Identification of novel metabolic pathways in Leishmania parasites
Leishmania parasites cause a spectrum of diseases in people by specifically targeting macrophages in the mammalian host. Comparatively little is known about the metabolism of the intracellular parasites stages that could be the targets of new drugs.
This project will use genetic (gene deletion/overexpression), as well as newly developed metabolomics approaches to identify parasite and/or host metabolic pathways that are essential for pathogenesis. We have previously shown that Leishmania synthesize a novel carbohydrate reserve material termed mannogen.
The aims of this project are to generate Leishmania mutants that are defective in mannogen synthesis and/or degradation. These mutants will be characterized using metabolite profiling and (13C)-isotope labeling experiments to detect changes in cellular metabolism. The extent to which the loss of these pathways affects virulence will be assessed in macrophage tissue culture. The findings of this project will inform further gene deletion studies and lead to the identification of metabolic pathways essential for virulence (and hence drug targets).
- McConville MJ and Naderer T. Metabolic pathways required for intracellular survival of Leishmania. Annu Rev Microbiol 2011; 65: 543-561.
- Ramakrishnan S, Docampo MD, Macrae JI, Pujol FM, Brooks CF, van Dooren GG, Hiltunen JK, Kastaniotis AJ, McConville MJ, Striepen B. The apicoplast and endoplasmic reticulum cooperate in fatty acid biosynthesis in the apicomplexan parasite Toxoplasma gondii. J Biol Chem 2011; 287: 4957-4971.
- Saunder EC, Ng, WW, Chambers JM, Ng M, Naderer T, Krömer JO, Likic VA, McConville MJ. Isotopomer profiling of Leishmania mexicana promastigotes reveals important roles for succinate fermentation and apartate uptake in tricarboxylic acid cycle (TCA) anaplerosis, glutamate synthesis and growth. J Biol Chem 2011; 286: 27706-27717.
- Naderer T, Heng J, McConville MJ. Evidence that intracellular stages of Leishmania major utilize amino sugars as a major carbon source. PlosPathogen 2010; 6 (12): e1001245.
- Sernee FM, Ralton JE, Dinev Z, Khairallah GN, O'Hair RA, Williams SJ, McConville MJ. Leishmania b1-2 mannan is assembled on a novel mannose-cyclic phosphate primer. Proc Natl Acad Sci, USA 2006; 103(25): 9458-63.
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