Organisms belonging to the Mycobacterium avium-Mycobacterium intracellular complex (MAC) are the most common cause of systemic bacterial infections in patients with the Acquired Immunodeficiency Syndrome (AIDS), and the incidence of MAC infection in non-AIDS patients is also increasing.l In the last 28 months of support by this grant, we have identified cytokines that trigger intracellular killing of MAC by macrophages, defined pathways for cell activation and intracellular killing of MAC, characterized macrophage cationic bactericidal proteins responsible for non-oxidative killing of MAC, isolated cell wall-associated proteins and evaluated some of their roles in the pathogenesis of MAC infection, studied the interactions between immune cells and MAC and evaluated the response of T cells from HIV-1 sero-positive and sero-negative individuals to MAC-derived antigens. We propose to continue and expand our investigations in the following areas: 1 - Evaluate the initial interaction between MAC and the host, by investigating the mechanisms(s) of MAC binding to intestinal mucosal cells and the effect of antibodies in preventing colonization; 2 - Clone and express the genes encoding for MAC-derived putative protein virulence factors in E. coli and mycobacterial that do not cause systemic disease in order to determine whether transformed mycobacterial can cause invasive disease in beige mice; 3 - Define the regulatory role of MAC cell wall proteins (including recently purified 33 KDa and 65 KDa) moieties by evaluating the ability of peptides generated from these proteins to stimulate alphabeta TCR+ and gammadelta TCR+ cells and alter macrophage functions, and compare the effects of these peptides with the activity of MAC-derived lipoarabinomannan and glycopeptidolipid; 4 - Since some host cells (such as macrophages bearing the CD14+/CD16+ phenotype, endothelial cells, and fibroblasts) take up MAC but have little or no cidal activity, we plan to assess cytotoxicity of gammadelta and NK cells against these potential sanctuaries of MAC. Release of organisms following lysis could facilitate uptake by more efficient, bactericidal phagocytes; 5 - We plan to study further the intracellular killing of MAC within macrophages by isolating bactericidal cationic proteins (BDCPs/defensins) and define their mechanism of activity. We also seek to evaluate the potential macrophage activating role of any new recombinant cytokine. The studies will use HIV-1 infected individuals, HIV-1 seronegative patients with severe localized or systemic MAC infection and healthy controls. The results of these studies are likely to provide new insights into the pathogenesis of MAC infection in patients with and without AIDS.
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