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

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.

Chagas disease is caused by the insect-transmitted protozoan Trypanosoma cruzi and is the most important parasitic infection in Latin America, affecting 6 - 8 million people. After an initial acute stage, the disease can remain latent for decades before re-emerging as a chronic condition characterised by cardiomyopathy and/or digestive-tract tissue damage. Current drugs are toxic and often non-curative. Investigations into the mechanisms of disease pathology and the underlying causes of treatment failure have been confounded by the complex and long-term nature of the infection. In addition, T. cruzi has the capacity to undergo a form of dormancy, a phenomenon that may explain 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.

We have developed a powerful range of approaches that can be applied to Chagas disease research. These include crucial advances in highly sensitive imaging procedures that allow T. cruzi infections to be followed in real time, both in vivo and in vitro, innovative high-throughput genetic modification technology, highly flexible cell sorting capacity under containment level 3, and transcriptome profiling. Our aims are to use whole genome functional screens to dissect the processes that trigger dormancy at a molecular and cellular level, to determine the biological relevance of the phenomenon in an in vivo context, and to assess its implications for drug development.

This project will provide new information and tools to aid the rational design of drugs able to kill parasites that are dormant and probably metabolically quiescent. Our close collaborative links with the global Chagas disease drug development community will ensure that findings can influence strategic direction and be rapidly integrated into the discovery pipeline.

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. It is a major public health problem throughout Latin America, and increasingly in other regions as a result of migration. The currently available drugs are characterised by toxicity and limited efficacy, and new therapeutic approaches are urgently required. This task is being tackled at an international level, with significant input from the academic and commercial sectors, and from not-for-profit drug development consortia.

Many aspects of T. cruzi biology remain to be resolved. Major questions include: how is the parasite able to survive as a life-long infection despite a vigorous immune response, and why are treatment failures so frequent. Recently, it has been observed that T. cruzi can exhibit a form of dormancy, a phenomenon that could explain its long-term persistence in the face of chemical and immune-mediated assault. Investigating the regulatory trigger(s) and role(s) of this phenotype are now widely recognised as one of the most important questions in the field. In this project, we will optimise imaging and genome-wide screening techniques and apply them to dissect the process of dormancy at the molecular level. The output of this work will impact on many aspects of Chagas disease research and beyond, with beneficiaries including:

(1) The 6 - 8 million people currently infected with T. cruzi and those who care for them. They will benefit through the provision of new information on the mechanisms of disease pathology and from an improved drug-development pipeline.

(2) Those in both the academic and commercial drug development sectors who will gain new information on the nature of parasite dormancy, allowing them to streamline Chagas disease drug design strategies so that they take account of the need to kill dormant or metabolically quiescent parasites.

(3) Researchers in basic parasite biology who will be provided with new information on the T. cruzi life cycle and disease pathogenesis. In addition, they will have free access to the reagents, constructs, parasite libraries and strains that we develop during this work.

(4) The UK health service, who are having to treat an increasing number of Chagas disease patients. As a national centre of excellence for research on this parasite, we maintain continual engagement with clinicians in this area, particularly at the Hospital for Tropical Diseases in London.

(5) Junior researchers, particularly those from disease endemic countries. The project will allow us to continue to offer training opportunities at the cutting edge of Chagas disease research.

(6) The lessons learned from our work on T. cruzi dormancy will have relevance to the global research community working on latent infections and the problem of pathogen persistence in the face of therapeutic challenge.