Mechanisms of Ferritin-iron Acquisition and Burkholderia pseudomallei Infection.

描述（由申请方提供）：类鼻疽伯克霍尔德菌（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。这种细菌引起类鼻疽病，这是一种包括从急性脓毒症到长期慢性表现的难以治疗的感染的疾病。我们 对细菌侵入、传播和在宿主中生存的各种因素的了解充其量也只是初步的，而对细菌生存至关重要的铁获取途径几乎一无所知。以前，人们认为，生物体采用铁收购系统常见于其他革兰氏阴性细菌病原体，但我们的初步数据表明，BP可能采用铁蛋白铁收购途径。本文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，我们将评估获得铁蛋白铁是否涉及蛋白水解降解， 铁蛋白支架其次，我们将获得铁蛋白铁收购存在的证据 通过鉴定铁蛋白-铁转运缺陷的突变体，第三，我们将调查在体内铁蛋白铁收购基因的要求，使用细胞培养和小鼠模型。这些研究的结果将大大改变我们目前对致病性革兰氏阴性菌铁获得机制的看法，并提供了更完整的Bp感染的发病机制。

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.