Modulation of Biodefense Responses to Microbial Pathogens

说明(申请人提供)：本次续展计划项目《微生物病原体生物防御反应的调控》由四个项目和三个核心组成，重点关注对B类和C类生物防御病原体及其产品的免疫反应。中心假设是，粘膜固有免疫反应和获得性免疫反应激活的早期事件分别决定了感染或细菌毒素暴露是否诱导免疫或损伤。每个项目都集中在主题的一个独特方面，以促进我们对传染病病原体或其毒素的粘膜免疫反应的全面了解。由于人类疾病很容易通过故意或意外地污染食物、水或空气而传播，我们的重点是接触环境的界面上的粘膜组织。项目1(Lefrancois)建议研究口腔单核细胞增多性李斯特菌感染(Lm)时肠道粘膜T细胞反应的调节机制。将采用一种模拟人类感染的新系统。项目2(McSorley)将研究一种新的复发沙门氏菌感染模型，并将确定诱导保护性免疫的关键要求。项目3(VELA)将确定肺部给药金黄色葡萄球菌肠毒素如何介导急性肺损伤。一种创新的蛋白质组挖掘策略将被用来测试这一新的假设，即T细胞对肠毒素的反应引导细胞损伤过程，这一过程在深刻的肺部病理中表现出来。项目4(Cauley)将研究支持肺部持续细胞免疫对抗流感病毒感染的机制。这些项目利用了活体模型、深入的细胞免疫技术和最先进的成像技术，并得到了三个核心的支持：行政管理、流式细胞术和荧光显微镜。这些项目和核心相互协作，相互促进，以实现计划的目标。再加上强有力的机构支持，预计在对病原体及其副产品的免疫反应调控方面将继续获得重大的新见解。

DESCRIPTION (provided by applicant): This renewal of the program project "Modulation of biodefense responses to microbial pathogens" is composed of four projects and three cores focused on the immune response to Category B and C Biodefense Pathogens and their products. The central hypothesis is that early events during activation of the mucosal innate and adaptive immune responses determine whether or not immunity or injury is induced in response to infection, or bacterial toxin exposure, respectively. Each project focuses on a unique aspect of the theme to advance our overall understanding of the mucosal immune response to infectious agents or their toxins. Since human disease can be easily spread by deliberate or accidental contamination of food, water, or air, our focus is on mucosal tissues at the interface with environmental exposure. Project 1 (Lefrancois) proposes to investigate the mechanisms regulating the intestinal mucosal T cell response to oral Listeria monocytogenes infection (LM). A novel system that mimics human infection will be employed. Project 2 (McSorley) will examine a new model of relapsing Salmonella infection and will define the critical requirements to elicit protective immunity. Project 3 (Vella) will determine how pulmonary administration of Staphylococcus aureus enterotoxin mediates acute lung injury. An innovative proteomic mining strategy will be used to test the novel hypothesis that T cell responses against enterotoxins guide a cell damage process that manifests in profound lung pathology. Project 4 (Cauley) will investigate the mechanisms that support sustained cellular immunity in the lungs against influenza virus infection. The projects utilize in vivo models, in-depth cellular immunological techniques and state-of-the-art imaging and are supported by 3 cores: administrative, flow cytometry and fluorescence microscopy. The projects and cores synergistically interact and mutually reinforce one another to achieve the goals of the program. Coupled with strong institutional support, it is anticipated that significant new insights in immune response regulatio to pathogens and their byproducts will continue to be obtained.