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

47 Citations (Scopus)

269 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

UN SDGs

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

SDG 3 Good Health and Well-being

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

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

UR - https://www.scopus.com/pages/publications/84937892741

U2 - 10.1016/j.ijpddr.2015.04.002

DO - 10.1016/j.ijpddr.2015.04.002

M3 - Article

C2 - 26042196

AN - SCOPUS:84937892741

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

UN SDGs

Keywords

ASJC Scopus subject areas

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

UN SDGs

Keywords

ASJC Scopus subject areas

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