评估接触铁蛋白-铁是否涉及蛋白质降解 铁蛋白支架。其次，我们将获得铁蛋白-铁获取存在的证据 通过鉴定在铁蛋白-铁转运过程中有缺陷的突变体来实现这一途径。第三，我们将使用细胞培养和小鼠模型来研究体内对铁蛋白-铁获取基因的需求。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细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图景。

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.