Mechanisms of Listeria-Specific Immunity

描述(由申请人提供)：这个项目的目标是确定如何通过激活抗原提呈细胞来调节对单核细胞增多性李斯特菌的免疫反应。李斯特菌通过模式识别受体和信号适配器网络激活APC。在细胞质进入时传递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样受体适配器MyD88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是必不可少的。我们已经确定了许多由李斯特菌胞质进入诱导的DC的关键分子。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的表达和细菌的胞浆进入。我们还确定了这些分子中的每一个在启动CD8T细胞增殖和功能中的作用。我们现在将通过检测Toll样受体、TLR接头和胞浆受体的作用来探索李斯特菌诱导DC成熟的分子基础。我们还将利用李斯特菌感染的DC作为免疫原，在体内确定这些分子在产生对李斯特菌的保护性免疫中的作用。然后我们将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，这些新的研究将揭示T细胞与受感染的抗原提呈细胞的相互作用如何引起保护性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。

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.