Functional analysis of molecular components of the habitat of Leishmania spp. - the protozoan parasites causing human leishmaniases

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Leishmania spp. are medically important intracellular proteozoan parasites. Using a proteomics approach we have previously comprehensively analysed parasite adaptation to its intracellular habitat in macrophages. Here we propose to extend and complement this approach by analysing the host cell-derived membrane and soluble proteins that contribute to this habitat. Specifically we propose to perform a comparative in silico analysis of host phagosomal multiprotein complexes between Leishmania- and latex bead-containing phagosomes to define functionally relevant differences. . Furthermore, we will pursue the relevance of one already identified difference and test the hypothesis that i) Cholesterol/lipid accumulation in Leishmania-PVs, ii) up-regulation of host cell cholesterol synthesis pathways, iii) inhibition of membrane raft dependent signalling cascades and iv) up-regulation of fatty acid catabolism in parasites are mechanistically linked and interdependent. Finally, we simultaneously want to establish experimental platforms based on ES cell- and transgenic mouse-derived primary phagocytic cells that will allow to harness the power of reverse genetics or RNAi to analyse phagosomal protein function in different cell contexts.