Role of neutrophils and elastase in melioidosis

 描述(申请人提供)：假腮腺伯克霍尔德氏菌(B.P.)是一种革兰氏阴性细胞内细菌，可引起类鼻疽病，这是东南亚和其他热带地区的地方性肺炎。B.P.被疾病控制中心和NIAID列为1级B类潜在生物恐怖分子。B.P.拥有迄今为止最大的细菌基因组之一，水平基因转移、重组和高突变率被证明是临床分离株基因组高度不稳定性和变异性以及它们定植宿主的能力的原因。利用类鼻疽病的小鼠模型，我们最近发现IL-1在类鼻疽病中是有害的。这是非常令人惊讶和违反直觉的，因为众所周知，IL-1ü对几种细菌和病毒感染具有保护作用。我们的初步数据表明，IL-1的有害作用是由于中性粒细胞过度募集到肺中所致。这反过来会导致中性粒细胞弹性蛋白酶的释放，导致组织损伤，产生缓激肽和血管渗漏，从而决定发病率和死亡率。综上所述，我们的研究确定中性粒细胞募集和弹性酶释放是治疗类鼻疽的潜在治疗靶点。我们研究的目的是确定中性粒细胞募集到感染肺的机制，并了解弹性蛋白酶在类鼻疽病中有害作用的基础。旨在抑制这些途径的药理干预措施将使用现有的人体测试药物进行测试，这一事实增加了我们的研究将迅速转化为临床的可能性。我们的研究还将确定不同的中性粒细胞招募和弹性蛋白酶释放是否解释了一组B.P.不同的致病性。临床分离以及持续感染的建立是否受这些途径的影响。目的1：确定类二十碳化合物和补体在类鼻疽病中性粒细胞募集中的作用。目的2：探讨中性粒细胞弹性蛋白酶在急性类鼻咽癌持续感染和缓激肽生成中的作用。目的：检测假鼻疽杆菌临床分离株诱导炎性小体激活和导致IL-1？和弹性蛋白酶依赖的发病率和死亡率的能力。

 DESCRIPTION (provided by applicant): Burkholderia pseudomallei (B.p.) is a Gram-negative intracellular bacterium that causes melioidosis, a pneumonic disease endemic to South-East Asia and other tropical regions. B.p. is classified as Tier 1 category B potential bioterrorism agent by the Center for Disease Control and NIAID. B.p. possesses one of the largest bacterial genome characterized so far and horizontal gene transfer, recombination and high mutation rate have been shown to account for the high genome instability and variability observed among clinical isolates and their ability to colonize the host. Using a mouse model of melioidosis, we have recently found that IL-1ß is deleterious in melioidosis. This is very surprising and counterintuitive considering that IL- 1ß is known to be protective against several bacterial and viral infections. Our preliminary data indicate that IL-1ß deleterious effect is due to excessive recruitment of neutrophils to the lung. This, in turn, leads to release of neutrophil elastase causing tissue damage, generation of bradykinin and vascular leakage that determines morbidity and mortality. Taken together, our studies identified neutrophils recruitment and elastase release as potential therapeutic targets for treatment of melioidosis. The goal of our studies is to identify the mechanisms responsible for neutrophils recruitment to the infected lung and understand the basis for the deleterious role of elastase during melioidosis. Pharmacological interventions aimed at inhibiting these pathways will be tested using existing human-tested drugs, a fact that increases the likelihood that our studies will have a rapid translation into the clinic. Our studies will also determine whether differential neutrophil recruitment and elastase release account for different pathogenicity of a panel of B.p. clinical isolates and whether establishment of persistent infection is affected by these pathways. Aim 1: Determine the role of eicosanoids and complement in neutrophil recruitment during melioidosis. Aim 2: Determine the role of neutrophil elastase in the establishment of persistent infection and the generation of bradykinin during acute melioidosis. Aim 3: Test B. pseudomallei clinical isolates for their ability to induce inflammasome activation and cause IL-1ß- and elastase-dependent morbidity and mortality.