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High treatment failure rates in Trypanosoma brucei gambiense sleeping sickness: the interface between drug resistant parasites and advanced disease stage.
Human African trypanosomosis (HAT), caused by Trypanosoma brucei (T.b.) gambiense, constitutes a serious health problem in sub-Sahara Africa. In HAT foci where high treatment failure rates are observed, we isolated parasites that are resistant against melarsoprol, which was up to recently the only drug available to treat the central nervous system (CNS) stage of HAT. However, melarsoprol resistant parasites were also isolated from patients with late stage HAT that became cured after treatment with melarsoprol. Drug resistance is thus not sufficient to explain treatment outcome (cure or relapse) at the level of the individual patient. A factor that might contribute to treatment failure is the progress of the disease in the CNS before melarsoprol treatment is installed. To monitor the efficacy of treatment in function of disease progression, we will use a T.b. gambiense infection model in mice that are infected with trypanosomes that are genetically modified with a luciferase gene as a bioluminescent reporter. These bioluminescent trypanosomes can be tracked within a living host using in vivo bioluminescence imaging to enable accurate assessment of treatment outcome. To verify whether naturally occurring drug resistance plays a major role in defining treatment outcome, we will infect the mice with a natural melarsoprol resistant T.b. gambiense strain and with the same strain but rendered melarosprol sensitive by neutralizing the gene that is responsible for drug resistance.
Date:1 Jan 2016 → 31 Dec 2018