Combination chemotherapy of Human African trypanosomiasis: the potential of drug synergism and the blood-brain barrier

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Our goal is to gain a greater understanding and improve treatment of Human African Trypanosomiasis (HAT), also known as sleeping sickness. HAT is a major cause of suffering and death in 36 countries throughout sub-Saharan Africa and is always fatal if untreated. The disease is caused by parasites called trypanosomes that are spread by the bite of the tsetse fly. The East African form of HAT is caused by T.b.rhodesiense and the West African form by T.b.gambiense. In early-stage disease the parasites invade the bloodstream and major organs, and at the late-stage the central nervous system (CNS) is invaded. For the parasites to enter the CNS they must cross a structure called the ‘blood-brain barrier’ (BBB). We use a mouse model that closely mirrors the human disease, characterised by the development of a severe inflammatory reaction in the brain. Melarsoprol, the drug most frequently used for CNS infection, kills 5% of all patients who receive it due to brain inflammation. Because of this problem new methods of treating CNS disease are urgently needed. We will use reduced dosages of melarsoprol combined with other drugs to treat trypanosome-infected mice. MRI , a powerful method of visualising the BBB, will be used to monitor BBB function . This project will highlight which drug combinations are the most effective.