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Mitochondria, interferon-gamma and genetics in Chagas Disease cardiomyopathy: pathogenesis, therapeutic targets and prognostic markers

Abstract

Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi, is a neglected disease affecting around 6 million people, with no effective antiparasitic drugs or vaccines. About 30% of CD patients develop chronic Chagas disease cardiomyopathy (CCC), an inflammatory cardiomyopathy that occurs decades after the initial infection, while most infected patients (60%) remain asymptomatic in the so-called indeterminate form (IF). Death results from heart failure or arrhythmia in a subset of CCC patients. Myocardial fibrosis, inflammation and mitochondrial dysfunction are involved in the arrhythmia substrate and triggering events. Survival in CCC is worse than in other cardiomyopathies. There are no early prognostic markers for sudden cardiac death (SCD), which may occur even in Chagas disease patients without advanced disease. Thus, identifying an early biomarker could optimize the allocation of implantable cardioverter defibrillators (ICD), the standard prophylaxis/therapy of SCD patients. Distinct from other cardiomyopathies, CCC displays a Th1-T cell rich myocarditis with abundant IFN-G and TNF-A, and selectively lower levels of mitochondrial energy metabolism enzymes in the heart. IFN-³ and TNF-± signalling, which are constitutively upregulated in CD patients, negatively affect mitochondrial function. A genetic component in disease susceptibility was suggested by case-control studies that identified gene polymorphisms associated to CCC development. In a pilot genome-wide association (GWA) study, our group identified common polymorphisms associated with atrioventricular block/pacemaker use in CCC patients. Whole exome sequencing (WES) in nuclear families with multiple CCC/IF cases has disclosed rare heterozygous pathogenic variants in mitochondrial and inflammatory genes segregating in CCC cases. We here aim to study the pathophysiology and genetics of CCC, in order to identify novel therapeutics and biomarkers that may improve survival of CCC patients. In our first subproject, we will explore the pathophysiology of mitochondria and cytokines in CCC by performing functional studies with CRISPR-Cas9-gene edited cardiomyocyte cell lines and induced pluripotential stem cell (iPSC)-derived cardiomyocytes from the patients carrying or not the variants of interest under the effect of IFN-G and TNF-A. Subproject 2 involves the search for mitochondria-targeted therapy. Using cytokine-induced mitochondrial dysfunction as a therapeutic target, we will screen an FDA (Food and Drug Administration)-approved drug library to identify compounds mitigating IFN-G+TNF-A-induced mitochondrial dysfunction and validate the best hits in iPSC-derived cardiomyocytes and IFN-G transgenic mice that develop inflammatory cardiomyopathy. 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 for arrhythmic forms and SCD in Chagas. In subproject 3, we will perform a cross-sectional GWA study, with a large sample size of arrhythmic and non-arrhythmic cases of CCC, identifying genetic markers associated with device (pacemaker and ICD) use. In subproject 4, we will assess the prognostic value of common genetic markers in longitudinal followup cohorts of arrhythmic forms of CCC, with outcomes such as ventricular tachycardia, SCD and all-cause death. In subproject 5, we will use whole exome sequencing to compare the genetic (nuclear and mitochondrial DNA) landscape of unrelated patients across the spectrum of Chagas disease and non-inflammatory cardiomyopathies. In subproject 6, we will use single cell RNA sequencing to probe peripheral blood cells from different forms of chronic Chagas disease for various phenotypes and trajectories related to the polarized differentiation of IFN-G producing T cells observed in CCC. (AU)

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