COMPARTMENTALIZATION OF BACTERIAL ANTIGENS

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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.