Chimerization at the AQP2-AQP3 locus is the genetic basis of melarsoprol-pentamidine cross-resistance in clinical Trypanosoma brucei gambiense isolates

Fabrice Graf; Nicola Baker; Jane C. Munday; Harry P. de Koning; David Horn; Pascal Mäser

doi:10.1016/j.ijpddr.2015.04.002

Chimerization at the AQP2-AQP3 locus is the genetic basis of melarsoprol-pentamidine cross-resistance in clinical Trypanosoma brucei gambiense isolates

Fabrice Graf, Nicola Baker, Jane C. Munday, Harry P. de Koning, David Horn, Pascal Mäser

Research output: Contribution to journal › Article › peer-review

46 Citations (Scopus)

Abstract

Aquaglyceroporin-2 is a known determinant of melarsoprol-pentamidine cross-resistance in Trypanosoma brucei brucei laboratory strains. Recently, chimerization at the AQP2-AQP3 tandem locus was described from melarsoprol-pentamidine cross-resistant Trypanosoma brucei gambiense isolates from sleeping sickness patients in the Democratic Republic of the Congo. Here, we demonstrate that reintroduction of wild-type AQP2 into one of these isolates fully restores drug susceptibility while expression of the chimeric AQP2/3 gene in aqp2-aqp3 null T. b. brucei does not. This proves that AQP2-AQP3 chimerization is the cause of melarsoprol-pentamidine cross-resistance in the T. b. gambiense isolates.

Original language	English
Pages (from-to)	65-68
Number of pages	4
Journal	International Journal for Parasitology: Drugs and Drug Resistance
Volume	5
Issue number	2
DOIs	https://doi.org/10.1016/j.ijpddr.2015.04.002
Publication status	Published - 1 Aug 2015
Externally published	Yes

Keywords

Aquaporin
Drug resistance
Human African trypanosomiasis
Melarsoprol
Pentamidine
Reverse genetics
Sleeping sickness
Trypanosoma brucei gambiense

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ijpddr.2015.04.002Licence: CC BY

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title = "Chimerization at the AQP2-AQP3 locus is the genetic basis of melarsoprol-pentamidine cross-resistance in clinical Trypanosoma brucei gambiense isolates",

abstract = "Aquaglyceroporin-2 is a known determinant of melarsoprol-pentamidine cross-resistance in Trypanosoma brucei brucei laboratory strains. Recently, chimerization at the AQP2-AQP3 tandem locus was described from melarsoprol-pentamidine cross-resistant Trypanosoma brucei gambiense isolates from sleeping sickness patients in the Democratic Republic of the Congo. Here, we demonstrate that reintroduction of wild-type AQP2 into one of these isolates fully restores drug susceptibility while expression of the chimeric AQP2/3 gene in aqp2-aqp3 null T. b. brucei does not. This proves that AQP2-AQP3 chimerization is the cause of melarsoprol-pentamidine cross-resistance in the T. b. gambiense isolates.",

keywords = "Aquaporin, Drug resistance, Human African trypanosomiasis, Melarsoprol, Pentamidine, Reverse genetics, Sleeping sickness, Trypanosoma brucei gambiense",

author = "Fabrice Graf and Nicola Baker and Munday, \{Jane C.\} and \{de Koning\}, \{Harry P.\} and David Horn and Pascal M{\"a}ser",

year = "2015",

month = aug,

day = "1",

doi = "10.1016/j.ijpddr.2015.04.002",

language = "English",

volume = "5",

pages = "65--68",

journal = "International Journal for Parasitology: Drugs and Drug Resistance",

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Chimerization at the AQP2-AQP3 locus is the genetic basis of melarsoprol-pentamidine cross-resistance in clinical Trypanosoma brucei gambiense isolates. / Graf, Fabrice; Baker, Nicola; Munday, Jane C. et al.
In: International Journal for Parasitology: Drugs and Drug Resistance, Vol. 5, No. 2, 01.08.2015, p. 65-68.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Chimerization at the AQP2-AQP3 locus is the genetic basis of melarsoprol-pentamidine cross-resistance in clinical Trypanosoma brucei gambiense isolates

AU - Graf, Fabrice

AU - Baker, Nicola

AU - Munday, Jane C.

AU - de Koning, Harry P.

AU - Horn, David

AU - Mäser, Pascal

PY - 2015/8/1

Y1 - 2015/8/1

N2 - Aquaglyceroporin-2 is a known determinant of melarsoprol-pentamidine cross-resistance in Trypanosoma brucei brucei laboratory strains. Recently, chimerization at the AQP2-AQP3 tandem locus was described from melarsoprol-pentamidine cross-resistant Trypanosoma brucei gambiense isolates from sleeping sickness patients in the Democratic Republic of the Congo. Here, we demonstrate that reintroduction of wild-type AQP2 into one of these isolates fully restores drug susceptibility while expression of the chimeric AQP2/3 gene in aqp2-aqp3 null T. b. brucei does not. This proves that AQP2-AQP3 chimerization is the cause of melarsoprol-pentamidine cross-resistance in the T. b. gambiense isolates.

AB - Aquaglyceroporin-2 is a known determinant of melarsoprol-pentamidine cross-resistance in Trypanosoma brucei brucei laboratory strains. Recently, chimerization at the AQP2-AQP3 tandem locus was described from melarsoprol-pentamidine cross-resistant Trypanosoma brucei gambiense isolates from sleeping sickness patients in the Democratic Republic of the Congo. Here, we demonstrate that reintroduction of wild-type AQP2 into one of these isolates fully restores drug susceptibility while expression of the chimeric AQP2/3 gene in aqp2-aqp3 null T. b. brucei does not. This proves that AQP2-AQP3 chimerization is the cause of melarsoprol-pentamidine cross-resistance in the T. b. gambiense isolates.

KW - Aquaporin

KW - Drug resistance

KW - Human African trypanosomiasis

KW - Melarsoprol

KW - Pentamidine

KW - Reverse genetics

KW - Sleeping sickness

KW - Trypanosoma brucei gambiense

U2 - 10.1016/j.ijpddr.2015.04.002

DO - 10.1016/j.ijpddr.2015.04.002

M3 - Article

SN - 2211-3207

VL - 5

SP - 65

EP - 68

JO - International Journal for Parasitology: Drugs and Drug Resistance

JF - International Journal for Parasitology: Drugs and Drug Resistance

IS - 2

ER -

Chimerization at the AQP2-AQP3 locus is the genetic basis of melarsoprol-pentamidine cross-resistance in clinical Trypanosoma brucei gambiense isolates

Abstract

Keywords

UN SDGs

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