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Comparative genomics of drug resistance in Trypanosoma brucei rhodesiense.

  • Graf FE Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051, Basel, Switzerland.
  • Ludin P Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051, Basel, Switzerland.
  • Arquint C Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051, Basel, Switzerland.
  • Schmidt RS Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051, Basel, Switzerland.
  • Schaub N Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051, Basel, Switzerland.
  • Kunz Renggli C Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051, Basel, Switzerland.
  • Munday JC Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G12 8TA, UK.
  • Krezdorn J Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G12 8TA, UK.
  • Baker N Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK.
  • Horn D Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK.
  • Balmer O Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051, Basel, Switzerland.
  • Caccone A Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA.
  • de Koning HP Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G12 8TA, UK.
  • Mäser P Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051, Basel, Switzerland. pascal.maeser@unibas.ch.
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  • 2016-03-15
Published in:
  • Cellular and molecular life sciences : CMLS. - 2016
African trypanosomes
Aquaporin
Melarsoprol
Pentamidine
Purine permease
RNA-binding protein
Amino Acid Sequence
Aquaporins
Comparative Genomic Hybridization
DNA, Protozoan
Drug Resistance
Genome, Protozoan
Heterozygote
Humans
Male
Melarsoprol
Nucleoside Transport Proteins
Parasitic Sensitivity Tests
Pentamidine
Phenotype
Polymorphism, Single Nucleotide
Protozoan Proteins
RNA-Binding Proteins
Sequence Alignment
Trypanocidal Agents
Trypanosoma brucei rhodesiense
Trypanosomiasis, African
English 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.
Language
  • English
Open access status
hybrid
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Persistent URL
https://sonar.ch/global/documents/135490
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