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.
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