Molecular pathogenesis and genetics in Chagas Disease cardiomyopathy: therapeutic and prognostic targets

Abstract

Chagas disease, caused by the protozoan Trypanosoma cruzi, affects 15 million people. About 30% of Chagas disease patients develop Chronic Chagas disease cardiomyopathy (CCC), an particularly lethal inflammatory cardiomyopathy that occurs decades after the initial infection, while most patients remain asymptomatic (ASY;60%). Clinical severity in Chagas disease is correlated with the occurrence of myocarditis, and survival is worse than for that of non-inflammatory cardiomyopathy. CCC heart lesions present a Th1 T cell-rich myocarditis, with cardiomyocyte hypertrophy and prominent fibrosis. Development of effective drugs for CCC is hampered by the limited knowledge of Its pathogenesis. Familial aggregation of CCC cases, as well as the fact that only 30% of infected patients develop CCC, suggest there might be a genetic component to disease susceptibility. Moreover, previous case-control studies have identified some genes associated to human susceptibility to CCC. The outcome of Chagas disease is ultimately defined in the patients' hearts, a consequence of inflammation and myocardial tissue response. We thus hypothesize that expression of many pathogenetically relevant genes and proteins in the myocardial tissue of CCC patients is controlled by genetic polymorphisms. In previous studies supported by FAPESP, we have identified differentially expressed genes and proteins, as well as DNA methylation and microRNA expression profiles in the heart of Chagas cardiomyopathy patients. In addition, we identified relevant genetic variants using genomic analyses such as GWAS (genome wide association study) in large cohorts of patients and whole exome sequencing of families with multiple cases of Chagas disease cardiomyopathy. During this visit, we will perform an integrative analysis of the data in all levels, which will indicate gene and protein expression regulation that are leading to the identification of key pathogenesis factors. We will write a grant proposal for international funding agencies to continue the studies. We will finalize writing 6 manuscripts; 9 students will be trained on genetic analysis; scientific seminars and a course on genetics of human disease will be offered to the academic community. (AU)