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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI068538-02
Application #
7244049
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Wali, Tonu M
Project Start
2006-06-01
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2010-05-31
Support Year
2
Fiscal Year
2007
Total Cost
$241,779
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Machado, Fabiana S; Dutra, Walderez O; Esper, Lisia et al. (2012) Current understanding of immunity to Trypanosoma cruzi infection and pathogenesis of Chagas disease. Semin Immunopathol 34:753-70
Nagajyothi, Fnu; Weiss, Louis M; Silver, David L et al. (2011) Trypanosoma cruzi utilizes the host low density lipoprotein receptor in invasion. PLoS Negl Trop Dis 5:e953
Ferreira, Adaliene Versiani Matos; Segatto, Marcela; Menezes, ZĂ©lia et al. (2011) Evidence for Trypanosoma cruzi in adipose tissue in human chronic Chagas disease. Microbes Infect 13:1002-5
Nagajyothi, Fnu; Zhao, Dazhi; Machado, Fabiana S et al. (2010) Crucial role of the central leptin receptor in murine Trypanosoma cruzi (Brazil strain) infection. J Infect Dis 202:1104-13
Villalta, Fernando; Scharfstein, Julio; Ashton, Anthony W et al. (2009) Perspectives on the Trypanosoma cruzi-host cell receptor interactions. Parasitol Res 104:1251-60
Mukherjee, Shankar; Nagajyothi, Fnu; Mukhopadhyay, Aparna et al. (2008) Alterations in myocardial gene expression associated with experimental Trypanosoma cruzi infection. Genomics 91:423-32
Nagajyothi, Fnu; Desruisseaux, Mahalia S; Thiruvur, Niranjan et al. (2008) Trypanosoma cruzi infection of cultured adipocytes results in an inflammatory phenotype. Obesity (Silver Spring) 16:1992-7
Nagajyothi, Fnu; Desruisseaux, Mahalia S; Thiruvur, Niranjan et al. (2008) Trypanosoma cruzi Infection of Cultured Adipocytes Results in an Inflammatory Phenotype. Obesity (Silver Spring) :
Ny, Lars; Li, Hua; Mukherjee, Shankar et al. (2008) A magnetic resonance imaging study of intestinal dilation in Trypanosoma cruzi-infected mice deficient in nitric oxide synthase. Am J Trop Med Hyg 79:760-7
Ashton, Anthony W; Mukherjee, Shankar; Nagajyothi, F N U et al. (2007) Thromboxane A2 is a key regulator of pathogenesis during Trypanosoma cruzi infection. J Exp Med 204:929-40

Showing the most recent 10 out of 11 publications