COMPARTMENTALIZATION OF BACTERIAL ANTIGENS

描述（改编自申请人摘要）：长期目标 这项研究的目的是了解细菌抗原的各个方面 影响宿主防御的性质和程度，以及 由此产生的免疫反应改变了感染的进程。克- 阳性细菌，单核细胞增生李斯特菌（LM），提供了一个很好的 模型来解决这些问题，因为病原体和鼠 宿主易于实验操作。调查人员已 建立了一个用于构建重组LM（rLM）的遗传系统， 表达外源抗原，操纵细菌的分子工具， 抗原和致病过程，以及 表征由rLM菌株诱导的免疫应答。通过 操纵抗原分泌，他们已经表明，分泌和 非分泌的细菌蛋白有效地引发CD 8 T细胞。然而，在这方面， 只有分泌的细菌蛋白作为CTL的保护性抗原， 介导的免疫。因此，抗原区室化导致抗原区室化。 CTL引发和保护性免疫之间的明显二分法。的 本提案的目的是了解 对这种二分法负责。具体而言，它们将： 1)通过以下方法检查活化初始和记忆CD 8 T细胞的动力学： 分泌型与非分泌型细菌抗原。这些研究将 直接测试一个长期存在的假设，即分泌蛋白质是 免疫系统在非分泌型之前识别，因此 更有针对性的疫苗。 2)测试定量差异模型，该模型规定CTL 对非分泌型细菌抗原的应答太弱和/或太 以防止LM感染的进展。 3)测试细胞趋向性模型，该模型规定非分泌抗原 仅由一部分受感染的细胞呈现。因此，CTL 特异于非分泌抗原的细胞不能识别所有的 感染的细胞，因此不能控制感染。 这些研究的结果应揭示负责的机制 对于CTL引发和保护性免疫之间的二分法， 抗原区室化的结果。阐明基本的 机制将对我们理解 细胞内细菌的免疫监视，用于设计有效的 疫苗，将诱导有效的反应，并选择候选人 可以作为保护目标的抗原。

DESCRIPTION (Adapted from the Applicant's Abstract):The long term, goal of this study is to understand how various aspects of bacteria antigens influence the nature and magnitude of host defense, and how the resulting immune response modifies the course of infection. The Gram- positive bacterium, Listeria monocytogenes (LM), offers an excellent model to address these questions since both the pathogen and the murine host are amenable to experimental manipulation. The investigators have developed a genetic system for constructing recombinant LM (rLM) expressing foreign antigens, molecular tools for manipulating bacterial antigens and the pathogenic process, and a murine model for characterizing immune responses induced by the rLM strains. By manipulating antigen secretion, they have shown that both secreted and non-secreted bacterial proteins efficiently prime CD8 T cells. However, only secreted bacterial proteins serve as protective antigens for CTL- mediated immunity. Thus, antigen compartmentalization results in a striking dichotomy between CTL priming and protective immunity. The objective of this proposal is to understand the mechanism(s) that is responsible for this dichotomy. Specifically, they will: 1) examine the kinetics of activating naive and memory CD8 T cells by secreted vs. non-secreted bacterial antigens. These studies will directly test a long standing hypothesis that secreted proteins are recognized by the immune system before non-secreted ones, and thus are more relevant vaccine targets. 2) test a Quantitative Difference model which stipulates that CTL responses to non-secreted bacterial antigens are too weak and/or too late to prevent the progression of LM infection. 3) test a Cell Tropism model which stipulates that non-secreted antigens are presented only by a subset of infected cells. As a result, CTL specific to the non-secreted antigen are unable to recognize all infected cells and thus, cannot control infection. The results of these studies should unveil the mechanism(s) responsible for the dichotomy between CTL priming and protective immunity as a result of antigen compartmentalization. Elucidation of the underlying mechanisms will have important implications in our understanding of immune surveillance of intracellular bacteria, for designing effective vaccines that will induce a potent response, and for selecting candidate antigens that can serve as protective targets.