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Comparative genomics of drug resistance in Trypanosoma brucei rhodesiense

Graf, Fabrice E. and Ludin, Philipp and Arquint, Christian and Schmidt, Remo S. and Schaub, Nadia and Kunz Renggli, Christina and Munday, Jane C. and Krezdorn, Jessica and Baker, Nicola and Horn, David and Balmer, Oliver and Caccone, Adalgisa and de Koning, Harry P. and Mäser, Pascal. (2016) Comparative genomics of drug resistance in Trypanosoma brucei rhodesiense. Cellular and molecular life sciences, 73 (17). pp. 3387-3400.

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Official URL: http://edoc.unibas.ch/44673/

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Abstract

Trypanosoma brucei rhodesiense is one of the causative agents of human sleeping sickness, a fatal disease that is transmitted by tsetse flies and restricted to Sub-Saharan Africa. Here we investigate two independent lines of T. b. rhodesiense that have been selected with the drugs melarsoprol and pentamidine over the course of 2 years, until they exhibited stable cross-resistance to an unprecedented degree. We apply comparative genomics and transcriptomics to identify the underlying mutations. Only few mutations have become fixed during selection. Three genes were affected by mutations in both lines: the aminopurine transporter AT1, the aquaporin AQP2, and the RNA-binding protein UBP1. The melarsoprol-selected line carried a large deletion including the adenosine transporter gene AT1, whereas the pentamidine-selected line carried a heterozygous point mutation in AT1, G430R, which rendered the transporter non-functional. Both resistant lines had lost AQP2, and both lines carried the same point mutation, R131L, in the RNA-binding motif of UBP1. The finding that concomitant deletion of the known resistance genes AT1 and AQP2 in T. b. brucei failed to phenocopy the high levels of resistance of the T. b. rhodesiense mutants indicated a possible role of UBP1 in melarsoprol-pentamidine cross-resistance. However, homozygous in situ expression of UBP1-Leu(131) in T. b. brucei did not affect the sensitivity to melarsoprol or pentamidine.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Mäser, Pascal and Balmer, Oliver and Ludin, Philipp
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Birkhäuser
ISSN:1420-9071
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:01 Dec 2016 15:00
Deposited On:01 Dec 2016 15:00

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