The Regulation of Infection-Induced Cardiac Autoimmunity and Natural Dissemination of Trypanosoma cruzi in Experimental Chagas Heart Disease

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Chagas heart disease, caused by infection with the protozoan parasite Trypanosoma cruzi, is still regarded as a major public health problem in Central and South America. The finding of cardiac specific autoimmunity during infection in both humans and experimental animals has provided a basis for investigation of its potential role in disease pathogenesis for many years. However, the complex nature of Chagas disease has left questions of the true mechanisms of cardiac inflammation, in addition to an understanding of the natural course of infection, largely unanswered. My thesis research consisted of investigating aspects of parasite infection-induced cardiac autoimmune responses and the spatiotemporal dissemintation of T. cruzi in an experimental model of Chagas heart disease. The infection of A/J mice with the Brazil strain of T. cruzi results in the development of acute myocarditis with both humoral and cellular autoreactivity by 21 days post infection. To test the hypothesis that the magnitude of the autoimmune response is directly proportional to the amount of damage elicited by the parasite, I administered a trypanocidal drug, benznidazole, to mice to reduce the number of viable parasites following infection and determined that treatment not only decreased disease severity and eliminated mortality, but also significantly reduced cardiac myosin-specific DTH and antibody production. With a strong enough secondary cardiac insult, the autoreactivity and myocarditis could be restored, indicating the reestablishment of self-tolerance after the eradication of the parasite was not permanent in our disease model. Overall, an important link between the levels of live parasite and the presence of autoimmunity was provided, suggesting that treatments designed, such as vaccines, to specifically target the parasite will likely reduce or eliminate the induction of autoimmunity as well. To further understand the natural course of infection, I engineered firefly luciferase-expressing T. cruzi in order to non-invasively monitor the dissemination of parasites in mice over time using bioluminescence imaging technology. For a more in-depth analysis of parasite tropism during infection, the tissue distribution of T. cruzi was determined by imaging heart, spleen, skeletal muscle, lungs, kidneys, liver and intestines ex vivo. This novel parasite line has already provided interesting results illustrating the natural dissemination of T. cruzi during infection and will continue to serve as a tool for studying a number of aspects of Chagas disease. In conclusion, these results not only provide encouragement for the future exploration of parasite-specific therapeutic strategies for Chagas disease by showing that elimination of T. cruzi is effective at reducing or eliminating autoimmunity, but also illustrate a novel tool that could be easily applied to the screening of such therapeutical agents via bioluminescence.

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  • 09/14/2018
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