Cardiac Cell Entry-Inhibition and Protection Therapy for Chronic Chagas Disease

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DESCRIPTION (provided by applicant): The obligate intracellular protozoan Trypanosoma cruzi causes Chagas' disease, a leading cause of morbidity and mortality in Latin America. It is a major economic burden in Latin America and in developed counties such as the USA, largely due to the approximately 30% of chagasic patients who progress to chronic Chagas cardiomyopathy. Chronic Chagas heart disease is characterized by generalized focal inflammation, fibrosis, arrhythmias, congestive heart failure and sudden death. There are no drugs capable of ameliorating chronic Chagas cardiomyopathy. Heart transplant is the only cure but it is not practical due to the difficulty is securing hearts. The goal of this proposal is to determine the optimal dose and kinetic regimen of a novel lead compound that, in accord with preliminary results, effectively block T cruzi entry into cardiomyocytes and cardiac fibroblasts, reversing cardiac parasitism, inflammation and fibrosis in a mouse model of chronic Chagas cardiomyopathy. The concept underlying the novel antitrypanosomal compound is similar to that antiviral Maraviroc, which works by blocking HIV entry into CD4 lymphocytes. Maraviroc is currently used to treat AIDS. We propose to determine 1) dose regimen of biologic entry cell inhibitor that optimally reduces cardiac parasitism in mice with chronic cardiomyopathy; 2) dose regimen of a synthetic peptide modeled on the biologic, which optimally reduces cardiac parasitism in mice with chronic cardiomyopathy; 3) whether swapping peptide motifs in the lead antitrypanosomal compound improves therapeutic efficiency; and 4) mechanisms underlying differential interaction of synthetic peptides with entry receptors on cardiac cells in stimulating either host cell invasion or trophic response that improves therapeutic efficiency. The project wil use biochemical, parasitological, genetic, cytochemical and non-invasive diagnostic approaches and highlights the translational value of understanding molecular mechanisms governing entry of intracellular microbes into their habitat.