Structure and function of trypanosome aquaporins in health and disease

Trypanosomes are single-celled parasites that cause significant disease in Africa causing Human African Trypanosomiasis, typically fatal without chemotherapy, and livestock diseases that are a major constraint on productivity for the rural poor in sub-Saharan Africa. Pentamidine is the main drug used during the early stages of the human disease and melarsoprol is used when trypanosomes have invaded the central nervous system. Unfortunately, drug resistance including pentamidine/ melarsoprol cross-resistance is increasingly common. Recently, the membrane protein responsible for uptake of both pentamidine and melarsoprol was identified as AQP2, an aquaporin. Aquaporins transport water and other small solutes (<100 Da). AQP2 is then very unusual in transporting the much larger pentamidine (340 Da) and melarsoprol (398 Da). Furthermore, AQP2 is also of clinical relevance since mutations in aqp2 gene are present in many clinical isolates cross- resistant to pentamidine/melarsoprol and the mutations have been shown to be sufficient to confer resistance. AQP2 plays a central role in drug resistance in trypanosomes and, through its unusual transport features, may also be of great importance to the biology of trypanosomes. Using a multi-discliplinary approach, this project aims to understand how this atypical aquaporin has evolved to transport very unusual molecules, and what is its biological implication in trypanosomes.