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）哪些细菌抗原被免疫系统识别，哪些因素影响细菌中抗原靶标的库，2）哪些免疫机制是保护性的，宿主免疫效应子如何抵消特定的毒力因子以产生保护性免疫，以及3）细菌逃脱免疫监视的可能性有多大以及通过何种机制。在本申请中，我们将使用单核细胞增生李斯特菌（LM）作为模型： 1.研究基因表达的调控如何影响细菌蛋白诱导免疫反应和作为保护性靶点的能力。这项研究的结果将帮助我们确定细菌抗原库的复杂性，并制定选择疫苗接种抗原靶点的一般指南。 2.测试针对LM的保护性免疫是由CTL介导的细胞溶解和细菌扩散到邻近细胞之间的竞争决定的模型。我们发现CTL细胞溶解功能可以抵消LM直接细胞-细胞传播的毒力策略，从而提出了这种模型。我们将测试这个模型的几个预测，并在这样做，我们希望确定与细菌毒力策略相关的免疫保护机制。 3.研究拮抗剂肽在T细胞靶点的形成和允许细菌逃避CTL监视中发挥作用的可能性。我们的初步结果已经证明了TCR拮抗作用对T细胞应答和保护性免疫的体内作用。我们将研究感染过程中体内激动剂/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理解细菌及其宿主之间决定感染结果的复杂相互作用，并将对有效疫苗的设计和保护性疫苗抗原的选择产生重要影响。

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.