Leishmania spp. are obligate intracellular parasites within their host's macrophage system. Given the macrophage's usual role in killing microbial invaders, the parasite must have developed a variety of strategies to ensure its success. The objectives of this proposal are firstly to identify the macrophage receptor(s) implicated in the initial stage of this interaction, by down-modulation of macrophage receptors of known specificity whilst measuring binding of the parasite ligands gp63 and LPG. These studies will be conducted with an artificial particle capable of carrying individual parasite ligands, thus facilitating definite characterization of the binding mechanisms. Further studies will examine whether a preferential pathway of infection exists by assaying the relative macrophage-activation levels induced by uptake via gp63 and LPG. We will also initiate a new program to characterize and raise monoclonal antibodies against determinants on the amastigote surface. These studies will be extended to an analysis of the amastigote/macrophage interaction exploiting the techniques developed previously in promastigote studies. In addition we are now developing a molecular biology program, centered at present around study of the expression at both protein and transcriptional level, of the glycoprotein gp63. This abundant promastigote protein is present, but differentially processed in amastigotes. The genes encoding gp63 constitute a family of genes which show interesting heterogeneity both in their coding regions and their genomic organization. We intend to study the possible significance of these differences.
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