Organisms belonging to the Mycobacterium avium complex (MAC) are the most common systemic bacterial pathogens in patients with AIDS; however, the reason MAC infections are so common, in contrast to other intracellular pathogens such as Listeria and Nocardia, is unclear. Our working hypothesis is that MAC infections develop in the context of a T helper/inducer lymphocyte defect, but other factors which potentiate infection are a blunted host response related to microbial factors interacting with the cells of the immune system. MAC organisms, once phagocytosed by macrophages survive intracellularly because of (1) impaired activation by various cytokines elaborated by cells of the lymphatic system and possibly natural killer (NK) cells and (2) effect of arachidonic acid pathway metabolites that are triggered by the presence of intracellular MAC. As the MAC infection progresses, antigenic moieties such as protein or glycolipid antigens may activate a T suppressor cell response. Our proposed experiments involve the study of patient with HIV infection in the progressive stages of their disease, patients with MAC infections who do not have AIDS, and normal controls. We will focus on: (1) the effect of mycobacterial derived antigens on activation of T-lymphocytes, (2) the effect of activating cytokines, such as tumor necrosis factor, interferon-gamma, colony stimulating factors (M and GM) and interleukin-2 on macrophage activation when tested against a panel of AIDS isolates of the predominant serotypes, (3) the effect of activating cytokines on interaction of macrophages and NK cells, (4) production of macrophage defensins following activation by cytokines to determine if the more virulent (from human infection and from mouse challenge studies) strains are less susceptible to defensin killing or can abrogate a defensin response, (5) the measurement of intracellular cAMP levels following phagocytosis, and the effect of prostaglandin E2-inhibitors, such as indomethacin, in reversing a killing defect following phagocytosis of MAC organisms, (6) the interaction of macrophage activating cytokines in combination, (7) the effect of hormones like 1,25 (OH)2 Vitamin D3 on macrophage activation, and (8) the ability of mycobacterial antigens to induce a suppressor mononuclear cell response. These studies may help to define potentially reversible defects in host defense against MAC Infections in AIDS patients and identify promising therapeutic, if not prophylactic, approaches.
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