: The protozoan parasite Trypanosoma cruzi is the etiologic agent of Chagas' disease, an illness that causes severe morbidity and death among millions of Latin Americans. The most common, and most serious, adverse effect of chronic infection with this parasite is Chagas heart disease (CHD), a dilated cardiomyopathy of uncertain etiology. A number of mechanisms have been proposed for the pathogenesis of CHD, two of which are the subject of considerable controversy. Because parasites are scarce in or absent from the heart tissues of Chagas' patients who succumb to heart failure, autoimmunity has been proposed to be responsible for disease pathogenesis. More sensitive techniques, such as in situ PCR and immunohistochemistry, have been used to analyze these hearts and, indeed, parasite DNA and antigen are present. These findings support the hypothesis that parasite-induced damage plus host immunity to parasite antiqens is the inflammatory stimulus. Another confounding factor is that different combinations of parasite and animal strains give different outcomes, which, in actuality, is reflective of the human disease. To test the autoimmunity hypothesis for CHD pathogenesis, while simultaneously considering the parasite immunity hypothesis, we developed a mouse model of CHD (T. cruzi Brazil strain infection of male A/J mice) in which strong cardiac autoimmunity and parasite-specific immunity rapidly develop upon infection. Our research during the past several years indicates that (i) cardiac autoimmunity develops upon infection that is of similar magnitude and quality as that induced by immunization with cardiac proteins in adjuvant (purely autoimmune), (ii) autoimmunity involving a number of cardiac antigens develops in infected animals, (iii) autoimmunity to cardiac myosin may develop via the mechanisms of molecular mimicry and bystander activation, and (iv) selective suppression of myosin autoimmunity does not eliminate tissue inflammation in infected animals, suggesting that other autoimmune responses may be significant and/or that parasite-specific immunity hypothesis is sufficient to give tissue inflammation.
The Specific Aims of our research are (i) to investigate the molecular mimicry mechanism of myosin autoimmunity in CHD, (ii) to identify additional cardiac auto-antigens and determine their roles in CHD pathogenesis and (iii) to test the autoimmune and parasite immune hypotheses for CHD pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075822-03
Application #
6999368
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Massicot-Fisher, Judith
Project Start
2004-01-01
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
3
Fiscal Year
2006
Total Cost
$284,875
Indirect Cost
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Coates, Bria M; Sullivan, David P; Makanji, Ming Y et al. (2013) Endothelial transmigration by Trypanosoma cruzi. PLoS One 8:e81187
Bonney, Kevin M; Taylor, Joann M; Daniels, Melvin D et al. (2011) Heat-killed Trypanosoma cruzi induces acute cardiac damage and polyantigenic autoimmunity. PLoS One 6:e14571
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