Chimerization at the AQP2-AQP3 locus is the genetic basis of melarsoprol-pentamidine cross-resistance in clinical Trypanosoma brucei gambiense isolates
- Resource Type
- Authors
- Pascal Mäser; Harry P. de Koning; Fabrice E. Graf; Jane C. Munday; David Horn; Nicola Baker
- Source
- International Journal for Parasitology: Drugs and Drug Resistance
International Journal for Parasitology: Drugs and Drug Resistance, Vol 5, Iss 2, Pp 65-68 (2015)
- Subject
- Trypanosoma brucei gambiense
Drug Resistance
Melarsoprol
Locus (genetics)
Drug resistance
Biology
Trypanosoma brucei
urologic and male genital diseases
lcsh:Infectious and parasitic diseases
parasitic diseases
medicine
lcsh:RC109-216
Pharmacology (medical)
Gene
Pentamidine
Pharmacology
Genetics
Aquaporin 3
Aquaporin 2
urogenital system
Brief Report
Aquaporin
Human African trypanosomiasis
Sleeping sickness
medicine.disease
biology.organism_classification
Virology
Trypanocidal Agents
Reverse genetics
3. Good health
Infectious Diseases
Gene Expression Regulation
Parasitology
Trypanosomiasis
medicine.drug
- Language
- ISSN
- 2211-3207
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
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.