Mechanisms of Listeria-Specific Immunity

李斯特菌特异性免疫机制

• 批准号: 7013151
• 负责人: ELIZABETH HILTBOLD SCHWARTZ
• 金额: $ 35.03万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013151
• 关键词: Listeria; Listeria infections; T lymphocyte; antigen presentation; antigen presenting cell; bacteria infection mechanism; bactericidal immunity; biological signal transduction; cell cell interaction; dendritic cells; genetically modified animals; host organism interaction; immune response; laboratory mouse; leukocyte activation /transformation; molecular biology; nuclear receptors; protein structure function; tissue /cell culture; toll like receptor

DESCRIPTION (provided by applicant): The goal of this project is to determine how the immune response to Listeria monocytogenes is regulated by activation of antigen presenting cells. Listeria trigger APC activation through a network of pattern recognition receptors and signaling adapters. Signals transduced upon cytoplasmic entry are required for virulence of the bacteria and for development of protective immunity. Likewise, signaling through the Toll-like receptor adapter MyD88 is essential for a significant portion of the DC maturation response induced by listerial infection. We have identified many of the key molecules induced in DC by listerial cytoplasmic entry. We determined that the expression of costimulatory molecules and inflammatory cytokines by DC was dependent upon expression of the hemolysin, LLO and bacterial cytoplasmic entry. We have also determined the role of each of these molecules in priming CD8+ T cell proliferation and function. We will now explore the molecular basis for DC maturation induced by Listeria by examining the role of Toll-like receptors, TLR adapters, and cytosolic receptors with the studies proposed in Specific Aim 1. We will also determine the role of these molecules in generating protective immunity to Listeria using Listeria-infected DC as an immunogen in vivo. We will then determine the role of costimulatory molecules and cytokines induced by listerial infection in the formation of the immunological synapse with the studies proposed in specific aim 2. These novel studies will reveal how the interaction of T cells with infected antigen presenting cells gives rise to protective T cell responses. Our studies will provide important insights into the interaction of this intracellular bacteria with the host immune system and will aid the design of efficacious vaccines against this pathogen.

描述（由申请人提供）：本项目的目的是确定如何通过激活抗原呈递细胞来调节对单核细胞增生李斯特菌的免疫应答。李斯特菌通过模式识别受体和信号适配器的网络触发APC激活。进入细胞质后转导的信号是细菌毒力和保护性免疫发展所必需的。同样地，通过Toll样受体衔接子MyD88的信号传导对于由病毒感染诱导的DC成熟应答的重要部分是必不可少的。我们已经确定了许多关键分子诱导的树突状细胞的胞质进入。我们确定DC表达共刺激分子和炎性细胞因子依赖于溶血素、LLO和细菌胞质进入的表达。我们还确定了这些分子中的每一种在引发CD8+ T细胞增殖和功能中的作用。我们现在将通过具体目标1中提出的研究来检查Toll样受体、TLR接头和胞质受体的作用，探索李斯特菌诱导DC成熟的分子基础。我们还将确定这些分子在使用李斯特菌感染的DC作为体内免疫原产生对李斯特菌的保护性免疫中的作用。然后，我们将确定在特定目标2中提出的研究中，由病毒感染诱导的共刺激分子和细胞因子在免疫突触形成中的作用。这些新的研究将揭示T细胞与受感染的抗原呈递细胞的相互作用如何引起保护性T细胞应答。我们的研究将为这种细胞内细菌与宿主免疫系统的相互作用提供重要的见解，并将有助于设计针对这种病原体的有效疫苗。