The currently emerging tuberculosis epidemic, when viewed in the context of parallel problems such as emerging drug resistance, and the high susceptibility of HIV-positive individuals, is a great cause for concern. Moreover, at the basic scientific level much is still unknown about the host-parasite relationship, including what specific antigens are recognized to initially trigger host immunity, and the mechanisms underlying the clearly complex T cell-mediated cellular response to Mycobacterium tuberculosis infection. Accordingly, in this competing continuation application, we propose to continue to perform basic research in the mouse infection model in these areas; specifically, the spectrum of antigen recognition by defined T cell subsets, including how this changes during the course of the infection, and continued work into precisely defining the role of such T cell subsets, including the kinetics of their emergence and loss, and their relative contributions to the expression of specific resistance. For the first, we will use methods standardized over the past several years within the Mycobacteria Research Laboratories, CSU, to produce highly purified subcellular fractions of native mycobacterial protein antigens, and then use these fractions in in vitro assays to measure the cytokine response of purified T cell subsets harvested from mice infected with virulent M.tuberculosis. For the second, we will continue previous work under this Program aimed at defining the precise nature of the T cell response, including the expression of protective immunity, DTH, and memory immunity, and the relative contributions of CD4, CD8, and gamma delta T cell subsets to these parameters. In addition, we will investigate the roles of chemokines and cytokines in the regulation of immunity to the infection, using modern RT-PCR technology and the realistic low dose aerosol lung infection model. Finally, the roles of specific cell subsets and cytokines will also be approached using a variety of gene disrupted mouse models, already established as breeding colonies in our laboratory. We anticipate these proposed experiments will provide useful new information regarding the relative roles of T cell subsets in acquired immunity to the infection, the spectrum of T cell subset cytokine production, the antigenic targets of this production, and how these parameters change as the course of the infection progresses from a state of active to quiescent disease. As previously in this Program, the proposed work will draw upon the broad expertise of various members of the Mycobacteria Research Laboratories, CSU, as well as a number of highly qualified consultants/collaborators.
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