Chagasic Cardiomyopathy (CCM) caused by the intracellular protozoan Trypanosoma cruzi is a major cause of mortality and morbidity in the endemic regions of Latin America with an estimated 15 million infected with or are carriers of the disease. Globalization has increased the risk of Chagas disease in developed countries including North America, Europe and Australia. We demonstrated that elevated cholesterol increased the rate of T. cruzi invasion and that this parasite utilizes LDLr to invade host cells. Parasite invasion was associated with a significant increase in the levels of LDL in organs such as heart, liver and adipose tissue. Immunofluorescence analysis demonstrated altered lysosomal pH and function during acute infection. Increased fatty acid (FA) and cholesterol metabolism was observed in the hearts of infected mice. Transmission electron microscopy revealed altered mitochondria, ER and sarcomeres in the heart of infected mice. Whole body lipid homeostasis depends on diet, lipid biosynthesis and clearance of liver and lipolysis and adipogenesis of adipose tissue. We have documented there is a better survival rate for high fat diet (HFD) mice during acute infection with the reduced rate of lipolysis; however, the surviving mice developed cardiac dysfunction with dysfunctional mitochondria and altered lipid homeostasis at later stages of infection and fat necrosis. Acute infection caused fatty liver with increased cholesterol accumulation and inflammation. Cholesterol, triglyceride, FA and glucose metabolism are significantly altered in the liver of infected mice. Our observations suggest that T. cruzi infection alters systemic and whole body lipid homeostasis for parasite survival at different stages of infection and modulates the function of heart by increased adipogenesis and lipogenesis in the myocardium during infection. Based on these observations we hypothesize that the elevated intracellular lipid levels during invasion and acute infection, and the demand for cholesterol biosynthesis during chronic infection may exhaust intracellular ER and mitochondrial oxidative capacity and thus contribute to the development of CCM. Also, we believe a significant correlation between the host lipid levels (diet, serum lipid profile, lipid biosynthesis and clearance of liver and adipocyte) and the progression of CCM exist. In order to fully appreciate the role of lipid homeostasis in the development of human CCM, novel transgenic mice models huApo-B and FAT-ATTAC will be used to demonstrate the link between diet/serum lipids/adipocyte and CCM. Understanding the factors responsible for chronic CCM will aid in the development of new approaches to prevent progression of chagasic heart disease. In addition, this proposal will provide important data on the potential interactions of the epidemics of obesity, diabetes and dyslipidemia due to demographic and epidemiologic transition to a western diet in Chagas endemic regions that can result in changes in the pathophysiology of Chagas Disease.
Low Density Lipoprotein receptor (LDLr) and cholesterol play a major role in the mechanism of Trypanosoma cruzi invasion and progression of Chagas disease. Chagas disease is a neglected tropical disease characterized by myocarditis and cardiomyopathy. It is estimated that 15 million people are infected with or carriers of the disease in Latin and South America. Obesity and diabetes have become more prevalent in Chagas-endemic area. Chronically infected immigrants in the United States estimated at 300,000. T. cruzi utilizes LDLr for invasion and infection results in accumulation of cholesterol in cells/tissues, contributing to the pathogenesis of adipose tissue and liver dysfunction and cardiomyopathy. The studies proposed in this application will establish link between infection induced intracellular cholesterol/fatty acid levels, metabolic dysfunction and cardiomyopathy, which offers the best chance for early intervention strategies aimed at preventing this devastating heart disease and to understand the interactions of the epidemics of diabetes and obesity with Chagas disease.
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