Cellular Immune Surveillance of Intracellular bacteria

描述(申请人提供)：我们研究的长期目标是了解1)什么细菌抗原被免疫系统识别，什么因素影响细菌中的抗原靶标，2)什么免疫机制是保护的，宿主免疫效应器如何抵消特定的毒力因子产生保护性免疫，以及3)细菌逃脱免疫监视的可能性和机制。在本应用程序中，我们将使用单核细胞增生性李斯特氏菌(Listeria moneuctogen，LM)作为模型来： 1.研究基因表达的调节如何影响细菌蛋白诱导免疫反应和作为保护目标的能力。这项研究的结果将有助于我们确定细菌抗原库的复杂性，并为疫苗抗原靶标的选择制定一般指南。 2.测试一个模型，即对LM的保护性免疫是由CTL介导的细胞溶解和细菌传播到邻近细胞之间的竞争决定的。这一模型是由我们发现CTL细胞溶解功能来抵消LM的直接细胞-细胞传播的毒力策略而提出的。我们将测试这个模型的几个预测，在这样做的过程中，我们希望确定与细菌毒力策略相关的免疫保护机制。 3.研究拮抗肽可能在形成T细胞靶标和允许细菌逃逸CTL监视方面发挥作用。我们的初步结果证实了TCR拮抗剂对T细胞反应和保护性免疫的体内效应。我们将研究感染期间体内激动剂/拮抗剂相互作用的几个方面。 这些研究的结果将有助于我们了解细菌与宿主之间复杂的相互作用，这些相互作用决定了感染的结果，并将对设计有效的疫苗和选择保护性疫苗抗原具有重要意义。

DESCRIPTION (provided by applicant): The long-term objectives of our study are to understand 1) what bacterial antigens are recognized by the immune system and what factors influence the repertoire of antigenic targets in bacteria, 2) what immune mechanisms are protective and how host immune effectors counteract specific virulence factors to bring about protective immunity, and 3) how likely and by what mechanisms bacteria may escape immune surveillance. In this application, we will use Listeria monocytogenes (LM) as a model to: 1. Examine how regulation of gene expression affects the ability of a bacterial protein to induce immune responses and to serve as a protective target. The results of this study will help us define the complexity of the antigenic repertoire of bacteria and develop general guidelines for the selection of antigenic targets for vaccination. 2. Test a model that protective immunity against LM is determined by a race between CTL-mediated cytolysis and bacterial spread into neighboring cells. This model is suggested by our finding that CTL cytolysis functions to counteract LM's virulence strategy of direct cell-cell spread. We will test several predictions of this model and in doing so we hope to identify mechanisms of immune protection that correlate with bacterial virulence strategies. 3. Investigate the possibility that antagonist peptides may play a role in shaping the repertoire of T cell targets and in allowing bacterial escape of CTL surveillance. Our preliminary results have demonstrated the in vivo effect of TCR antagonism on T cell responses and protective immunity. We will study several aspects of agonist/antagonist interactions in vivo during infection. The results of these studies will help in our understanding of the complex interactions between bacteria and their hosts that determine the outcome of infection, and will have important implications for the design of effective vaccines and the selection of protective vaccine antigens.