Mechanisms of Infection Chronicity and Pathogenesis in Gastrointestinal Chagas disease

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Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. Chagas is a neglected tropical disease that affects millions of people from Latin America. Infected people carry the parasite for life but many never experience any symptoms. Others develop serious problems affecting the heart and/or the digestive tract. The reasons why people progress to different types of disease is not well understood. During chronic infections, only small numbers of parasites are present and they are located inside cells, within solid tissue. This has made it difficult to detect parasites and investigate their contribution to the disease process. We developed a technique that makes these experiments much easier. It is based on transgenic T. cruzi parasites that have been engineered to express a light-emitting enzyme. By measuring the intensity of light emitted by the parasites we can track and quantify them inside live mice and in specific organs. We have already applied this system to study the development of Chagas heart disease and to test whether drugs can cure T. cruzi infections in mice. In this project we will now apply this technology to investigate the digestive form of Chagas disease. First we will find out which parts of the mouse's digestive tract are affected by T. cruzi infection and ask whether parasites or mice with different genetics are associated with different levels of disease severity. Next we will analyse the microscopic changes that affect the gut's muscles and the parts of the nervous system that control them. We will also investigate how the mouse's immune system responds to T. cruzi, and find out if these responses play a part in the development of disease. Finally, we will test whether benznidazole, a drug that can cure mice of T. cruzi infection, can also prevent the development and progression of digestive pathology. Together these studies will provide a much better understanding of how T. cruzi causes chronic infections and leads to symptomatic Chagas disease affecting the GI tract. This will help accelerate the development of novel strategies to treat patients.