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）：该项目的目的是确定如何通过激活抗原呈递细胞来调节对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。细菌毒力和保护性免疫的发展需要转导的信号。同样，通过Toll样受体适配器MyD88的信号传导对于腹膜感染引起的DC成熟响应的很大一部分至关重要。我们已经确定了通过乳腹细胞质进入在DC中诱导的许多关键分子。我们确定DC通过DC的共刺激分子和炎症细胞因子的表达取决于血解素，LLO和细菌细胞质的表达。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。现在，我们将通过研究特定目的1中提出的研究来探讨李斯特菌诱导的直流成熟的分子基础。然后，我们将通过特定目标2中提出的研究来确定由李斯特氏感染诱导的共刺激分子和细胞因子在形成免疫突触中的作用。这些新型研究将揭示T细胞与感染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，并有助于设计有效的疫苗针对这种病原体。