Role of non-myeloid cells' pyroptosis in melioidosis

非髓系细胞焦亡在类鼻疽中的作用

基本信息

批准号：
10635662
负责人：
FABIO C RE
金额：
$ 50.7万
依托单位：
ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-17 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10635662
关键词：
Anti-Inflammatory Agents Applications Grants Attention Bacterial Infections Bone Marrow Burkholderia pseudomallei CASP1 gene Caspase Cell Death Cells Coagulation Process Cytoprotection Dinoprostone Disseminated Intravascular Coagulation Eicosanoid Production Eicosanoids Endemic Diseases Endothelial Cells Endotoxic Shock Epithelial Cells Epithelium Far East Gram-Negative Bacteria IL18 gene Infection Inflammasome Inflammation Inflammatory Innate Immune Response Interleukin-1 beta Leukotriene B4 Literature Lung Lytic Mediating Melioidosis Modeling Mus Myeloid Cells PTGS1 gene PTGS2 gene Pathogenesis Phospholipase A2 Platelet Activating Factor Play Predisposition Production Prostaglandins Publishing Reporting Role Testing Therapeutic Therapeutic Intervention Thromboplastin Thromboxanes alveolar epithelium cell type inhibitor mouse model pathogen pharmacologic radioresistant reconstitution response therapeutic development

项目摘要

Activation of caspase-1 and caspase-11 in the context of inflammasomes leads to processing and secretion of IL-1β and IL-18 and triggers a lytic cell death termed pyroptosis. Inflammasome activation and pyroptosis have been shown to protect the host from infection with a range of pathogens including Burkholderia pseudomallei, a gram-negative bacterium used as a mouse model of melioidosis. However, it is also becoming clear that inflammasome activation and pyroptosis can be deleterious to the host by triggering lethal eicosanoid storm, mediating lethal endotoxic shock, and causing disseminated intravascular coagulation (DIC). We have recently shown that the only functional inflammasome expressed by epithelial and endothelial cells is caspase-11, and that in a model of melioidosis caspase-11-dependent pyroptosis of lung epithelial cells is protective. Based on our preliminary results and the published literature we hypothesize that activation of caspase-11 in epithelial cells will protect the host from pneumonic melioidosis through induction of pyroptosis and preferential production of anti-inflammatory eicosanoids like prostaglandin E2. In contrast, caspase-11 activation in endothelial cells may prove deleterious because it may damage barrier integrity, induce DIC and excessive inflammation through release of Tissue Factor and LTB4. Thus, studying the function of caspase-11 selectively in epithelial or endothelial cells will allow us to identify the deleterious and the beneficial responses and therefore potentially indicate therapeutic avenues to inhibit the former and encourage the latter. In aim 1 we will focus on the role of caspase-11 in epithelial cells. We will test the role of caspase-11 and gasdermin D in the production of eicosanoids by lung epithelial cells. We will also test the susceptibility to melioidosis of mice that lack expression of caspase-11 in lung epithelial cells and determine the role of epithelial-derived eicosanoids in melioidosis. In aim 2 we will study the role of caspase-11 in endothelial cells. We will examine how caspase-11 controls production of eicosanoids and release of Tissue Factor in endothelial cells. We will test the susceptibility to melioidosis of mice that lack expression of caspase-11 in endothelial cells and establish the role of Tissue Factor, Platelet Activating Factor, and DIC in the pathogenesis of melioidosis.

炎症小体中 caspase-1 和 caspase-11 的激活导致 IL-1β 和 IL-18 的加工和分泌，并引发称为细胞焦亡的裂解性细胞死亡，炎症小体激活和细胞焦亡已被证明可以保护宿主免受感染。一系列病原体，包括类鼻疽伯克霍尔德氏菌，一种用作类鼻疽小鼠模型的革兰氏阴性细菌。然而，越来越清楚的是，炎症小体激活和焦亡可能通过引发致命的类二十烷酸风暴、介导致命的内毒素休克和引起弥散性血管内凝血（DIC）而对宿主有害。我们最近表明，上皮细胞表达的唯一功能性炎症小体。内皮细胞是 caspase-11，在类鼻疽 caspase-11 依赖性肺焦亡模型中根据我们的初步结果和已发表的文献，我们发现上皮细胞中 caspase-11 的激活将通过诱导细胞焦亡和优先产生抗炎类二十烷酸（如前列腺素 E2）来保护宿主免受肺类鼻疽。，内皮细胞中的 caspase-11 激活可能是有害的，因为它可能会损害屏障完整性，通过释放组织因子和诱导 DIC 以及过度炎症。 LTB4。因此，选择性研究 caspase-11 在上皮细胞或内皮细胞中的功能将使我们能够识别有害和有益的反应，从而指出抑制前者并促进后者的潜在治疗途径。 caspase-11 在上皮细胞中的作用我们将测试 caspase-11 和gasdermin D 在肺上皮产生类二十烷酸中的作用。我们还将测试肺上皮细胞中缺乏 caspase-11 表达的小鼠对类鼻疽病的易感性，并确定上皮来源的类二十烷酸在类鼻疽病中的作用。在目标 2 中，我们将研究 caspase-11 在内皮细胞中的作用。我们将研究 caspase-11 如何控制内皮细胞中类二十烷酸的产生和组织因子的释放。内皮细胞中缺乏 caspase-11 表达的小鼠对类鼻疽病的易感性，并确定了组织因子、血小板激活因子和 DIC 在类鼻疽发病机制中的作用。