Trypanosoma brucei; Amino acid permease; Ion channel; ABC transporter; Lipid precursor; Drug target; Xenopus laevis oocyte; Saccharomyces cerevisiae
Macêdo Juan P, Schmidt Remo S, Mäser Pascal, Rentsch Doris, Vial Henri J, Sigel Erwin, Bütikofer Peter (2013), Characterization of choline uptake in Trypanosoma brucei procyclic and bloodstream forms., in Molecular and biochemical parasitology
, 190(1), 16-22.
Greganova Eva (2013), In silico ionomics segregates parasitic from free-living eukaryotes, in Genome Biol Evol
, 5(10), 1902-1909.
Inbar Ehud, Canepa Gaspar E, Carrillo Carolina, Glaser Fabian, Suter Grotemeyer Marianne, Rentsch Doris, Zilberstein Dan, Pereira Claudio A (2012), Lysine transporters in human trypanosomatid pathogens., in Amino acids
, 42(1), 347-60.
Gonzalez-Salgado Amaia, Steinmann Michael E, Greganova Eva, Rauch Monika, Mäser Pascal, Sigel Erwin, Bütikofer Peter (2012), myo-Inositol uptake is essential for bulk inositol phospholipid but not glycosylphosphatidylinositol synthesis in Trypanosoma brucei., in The Journal of biological chemistry
, 287(16), 13313-23.
Serricchio Mauro, Bütikofer Peter (2011), Trypanosoma brucei: a model micro-organism to study eukaryotic phospholipid biosynthesis., in The FEBS journal
, 278(7), 1035-46.
By definition, an endoparasite scavenges nutrients from its host. Transport processes are therefore of particular importance to parasite metabolism, and the study of nutrient transporters will not only deepen our understanding of how endoparasites have adapted to life within a host, it will also reveal vulnerable points for chemotherapeutic intervention. The pharmacological potential of nutrient transporters is two-fold: on the one hand, transporters may be drug targets themselves if they are essential for parasite nutrition. On the other hand, transporters may be exploited to specifically target drugs into the parasite via pathways that are absent in the host. With the availability of parasite genome sequences, transporters can be investigated on the systems level. The aim of this Sinergia project is to identify, characterize, and pharmacologically evaluate nutrient transporter families from Trypanosoma brucei.T. brucei ssp. comprise the causative agents of human and livestock trypanosomosis, sleeping sickness and nagana. The parasites are transmitted by the blood-sucking tsetse fly and prevalent throughout tropical Africa. There is an urgent need for new, specific drugs against sleeping sickness as the current ones suffer from serious side effects and resistance problems. Trypanosomes are not only devastating pathogens; they have also become model organisms for molecular parasitology since they can be propagated axenically in vitro and are amenable to reverse genetics. Research on trypanosomal nutrient uptake has so far concentrated on transporters of purines, pyrimidines, and sugars. Here we are focusing on other transporter families that bear physiological significance and pharmacological potential:1. Amino acid permeases, for trypanosomes rely on exogenous amino acids as energy source, differentiation signals, and precursors for trypanothione synthesis.2. Transporters of the lipid precursors choline, ethanolamine and inositol, essential for the synthesis of phospholipids in T. brucei.3. Ion channels (K+, Ca2+, Cl-), prominent drug targets in other systems but hitherto unexplored in trypanosomes.4. ABC transporters, among which detoxification pumps are notorious for causing drug resistance in all kinds of pathogens.Computational prediction of transporters from T. brucei, comparative genomics, and transcriptomics [Mäser lab] will form the basis for selection of candidate transporters for experimental investigation. Functional characterization of trypanosomal transporters will be carried out by expression in the yeast Saccharomyces cerevisiae [Rentsch lab] and in Xenopus laevis oocytes [Sigel lab], with particular emphasis on potential inhibitors and toxic substrates. The physiological role and pharmacological potential of the identified transporters in bloodstream-form T. brucei will be addressed by reverse genetics [Bütikofer lab]. Finally, the obtained results can be validated in the mouse model [Mäser lab]. This joint effort will promote the understanding of parasite metabolism and open new chemotherapeutic strategies in a synergistic way.