The goal of this project is to study the cell biology of the intracellular parasite, Leishmania spp. This organism is an obligate intracellular of macrophages. Our work seeks to identify the receptors on macrophages responsible for leishmania recognition and the ligands on the parasite to which each receptor binds. Our hypothesis is that events which occur at the macrophage plasma membrane can affect subsequent events in the infectious process, including the intracellular survival of leishmania, macrophage-mediated inflammation associated with leishmania infection, and perhaps even the selection of the type of host immune response to leishmania. For this reason, we will use molecular approaches to identify the macrophage receptors involved in leishmania binding, and investigate the cellular signals generated following receptor ligation by leishmania. Our plan, is to utilize individual, cloned or purified, macrophage receptors and purified or cloned leishmania ligands to definitively identify the respective receptor ligand interactions involved in leishmania phagocytosis. The cellular responses which we will measure are the release of potential inflammatory mediators from infected macrophages, such as cytokines and toxic oxygen species. We have previously demonstrated that complement enhances leishmania interactions with macrophages. In this proposal we will define the role of complement and that of each of the macrophage complement receptors in leishmania phagocytosis, both in vitro and in vivo. This work seeks to understand the cell biology of leishmania phagocytosis. It may lead to a better understanding of the cell biology of intracellular parasitism, in general, and specifically it may define the cell and tissue tropism of the leishmania species.
