This is a program project to study the cell biology of Mycobacterium avium complex (MAC) infection. Although current anti-retroviral therapy of HIV infection delays progression to AIDS and prophylaxis of opportunistic infections delays or prevents these complications of the immunosuppression of AIDS, MAC and other mycobacteria infections remain significant problems complicating HIV. Patients who fail or cannot take combination anti- retroviral therapy for any reason remain highly susceptible to this and other opportunistic infections. While antibiotic prophylaxis has had some major impact on MAC disease, therapy remains difficult and both prophylaxis and therapy remain only partially successful. Better methods of prevention and treatment remain a high priority for this complication of HIV. To succeed at these aims requires a much better understanding of the pathogenesis of MAC infection. Our program fills this need by focusing on MAC pathogenesis. While the projects have been very interactive in these investigations, the studies have divided approximately into work or initial interactions between MAC and host cells; studies of the mechanism and effects of MAC modulation of the intracellular environment once the bacteria has infected its definitive host cell, the macrophage and investigations of the innate and acquired host response to infection, together with initiation of strategies for vaccine development. The studies will build on the previous findings of the program, including studies of MAC interaction with fibronectin and with the complement component C2a; determination of how MAC exerts its influence over the highly dynamic macrophage phagosome in which it establishes infection; development of novel vaccine strategies using targets developed in the pat and how MAC genes specifically expressed in the phagosome induce the immune evasion which characterize mycobacterial diseases. To achieve these ends, the projects will make use of a clinical core at the Washington University ACTU and of molecular biology core to coordinate efforts on molecular genetic approaches to pathogenesis. These coordinated efforts will enable the program will achieve its objective to develop a detailed understanding of the cell and molecular biology of the interaction of MAC with the host, in order to discover new and useful drug targets, prophylaxis methods, and therapeutic strategies.
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