Members of the MAC complex have recently come to the fore as one of the principle microbial infections in individuals immunocompromised by Acquired Immunodeficiency Syndrome caused by the HIV virus. MAC, and other mycobacterial pathogens, have evolved to survive within the macrophage, a cell more usually associated with the eradication of invading microbes. This interaction enables MAC to avoid both complement and the host's humoral response, and poses problems for effective chemotherapy. Parasitization of the macrophage requires the resolution of several problems. This project is designed to elucidate some of these survival strategies, and to provide information relevant to improvement of drug delivery and enhancement of macrophage activation. The problems encountered by the invading mycobacterium can be divided into two groups; first, entry and establishment of an intracellular infection, and second, avoidance of the host's immune response and subsequent macrophage activation. We propose isolation of the bacteria-containing phagosomes after uptake and at various times during compartment maturation to study the effects that MAC have on the """"""""normal"""""""" process of phagosome/endosome mixing. We shall also analyse the trafficking characteristics of the established MAC-containing vacuole, to determine its intersection with the endocytic pathway, relevant for drug targeting. In addition we intend to identify MAC proteins that are preferentially expressed in an intracellular environment and study the exocytic pathway from the MAC- containing vacuole, to determine the antigen presentation characteristics of the infected macrophage. The combination of biochemical, cell biological, and immunological approaches described in this project is supported by the strong collaborative nature of the overall program aimed at analysis of the cell biology of the intracellular MAC infection.
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