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Retooling Leishmania metabolism: from sand fly gut to human macrophage

Doron Rosenzweig^*, Derek Smith, Fred Opperdoes, Shay Stern, Robert W. Olafson and Dan Zilberstein^*,1

^* Faculty of Biology and

Faculty of Chemical Engineering, Technion—Israel Institute of Technology, Haifa, Israel;

UVic Proteome Center, University of Victoria, British Columbia, Canada; and

Research Unit for Tropical Diseases, Christian de Duve Institute of Cellular Pathology and Catholic University of Louvain, Brussels, Belgium

¹Correspondence: Faculty of Biology, Technion—Israel Institute of Technology, Haifa 32000, Israel. E-mail: danz{at}tx.technion.ac.il07-9254com

To survive extremely different environments, intracellular parasites require highly adaptable physiological and metabolic systems. Leishmania donovani extracellular promastigotes reside in a glucose-rich, slightly alkaline environment in the sand fly vector alimentary tract. On entry into human macrophage phagolysosomes, promastigotes differentiate into intracellular amastigotes. These cope with an acidic milieu, where glucose is scarce while amino acids are abundant. Here, we use an axenic differentiation model and a novel high-coverage, comparative proteomic methodology to analyze in detail protein expression changes throughout the differentiation process. The analysis identified and quantified 21% of the parasite proteome across 7 time points during differentiation. The data reveal a delayed increase in gluconeogenesis enzymes, coinciding with a decrease in glycolytic capacity. At the same time, β-oxidation, amino acid catabolism, tricarboxylic acid cycle, mitochondrial respiration chain, and oxidative phosphorylation capacities are all up-regulated. The results indicate that the differentiating parasite shifts from glucose to fatty acids and amino acids as its main energy source. Furthermore, glycerol and amino acids are used as precursors for sugar synthesis, compensating for lack of exogenous sugars. These changes occur while promastigotes undergo morphological transformation. Our findings provide new insight into changes occurring in single-cell organisms during a developmental process.—Rosenzweig D., Smith, D., Opperdoes, F., Stern, S., Olafson, R. W., Zilberstein D. Retooling Leishmania metabolism: from sand fly gut to human macrophage.

Key Words: proteomics • metabolomics • intracellular differentiation • gene expression

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