Role of neutrophils and elastase in melioidosis

 性状（由申请方提供）：类鼻疽伯克霍尔德菌（B. p.）是一种革兰氏阴性细胞内细菌，引起类鼻疽病，一种东南亚和其他热带地区特有的肺炎疾病。B. p.被疾病控制中心和NIAID列为第1级B类潜在生物恐怖主义制剂。B. p.拥有迄今为止表征的最大细菌基因组之一，并且水平基因转移、重组和高突变率已被证明是临床分离株中观察到的高基因组不稳定性和变异性及其定殖宿主的能力的原因。使用类鼻疽的小鼠模型，我们最近发现IL-1 β在类鼻疽中是有害的。这是非常令人惊讶和违反直觉的，因为已知IL-1 β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 β的有害作用是由于中性粒细胞过度募集到肺。这反过来又导致中性粒细胞弹性蛋白酶的释放，引起组织损伤，产生缓激肽和血管渗漏，决定发病率和死亡率。总之，我们的研究确定中性粒细胞募集和弹性蛋白酶释放作为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的有害作用的基础。旨在抑制这些途径的药理学干预措施将使用现有的人类测试药物进行测试，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是否差异性中性粒细胞募集和弹性蛋白酶释放解释了一组B. p.临床分离株的不同致病性，以及这些途径是否影响持续感染的建立。目的1：确定类花生酸和补体在类鼻疽病中性粒细胞募集中的作用。目标二：确定中性粒细胞弹性蛋白酶在急性类鼻疽持续感染和缓激肽生成中的作用。目标3：测试B。类鼻疽临床分离株诱导炎性小体活化并引起IL-1 β和弹性蛋白酶依赖性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.