Visualizing the innate and adaptive immune response to Listeria monocytogenes

描述(由申请人提供)：单核细胞增多性李斯特菌(Lm)感染可产生强大的先天和获得性免疫反应。因此，几种重组LM的减毒菌株正在作为疫苗载体进行研究。然而，与LIVE-LM相比，弱毒或灭活疫苗免疫不能诱导保护性细胞免疫。天然免疫反应的有效激活对于强大的启动和分化保护性CD8 T细胞反应是必要的。驱动高效和低效免疫反应的确切细胞机制还不是很清楚。建立保护性免疫反应依赖于淋巴器官内细胞的协调运动。这一运动受到多种因素的严格调控，包括宿主-病原体的相互作用和高度组织化的淋巴结构。控制时间事件的细胞机制导致天然免疫系统的强劲激活，进而诱导病原体特异性细胞介导的免疫，目前还知之甚少。特别是，宿主-病原体相互作用的作用及其在淋巴器官中的地理定位尚不清楚。了解病原体如何与体内的免疫细胞相互作用，对于开发有效和安全的微生物疫苗非常重要。在这里，我们将使用不同的免疫模型来检验总体假设，即李斯特菌细胞生态位的变化控制着脾内细菌的时间区隔。巨噬细胞在脾中的定位反过来调节先天免疫细胞的募集、局部迁移和分化。这些分层事件的适当进展最终决定了针对病原体的保护性适应性免疫的结果。在这项建议中，我们将可视化有效和无效的抗微生物免疫反应，目的是确定导致体内保护性免疫的免疫反应的关键检查点(S)。根据我们的初步数据和已发表的研究，我们提出了以下目标：1)确定活的LM或减毒的LM株免疫后的细胞趋向性、定位和抗原提呈。2)确定无效疫苗接种的解剖学机制。3)探讨活体巨噬细胞和细菌抗原在脾内转运的细胞机制。

DESCRIPTION (provided by applicant): Listeria monocytogenes (LM) infection generates a robust innate and adaptive immune response. As a result, several attenuated stains of recombinant LM are being investigated as vaccine vehicles. However, compared to infection with live-LM, immunization with attenuated or killed LM vaccines fails to induce protective cell mediated immunity. Potent activation of the innate immune response is necessary for the robust priming and differentiation of a protective CD8 T cell response. The precise cellular mechanisms that drive a productive vs. a poorly-productive immune response are not well understood. Mounting a protective immune response is dependent on the orchestrated movement of cells within lymphoid organs. This movement is carefully regulated by several factors including host-pathogen interactions and the highly organized lymphoid structure. The cellular mechanisms that control the temporal events that lead to the robust activation of the innate immune system that subsequently induce pathogen-specific cell mediated immunity are poorly understood. In particular, the role of host-pathogen interactions and their geographical localization within a lymphoid organ is poorly defined. Understanding how pathogens interact with immune cells in vivo is important to develop effective and safe microbial based vaccines. Here, we will use distinct immunization models to test the overall hypothesis that changes in the cellular niche of Listeria control the temporal compartmentalization of the bacteria in the spleen. The splenic localization of LM in turn regulates innate immune cell recruitment, local migration and differentiation. The proper progression of these hierarchical events ultimately dictates the outcome of the protective adaptive immunity rendered against the pathogen. In this proposal we will visualize an effective vs. an ineffective anti-microbial immune response with the goal of identifying the pivotal checkpoint(s) of an immune response that lead to protective immunity in vivo. Based on our preliminary data and published studies we propose the following aims: 1) To determine the cellular tropism, localization and antigen presentation after immunization with live-LM or attenuated LM strains. 2) To determine the anatomical mechanisms surrounding ineffectual vaccination. 3) To Determine the cellular mechanisms for the splenic trafficking of live-LM and bacterial antigens in vivo.