Visualizing the innate and adaptive immune response to Listeria monocytogenes

描述（由申请人提供）：单核细胞增生李斯特氏菌（LM）感染产生强大的先天性和适应性免疫反应。因此，正在研究几种重组LM减毒菌株作为疫苗载体。然而，与活LM感染相比，减毒或灭活LM疫苗免疫无法诱导保护性细胞介导的免疫。先天免疫反应的有效激活对于保护性 CD8 T 细胞反应的稳健启动和分化是必要的。驱动高效免疫反应和低效免疫反应的精确细胞机制尚不清楚。保护性免疫反应的产生取决于淋巴器官内细胞的协调运动。这种运动受到多种因素的仔细调节，包括宿主与病原体的相互作用和高度组织化的淋巴结构。人们对控制时间事件的细胞机制知之甚少，这些事件导致先天免疫系统的强烈激活，随后诱导病原体特异性细胞介导的免疫。特别是，宿主-病原体相互作用的作用及其在淋巴器官内的地理定位尚不清楚。了解病原体如何在体内与免疫细胞相互作用对于开发有效且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李斯特菌细胞生态位的变化控制脾脏中细菌的时间区划的总体假设。 LM 的脾定位反过来调节先天免疫细胞的招募、局部迁移和分化。这些分层事件的正确进展最终决定了针对病原体的保护性适应性免疫的结果。在本提案中，我们将可视化有效与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。根据我们的初步数据和已发表的研究，我们提出以下目标： 1) 确定活LM或减毒LM菌株免疫后的细胞趋向性、定位和抗原呈递。 2) 确定无效疫苗接种的解剖机制。 3) 确定体内活LM和细菌抗原脾脏运输的细胞机制。

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.