Understanding the molecular basis and role of parasite dormancy in Chagas disease

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Chagas disease is the most important parasitic infection in Latin America, affecting 6 - 8 million people. In addition, because of migration, it is becoming a global health problem, with thousands of infected individuals resident in Europe, including the UK. The disease results from infection with the insect-transmitted single-cell parasite Trypanosoma cruzi. Following the initial acute stage, the disease can remain latent for decades before re-emerging as a chronic condition characterised by heart disease and/or digestive-tract tissue damage. Current drugs are toxic and often non-curative. Because of the complex long-term nature of human infections, investigations into disease pathology and the reasons for treatment failure have been problematic. Recently, it has been reported that T. cruzi has the capacity to undergo a form of dormancy, a phenomenon that may have important roles in parasite persistence and the limited efficacy of current therapy. The mechanisms that trigger dormancy are unknown, and understanding the process represents a major challenge to the research community.In this project, we will exploit advances that we have made in parasite imaging technology and high-throughput T. cruzi genetic modification procedures to better understand dormancy. Our goals are to identify the biochemical mechanisms that trigger the process and to establish its biological role in the life-cycle of the parasite. The outcome of this research will have an immediate impact on therapeutic development. We will provide new information to aid the design of drugs that are able to kill parasites that are dormant and probably metabolically quiescent. Our close links with the global Chagas disease drug development community will ensure rapid integration of these findings into the discovery pipeline.