Chagas' disease caused by the protozoan parasite Trypanosoma cruzi, is an important cause of acute myocarditis and chronic cardiomyopathy in endemic regions of Latin America. In recent years it has also seen observed as an opportunistic infection in individuals with HIV/AIDS. In view of the increase of obesity, diabetes and AIDS in developing world, the relationship between obesity and infectious diseases has become an important issue. The role of glucose metabolism and the role of the fat cell in the pathogenesis of both acute and chronic Chagas' disease have never been fully explored. Preliminary data indicates that T. cruzi invades cultured fat cells and in addition invades and persists in adipose tissue where it upregulates inflammatory mediators. Moreover, infection with this parasite profoundly alters glucose metabolism and adiponectin levels. Thirty days after infection of mice with this parasite, there are alterations in the expressions of various cytokines and other adipose tissue-specific proteins. We plan to utilize a novel mouse model of inducible lipoatrophy that we have developed to determine the precise temporal involvement of adipocytes during both the acute and the chronic stages of Trypanosoma cruzi infection. In these mice we will characterize the metabolic alterations using the euglycemic clamp procedure. The adipocyte-derived factor adiponectin has been widely implicated in the pathogenesis of heart disease and is reduced both in HIV and acute Trypanosoma cruzi infection. Using a novel model of adiponectin null mice, the role of adiponectin in cardiac hypertrophy will be evaluated in Trypanosoma cruzi infected mice. In both of these mouse models infected with Trypanosoma cruzi we will examine fat from specific regions of the body at various time points from 15-300 days post infection by immunoblot analysis, histopathology and transmission electron microscopy. Employing a euglycemic insulin clamp, the underlying causes for the hypoglycemia observed during acute infection, specifically the regulation of hepatic glucose metabolism, will be examined. The effects of acute and chronic hyperglycemia on the reactivation of parasites in the chronic phase of Chagas' disease will be determined. Finally, we will gain new insights into the cardioprotective role of the adipokine adiponectin during the chronic phase of Trypanosoma cruzi infection. It is expected that these studies will contribute significantly towards a better understanding of Chagas' disease development in dysregulated metabolic states such as HIV lipodystrophic patients, associated with decreased insulin sensitivity and decreased circulating levels of adiponectin. ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
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Wali, Tonu M
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Albert Einstein College of Medicine
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