DOI: 10.25345/c5k35mt2w
title: MassIVE MSV000100255 - Mitochondria, Interferon-gamma and genetics in Chagas disease cardiomyopathy: Pathogenesis, therapeutic targets and prognostic markers
title: Chagas disease (CD), caused by theprotozoan parasite Trypanosoma cruzi, is a neglected disease affecting around 6million people, with no effective antiparasitic drugs or vaccines. About 30% ofCD patients develop chronic Chagas disease cardiomyopathy (CCC), aninflammatory cardiomyopathy that occurs decades after the initial infection,while most infected patients (60%) remain asymptomatic in the so-calledindeterminate form (IF). Death results from heart failure or arrhythmia in asubset of CCC patients. Myocardial fibrosis, inflammation and mitochondrialdysfunction are involved in the arrhythmia substrate and triggering events. Survivalin CCC is worse than in other cardiomyopathies. There are no early prognosticmarkers for sudden cardiac death (SCD), which may occur even in Chagas diseasepatients without advanced disease. Thus, identifying an early biomarker couldoptimize the allocation of implantable cardioverter defibrillators (ICD), thestandard prophylaxis/therapy of SCD patients. Distinct from othercardiomyopathies, CCC displays a Th1- T cell rich myocarditis with abundantIFN-gamma and TNF-alpha, and selectively lower levels of mitochondrial energymetabolism enzymes in the heart. IFN-G and TNF-A signalling, which areconstitutively upregulated in CD patients, negatively affect mitochondrialfunction. A genetic component in disease susceptibility was suggested bycase-control studies that identified gene polymorphisms associated to CCC development.In a pilot genome-wide association (GWA) study, our group identified commonpolymorphisms associated with atrioventricular block/pacemaker use in CCCpatients. Whole exome sequencing (WES) in nuclear families with multiple CCC/IFcases has disclosed rare heterozygous pathogenic variants in mitochondrial andinflammatory genes segregating in CCC cases. We here aim to study thepathophysiology and genetics of CCC, in order to identify novel therapeuticsand biomarkers that may improve survival of CCC patients. In our firstsubproject, we will explore the pathophysiology of mitochondria and cytokinesin CCC by performing functional studies with CRISPR-Cas9-gene editedcardiomyocyte cell lines and induced pluripotential stem cell (iPSC)-derivedcardiomyocytes from the patients carrying or not the variants of interest underthe effect of IFN-G and TNF-A. Subproject 2 involves the search formitochondria-targeted therapy. Using cytokine-induced mitochondrial dysfunctionas a therapeutic target, we will screen an FDA (Food and DrugAdministration)-approved drug library to identify compounds mitigatingIFN-G+TNF-A-induced mitochondrial dysfunction and validate the best hits iniPSC-derived cardiomyocytes and IFN-G transgenic mice that develop inflammatorycardiomyopathy. Such repositioned drugs could have a therapeutic role in CCC.In subprojects 3 to 5, we will study the genetic landscape of Chagas disease,analyzing rare and common genetic variants associated with each clinical form.We will identify gene polymorphisms and assess their prognostic value forarrhythmic forms and SCD in Chagas. In subproject 3, we will perform across-sectional GWA study, with a large sample size of arrhythmic andnon-arrhythmic cases of CCC, identifying genetic markers associated with device(pacemaker and ICD) use. In subproject 4, we will assess the prognostic value ofcommon genetic markers in longitudinal followup cohorts of arrhythmic forms ofCCC, with outcomes such as ventricular tachycardia, SCD and all-cause death. Insubproject 5, we will use whole exome sequencing to compare the genetic(nuclear and mitochondrial DNA) landscape of unrelated patients across thespectrum of Chagas disease and non-inflammatory cardiomyopathies. In subproject6, we will use single cell RNA sequencing to probe peripheral blood cells fromdifferent forms of chronic Chagas disease for various phenotypes andtrajectories related to the polarized differentiation of IFN-gamma producing Tcells observed in CCC.