Mycobacterium avium-intracellulare (MAC) is the most frequent opportunistic pathogen causing bacteremia in patients with AIDS. Evidence of MAC infection can be found in 50% of autopsied AIDS patients. Currently used anti-MAC antibiotics are toxic and generally ineffective. Attempts at more effective therapy are hampered by lack of knowledge about the basic biology of the organism. A recent NIH-sponsored workshop on Future Directions in Discovery and Development of Therapeutic Agents for Opportunistic Infections Associated with AIDS, the participants concluded that """"""""Developing a cure for MAC infection will require a major effort geared to understanding the basic properties of the organism..."""""""" To fill this need this Program Project application is submitted. Project 1 will examine the receptors used for recognition and phagocytosis of MAC. This project will examine the roles that specific receptors have in the subsequent intracellular localization of the organisms and in development of disease in a scid mouse model of MAC infection. Project 2 will examine the strategies that MAC uses to avoid intracellular killing. Particular emphasis will be on the biochemical, electron microscopic and immunologic characterization of the MAC-containing phagosome. Project 3 is a dissection of the intracellular events which occur after engulfment of MAC by macrophages. Exploiting novel assays in broken and semipermeable cells, this project will examine the molecular requirements for fusion of MAC- containing phagosomes with endosomes and lysosomes. Project 4 proposes a detailed examination of the interaction of MAC-infected cells with T cells to define protective epitopes in normal hosts. Further analysis of MAC infection in immunodeficient scid mice will define precisely the role of antigen-specific CD8 and CD4 T cells in host protection and in macrophage killing of MAC in vivo and in vitro. Project 5 will test the hypothesis that MAC infection specifically modulates macrophage effector functions in response to cytokine stimulation. These studies will include a detailed examination of the ability of infected macrophages to synthesize bactericidal effectors as well as cytokines, and will test the effects of isolated MAC lipoarabinomannans and glycopeptidolipids on macrophage functions. These studies will determine the molecular nature of the defect in macrophages infected in the absence of T cells, as in AIDS. Together, these highly interactive projects will bring the tools of modern molecular and cell biology and immunology to the study of MAC infection. In this way, we will acquire the knowledge of basic MAC biology required for improved therapy of this disease. As an added benefit, these studies will enhance our understanding of Mycobacterial infections in general.
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