Mycobacterium avium-intracellulare complex (MAC) causes severe disseminated disease in AIDS patients. The macrophage is the cell responsible for killing MAC and initiating the host immune response. Paradoxically, it also provides the milieu for MAC to proliferate. This project focuses on the first step in the pathogenesis of disease due to MAC, attachment to host cells. We have demonstrated that in the absence of complement and immunoglobulins monocyte-derived macrophages (MDM) bind MAC. We have isolated a receptor which: 1) retains its ability to bind MAC after purification; 2) crossreacts with antibody to vitronectin receptor (VnR), but not with antibody to fibronectin receptor (FnR) or laminin receptor (LmR); and 3) is bound by GRDGSPK-Sepharose and anti-a(v)-Sepharose. In vitro, in physiologic media, MDM attached to plastic wells bind MAC in the absence of opsonins. MDM in wells coated with antibody against VnR show 50% reduction in binding MAC. A 68 kD ligand has been isolated from MAC which blocks binding of MAC to MDM. We hypothesize: receptors on the surface of host cells and ligands on MAC control binding of MAC to the host cell surface and access to the host cell. The VnR is one such receptor.
The specific aims are to: 1) identify and characterize bacterial ligands produced by MAC which interact with MDM and the interaction of these ligands with the receptors on MDM; 2) prepare antibodies that block the binding of MAC by MDM; 3) in HIV-infected and non-HIV-infected persons, determine the ability of host cells to express molecules that bind MAC on their surface and for these cells to bind MAC; 4) determine the binding site of MAC-derived ligands and intracellular movement of VnR during phagocytosis of MAC; 5) determine if the ability of host cells to express molecules that bind MAC on their surface and to bind MAC is modulated by cytokines. This project will provide a basis for understanding the attachment of, and entry into host cells by MAC. The antibodies to receptors and purified ligands and fragments of ligands that contain the binding site will be available for use in in vitro and in vivo models of infection due to MAC. An understanding of how the molecules that mediate attachment of MAC to monocytes interact may offer new approaches to the prevention and control of MAC infection at the cellular level. Specifically, identification of key receptors on host cells for MAC and ligands on MAC may offer additional avenues by which infection due to MAC could be treated or prevented, for example, by developing compounds or reagents directed towards competing with the bacterial ligand for the receptor or preventing adhesion to host tissue.
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