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

Fabrice E. 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 E. Graf, Nicola Baker, Jane C. Munday, Harry P. de Koning, David Horn, Pascal Mäser (Lead / Corresponding author)

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

38 Citations (Scopus)

202 Downloads (Pure)

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 - Aug 2015

Keywords

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

ASJC Scopus subject areas

Infectious Diseases
Pharmacology (medical)
Pharmacology

UN SDGs

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

Access to Document

10.1016/j.ijpddr.2015.04.002Licence: CC BY

Final published versionFinal published version, 543 KBLicence: CC BY

Cite this

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

year = "2015",

month = aug,

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

language = "English",

volume = "5",

pages = "65--68",

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

issn = "2211-3207",

publisher = "Elsevier",

number = "2",

}

Chimerization at the AQP2-AQP3 locus is the genetic basis of melarsoprol-pentamidine cross-resistance in clinical Trypanosoma brucei gambiense isolates. / Graf, Fabrice E.; Baker, Nicola; Munday, Jane C. et al.

In: International Journal for Parasitology: Drugs and Drug Resistance, Vol. 5, No. 2, 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 E.

AU - Baker, Nicola

AU - Munday, Jane C.

AU - de Koning, Harry P.

AU - Horn, David

AU - Mäser, Pascal

PY - 2015/8

Y1 - 2015/8

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

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Melarsoprol-Pentamidine Cross Resistance in African Trypanosomes.

High-Throughput Decoding of Virulence Mechanisms in African Trypanosomes (Senior Investigator Award)

Cite this

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Melarsoprol-Pentamidine Cross Resistance in African Trypanosomes.

High-Throughput Decoding of Virulence Mechanisms in African Trypanosomes (Senior Investigator Award)

Cite this