Fat Tissue Regulates the Pathogenesis and Severity of Cardiomyopathy in Murine Chagas Disease

Abstract

Chronic Chagas cardiomyopathy (CCC) caused by a parasite Trypanosoma cruzi is a life-threatening disease in Latin America, for which there is no effective drug or vaccine. The pathogenesis of CCC is complex and multifactorial. Previously, we demonstrated T. cruzi infected mice lose a significant amount of fat tissue which correlates with progression of CCC. Based on this an investigation was undertaken during both acute and chronic T. cruzi infection utilizing the FAT-ATTAC murine model (that allows modulation of fat mass) to understand the consequences of the loss of adipocytes in the regulation of cardiac parasite load, parasite persistence, inflammation, mitochondrial stress, ER stress, survival, CCC progression and CCC severity. Mice were infected intraperitoneally with 5x104 and 103 trypomastigotes to generate acute and chronic Chagas models, respectively. Ablation of adipocytes was carried out in uninfected and infected mice by treatment with AP21087 for 10 days starting at 15DPI (acute infection) and at 65DPI (indeterminate infection). During acute infection, cardiac ultrasound imaging, histological, and biochemical analyses demonstrated that fat ablation increased cardiac parasite load, cardiac pathology and right ventricular dilation and decreased survival. During chronic indeterminate infection ablation of fat cells increased cardiac pathology and caused bi-ventricular dilation. These data demonstrate that dysfunctional adipose tissue not only affects cardiac metabolism but also the inflammatory status, morphology and physiology of the myocardium and increases the risk of progression and severity of CCC in murine Chagas disease. AUTHOR SUMMARYAn estimated eight million individuals worldwide are chronically infected with Trypanosoma cruzi, the causative agent of Chagas disease (CD). Of these infected individuals, 30% will develop chronic Chagas cardiomyopathy (CCC), a major cause of morbidity and mortality in CD endemic regions for which there is currently no effective drug or vaccine. The molecular mechanisms underlying CCC pathogenesis, progression and severity are complex, multi-factorial and not completely understood. Earlier, it was demonstrated that T. cruzi persists in adipose tissue, alters adipocyte physiology, and causes loss of body fat mass in T. cruzi infected mice with CCC. In this study, the authors examined the role of visceral fat pad (adipose tissue) in regulating the pathogenic signalling in the development and progression of CCC using a fat mass modulatable transgenic mouse CD model. Loss of fat cells increased cardiac lipid load and deregulated cardiac lipid metabolism leading to mitochondrial oxidative stress and endoplasmic reticulum stress and severe CCC. In addition, loss of fat cells increased cardiac parasite load during acute infection and altered immune signalling in the hearts of infected mice during chronic infection. These discoveries underscore the importance of adipose tissue in the development of CCC.