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Macrophage activation; Leishmania-macrophage interaction.听

鈥婤ecause of their potent microbicidal and tumoricidal capacities, macrophages play a major role in the immune response. Macrophage functions are not constitutive, being rather acquired (activation) in the presence of molecules such as cytokines or microbial-derived products. Binding of these molecules at the surface of a resting macrophage triggers intracellular signalling pathways, leading to the induction of gene expression and protein synthesis. These intracellular events culminate in the acquisition of phenotypes allowing the macrophage to perform specific immune functions.

One of my objectives is to gain a better knowledge of the molecular mechanisms leading to macrophage activation. This is essential for the development of novel pharmacological approaches based on the selective manipulation of intracellular signalling pathways. We concentrate our efforts on the role of a family of kinases known as听protein kinase C听(笔碍颁).

PKCs play a key role in intracellular signalling and the regulation of gene expression. To determine to which extent individual PKC isoenzymes regulate macrophage activity, we are genetically modifying macrophage cell lines to overproduce active PKC isoenzymes, as well as dominant-negative PKC mutants.

We also investigate the interaction between the intracellular parasite听尝别颈蝉丑尘补苍颈补听and the macrophage. Although the inside of a macrophage seems inhospitable, several intracellular microbes chose the macrophage as a host cell. Of course, these microbes evolved strategies to avoid or manipulate host immune defenses.

One of these strategies consists in modulating in their favor their host cell intracellular signalling pathways. Since听尝别颈蝉丑尘补苍颈补听interferes with macrophage activation through inhibition of PKCs, studying the underlying mechanisms will enhance our understanding of macrophage function regulation.

Finally, in the macrophage,听Leishmania听resides within a lysosomal vacuole. Using genetically defined听Leishmaniavirulence mutants, we have shown that this parasite can modulate the biogenesis of their vacuole using surface glycolipids. Defining the molecular composition of vacuoles induced by virulence mutants will contribute to our knowledge of basic microbial pathogenesis problems.