Mechanisms of Listeria-Specific Immunity

李斯特菌特异性免疫机制

• 批准号: 6866292
• 负责人: ELIZABETH HILTBOLD SCHWARTZ
• 金额: $ 35.88万
• 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/6866292
• 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）：该项目的目标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氏菌的免疫反应。李斯特菌通过模式识别受体和信号适配器网络触发 APC 激活。进入细胞质后转导的信号对于细菌的毒力和保护性免疫的发展是必需的。同样，通过 Toll 样受体接头 MyD88 发出的信号对于李斯特菌感染诱导的 DC 成熟反应的很大一部分至关重要。我们已经鉴定出许多由李斯特菌进入细胞质在 DC 中诱导的关键分子。我们确定 DC 的共刺激分子和炎症细胞因子的表达依赖于溶血素、LLO 和细菌细胞质进入的表达。我们还确定了这些分子在启动 CD8+ T 细胞增殖和功能中的作用。我们现在将通过特定目标 1 中提出的研究检查 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产生保护性细胞中的作用。使用感染李斯特菌的 DC 作为体内免疫原对李斯特菌产生免疫力。然后，我们将通过具体目标 2 中提出的研究来确定李斯特菌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。这些新颖的研究将揭示 T 细胞与受感染的抗原呈递细胞的相互作用如何产生保护性 T 细胞反应。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。