Chagas disease is caused by the parasite, Trypanosoma cruzi is a major cause of heart disease in Latin America and due to immigration is now being diagnosed in non-endemic areas of the world including the United States. Previously, we demonstrated that adipose tissue and the adipocyte are early targets of infection and storage sites for the parasite during the chronic phase. An important question is whether or not the infection of adipocytes is a major driving force for the initiation and progression of the disease both in the acute and chronic phases. This is central for understanding pathogenesis and treatment of Chagas disease. We are uniquely positioned to answer this question through the use of state-of-the-art mouse models that have previously established in the areas of obesity and diabetes. These rodent models will allow us to directly establish a cause/effect relationship between the parasitism of adipose tissue by the parasite and Chagas disease progression. In the current application we will evaluate the effect of T. cruzi infection of adipos tissue on the heart directly by employing two distinct mouse models. One in which there is a full component of adipose tissue but the inflammatory pathway is compromised only in the adipocyte and a second model in which the adipose tissue is totally ablated. The hypothesis is that adipose tissue inflammation is a critical mediator of the overall host response to T. cruzi infection and a determinant of the ensuing cardiomyopathy. We are taking advantage of these novel mouse models to determine the functional relevance of the adipocyte- mediated inflammatory response in T. cruzi infection and more specifically, the role of the adipocyte. To examine the role of the adipocyte on the development of Chagas disease we infect aP2-RID?/? transgenic mice (RID). These mice express the potently anti-inflammatory RID?/? complex in adipocytes. We will infect these mice with trypomastigotes of T. cruzi and assess parasitemia, mortality, histopathology of adipose tissue and heart, cardiac structure and function and parameters of innate and adaptive immunity in transgenic and WT control mice. The parasite load will be assessed by electron microscopy, qPCR and bioluminescence.
The second aim will further clarify the importance of adipose tissue and complement these studies and we will determine the temporal involvement of adipose tissue/adipocyte in the development of Chagasic heart disease. Herein, we will eliminate adipose tissue by FAT-ATTAC technology in a model of inducible lipoatrophy, at various time-points of infection. These studies will establish the importance of the adipocyte as a central player in the pathogenesis of Chagas disease.
Chagas disease, caused by the parasite Trypanosoma cruzi, is a major cause of heart disease in Latin America and is being diagnosed with increasing frequency in non-endemic areas of the world including the United States. Data accumulated over the past decade suggests that adipose tissue and the adipocytes or fat cells are important in the pathogenesis of this disease. Adipose tissue is an early target and a reservoir of the infection. In the present application a key question to be explored is whether or not the infection of adipocytes, the major cell-type in adipose tissue, is a major driving force for the initiation ad progression of the disease both in the acute and chronic phases. This is central for our understanding of the disease and potential treatment of Chagas disease. We are uniquely positioned to answer this question through the use of 'state-of-the-art' mouse models that have previously established in the areas of obesity and diabetes. These rodent models will allow us to directly establish a cause/effect relationship between the parasitism of adipose tissue by the parasite and disease progression. In this R21 application we will focus on the acute infection. We will use two mouse models one in which the adipose tissue is intact but the pro-inflammatory pathway in the adipocyte is impaired. A second model in which the adipose tissue is almost totally ablated. This will enable us to directly assess the impact of the adipocyte in ths infection on cardiac function and on the immunologic response to Trypanosoma cruzi infection.
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