Chimerization at the AQP2–AQP3 locus is the genetic basis of melarsoprol–pentamidine cross-resistance in clinical Trypanosoma brucei gambiense isolates. Issue 2 (August 2015)

• Record Type: Journal Article
• Authors: Graf, Fabrice E.; Baker, Nicola; Munday, Jane C.; de Koning, Harry P.; Horn, David; Mäser, Pascal
• Is Part Of: International journal for parasitology. Volume 5:Issue 2(2015)
• Page Start: 65
• Page End: 68
• Publication Date: 2015-08
• Subjects: Human African trypanosomiasis -- Sleeping sickness -- Trypanosoma brucei gambiense -- Drug resistance -- Melarsoprol -- Pentamidine -- Aquaporin -- Reverse genetics; Parasitic diseases -- Chemotherapy -- Periodicals; Drug resistance -- Periodicals; 616.96061
• DOI: 10.1016/j.ijpddr.2015.04.002
• Languages: English
• ISSNs: 2211-3207

Abstract

Highlights: Expression of AQP2 restores drug susceptibility in a resistant Trypanosoma brucei gambiense isolate. The AQP2/3 chimera from the resistant isolate does not complement AQP2 deletion. Hence AQP2/3 chimerization accompanied by loss of AQP2 is the cause of drug resistance. Graphical Abstract: 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.