Mycobacterium tuberculosis is a worldwide disease that affects over one- third of the world's population and is a leading cause of worldwide morbidity and mortality. M. tuberculosis is an intracellular pathogen that invades and multiplies within macrophages. The first step in host defense against this organism is binding to specific receptors on the macrophage surface and internalization via receptor-mediated phagocytosis. Two receptors on the macrophage surface are important in mediating uptake of M. tuberculosis. The mannose receptor binds directly to a mannose- containing ligand on the mycobacterial surface and carries the organism into the phagosomal compartment of the cell. Surfactant associated protein A (SP-A) in the lung acts as an opsonin and coats the surface of the mycobacterium through a mannose-dependent binding. These complexes are then internalized via the SP-A receptor on macrophages. Expression of these receptors is linked to the functional state of the macrophage: the mannose receptor is expressed predominantly on resident tissue macrophages and deactivated macrophages, while expression of the SP-A receptor is highest on circulating monocytes and activated macrophages. It has been postulated that survival or killing is directly related as to which of these two receptors is used for entry: uptake via the mannose receptor leads to survival, while uptake through the SP-A receptor leads to killing. In the setting of HIV infection, host defense against M. tuberculosis is severely impaired. Both direct infection of tissue macrophages and interaction of released HIV proteins with macrophages alter a variety of functions of this cell. It is the hypothesis of this proposal that HIV or its constituents modulate macrophage phagocytic functions through production of macrophage deactivating cytokines, resulting in altered intracellular mycobacterial growth.
The specific aims of this proposal are: 1) to examine the effect of macrophage-deactivating cytokines (IL-10 and TGFbeta) on expression of the mannose and SP-A receptors and subsequent M. tuberculosis survival; 2) to examine the role of HIV-derived proteins in regulation of these receptors and mycobacterial survival; and, 3) to examine the effect of direct infection of macrophages by HIV on expression of these receptors and mycobacterial survival.
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