Targeting purinergic signaling in Chagas disease

Project Summary Chagas disease, a major public health problem in Latin America, is caused by the infection with the protozoan parasite Trypanosoma (T.) cruzi and has been spread to non-endemic regions by migratory movements. Chagas cardiomyopathy represents the most severe complication of chronic Chagas disease in Argentina. This important illness has become a frequent cause of heart failure, cardio-embolic stroke, and sudden death in our and other endemic countries. There are still no effective prophylactic vaccines, and chemotherapy mainly relies on benznidazole, a 60-year-old drug linked to prolonged treatment and significant side effects. This parasite is an obligate intracellular pathogen that can infect any nucleated cell, but the clinically relevant niches are the cardiomyocytes since the parasite remains in the heart for several decades before the development of the cardiomyopathy. Therefore, one of the main challenges in understanding Chagas disease immunopathology is to find out why the parasite is not completely eliminated, being able to sustain a pathological inflammatory environment. After infection, the influx of immune cells consumes large amounts of oxygen, and ischemic cells rapidly respond to the hypoxic and inflammatory environment by releasing ATP to the extracellular milieu. This extracellular ATP (eATP) triggers microbicidal immune responses but is quickly hydrolyzed to the potent immunosuppressive metabolite adenosine, mainly via the concerted activity of CD39 and CD73 ectoenzymes. Increasing evidence suggests that the balance of purinergic signaling determines the immune response's outcome in different pathological scenarios. We hypothesize that the balance of purinergic responses to eATP and the nucleosides generated by CD39 and CD73 determines anti-T. cruzi immunity and triggers pathogenic mechanisms in Chagas disease. Hence, manipulating these signaling pathways could provide new approaches to limiting cardiac pathology. The central hypothesis will be tested by pursuing three specific aims: 1) Validate the participation of purinergic signaling in the cardiac response to T. cruzi infection in advanced human Chagas disease, 2) Determine the impact of CD39-CD73 ectoenzymes on the cellular immune response, and the progression of Chagas cardiomyopathy by employing experimental murine models, 3) Explore the benefits of pharmacological targeting of purinergic signaling in a mouse model of Chagas cardiomyopathy. These investigations will provide a comprehensive understanding of crucial mechanisms through which T. cruzi infection subverts immune response to sustain parasite persistence and a detailed insight into the biology of the cardiac response to infection. 1