COMPARTMENTALIZATION OF BACTERIAL ANTIGENS

描述(改编自申请者摘要)：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规模，以及如何 由此产生的免疫反应改变了感染的过程。格拉姆-- 阳性细菌，单核细胞增生性李斯特氏菌(Lm)，提供了一种极好的 模型来解决这些问题，因为病原体和小鼠 宿主容易受到实验性的操纵。调查人员已经 建立了构建重组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，以及一个小鼠模型 鉴定RLM菌株诱导的免疫反应。通过 通过操纵抗原分泌，他们已经证明了分泌和 非分泌型细菌蛋白能有效激活CD8T细胞。然而， 只有分泌的细菌蛋白作为CTL的保护性抗原- 中介免疫。因此，抗原区隔作用会导致 CTL启动和保护性免疫之间存在明显的二分法。这个 这项建议的目的是了解(S)的机制，即 对这种二分法负有责任。具体地说，他们将： 1)检测激活幼稚和记忆性CD8 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，即分泌的蛋白质是 被免疫系统识别的先于非分泌性细胞，因此 更多相关的疫苗目标。 2)检验一个数量差异模型，该模型规定CTL 对非分泌性细菌抗原的反应太弱和/或太强 为防止肺炎衣原体感染的进展，应及早采取措施。 3)测试细胞趋向性模型，该模型规定非分泌性抗原 仅由受感染细胞的子集呈现。因此，CTL 对非分泌性抗原的特异性无法识别所有 被感染的细胞，因此不能控制感染。 这些研究的结果应该会揭示责任的机制(S) 对于CTL启动和保护性免疫之间的二分法 抗原区划的结果。对潜在原因的解释 机制将对我们理解 胞内细菌的免疫监测，为设计有效的 将会引起强烈反应的疫苗，并用于选择候选人 可作为保护性目标的抗原。

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.