This proposal presents a new central working hypothesis which holds that the more virulent strains of M. avium actively contribute to immune dysfunction in infected mice. The mechanism for this, the applicants hypothesize, involves incorrect signaling by infected macrophages, which sets in motion events leading to a dramatic drop in T cells able to specifically recognize mycobacterial antigens, and is in keeping with their observations of increasing numbers of dead lymphocytes, apoptic cells within granulomas, and an almost complete absence of lymphocytes in advanced tissue lesions. To test this hypothesis, the applicants will look at the progression of these events using both in vivo and in vitro approaches. In the former, they will exploit their expertise in using various mutant and gene disrupted mouse models to dissect the components of immunity that allow or prevent the proper expression of acquired cellular immunity to the progressive virulent infection. In the latter, they will use cloned isolates representative of the different colony forms of M. avium to define the response at the macrophage level that allows or prevents bacterial growth, including whether this correlates with certain patterns of cytokine release, and the expression of T cell directed signals such as B7, to try to determine the conditions under which mis-directed signaling might occur [apoptosis-directed; TH2 directed, etc.]. As an added variable, they will examine these events using cells from innately resistant or susceptible mouse strains to try to define the influence of the host haplotype on these parameters. Finally, they will test the hypothesis that appropriate chemotherapy can restore the correct immunologic functions/signals, using both established regimens, as well as new compounds recently identified in their laboratory as active.
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