Modulation of Biodefense Responses to Bacterial Pathogen

项目说明(申请人提供)：项目申请《对细菌病原体的生物防御反应的调节》由康涅狄格大学健康中心免疫学部提出。该计划由三个项目和三个核心组成，重点是对细菌及其产品的免疫反应，所有这些项目都被列为NIH生物防御计划名单上的B类实体。该计划的主题是定义启动抗微生物免疫反应的参数，并检查促进免疫的细菌产品，或在肠毒素的情况下，粘膜组织中的病理学。核心假设是，T细胞-抗原提呈细胞(APC)相互作用的早期事件决定了是否对疫苗接种诱导了长期免疫，或者是否对细菌毒素产生了损害。每个项目都集中在主题的一个独特方面，以促进我们对细菌抗原的免疫反应的理解。项目1(Lefrancois)建议研究T细胞对活的或热致死的单核细胞增多性李斯特菌的反应。将研究T细胞-APC的相互作用，以及T细胞帮助和Toll样受体在优化反应中的作用。测试细菌产物或共刺激激动剂增强反应的实验将与其他两个项目合作进行。项目2(McSorley)专注于CD4T细胞对鼠伤寒沙门氏菌鞭毛蛋白的反应，并将测试鞭毛蛋白能否在体内激活APC，从而成为有效的佐剂或疫苗。项目3(VELLA)旨在确定葡萄球菌肠毒素B(SEB)如何通过T细胞相互作用影响APC功能，并将建立SEB损伤的肺粘膜损伤模型。这三个项目的组成部分都旨在检查感染或毒素攻击后T细胞-APC的相互作用，天然免疫反应也是一个常见的话题。这些研究为实现增强保护性免疫的目标提供了天然的桥梁。这些项目利用活体模型和深入的细胞免疫学技术，并得到三个核心的支持：行政管理、流式细胞术和荧光显微镜/免疫组织化学。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，预计将在对病原体及其副产品的免疫反应调控方面获得重要的新见解。

DESCRIPTION (provided by applicant): The program project application "Modulation of biodefense responses to bacterial pathogens" is proposed from the Division of Immunology, U. Connecticut Health Center. This program is composed of three projects and three cores focused on the immune response to bacteria and their products, all of which are included as category B entities on the NIH Biodefense Program list. The program theme is to define the parameters for initiation of anti-microbial immune responses and also examines bacterial products in promoting immunity, or in the case of enterotoxins, pathology, in mucosal tissues. The central hypothesis is that early events in T cell-antigen presenting cell (APC) interactions determine whether or not long-term immunity is induced in response to vaccination, or whether damage is initiated in response to a bacterial toxin. Each project focuses on a unique aspect of the theme to advance our understanding of the immune response to bacterial antigens. Project 1 (Lefrancois) proposes to investigate the T cell response to live or heat killed Listeria monocytogenes. T cell-APC interactions will be examined as will the role of T cell help and Toll-like receptors in optimizing the response. Experiments testing augmentation of the response by bacterial products or costimulatory agonists will be performed in collaboration with the other two projects. Project 2 (McSorley) is focused on the CD4 T cell response to Salmonella typhimurium flagellin and will test whether flagellin can activate APC in vivo and thus be an effective adjuvant or vaccine. Project 3 (Vella) aims to define how staphylococcal enterotoxin B (SEB) influences APC function via T cell interactions and will develop a model of lung mucosa injury to SEB insult. Components of all three projects are aimed at examining T cell-APC interactions following infection or toxin challenge and the innate immune response is also a common topic. These studies provide a natural bridge towards the goal of augmentation of protective immunity. The projects utilize in vivo models and in-depth cellular immunological techniques and are supported by 3 cores: administrative, flow cytometry and fluorescence microscopy/immunohistochemistry. 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 regulation to pathogens and their byproducts will be obtained.