Mycobacterium avium(MAC) is the causative agent of the most common opportunistic infections in AIDS patients, and treatment is difficult due to the lack of effective antibiotics. In this application we propose to examine the role of T cells and macrophages in immunity to MAC infections using an in vivo model in mice. The basic hypothesis is that immunity to MAC is the result of a bi-directional interaction between T cells and macrophages, and in HIV-1 infection, this interaction is prevented by the elimination of CD4+ T cells. We will first examine the T cell response to MAC by murine and human T cells. Protective T cell clones from MAC-infected BALB/c mice will be generated, and tested by transfer into SCID mice. We will generate and test murine Th1-CD4, Th2-CD4, and CD8 T cell lines and clones as well as MAC-specific human T cell clones from MAC infected, non-AIDS patients. Second, the T cell inducing determinant recognized by each of these T cells will then be identified by examining 1)secreted antigens, 2) sonicates of MAC, and 3) bacterial expression libraries, expressing fragments of the MAC genome. The actual epitope will be further defined using synthetic peptides. Once identified, the determinants will then be tested for their ability to induce protective immune responses against MAC infection. The third area of investigation will examine the activation of macrophages into becoming microbicidal for MAC in the presence or absence of T cells. Macrophages from SCID mice or from SCID mice to which the protective T cell clones have been transferred will be examined for their killing ability. We will then identify the signals and/or factors generated by T cells,in combination with IFN-gamma which can enhance the anti-MAC activity of macrophages. From these experiments, using this mouse model which is similar to AIDS, we will be able potentially to elucidate methods for activating macrophages to be able to clear MAC infections. The overall goal of this project is to increase our understanding of the basic immunobiology of MAC infections. In addition to MAC infections, many of the findings should relate to other Mycobacterial infections, including M. tuberculosis. This new information should significantly add to the design of effective treatments and vaccines against MAC infections.
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