The protozoan parasite Trypanosoma cruzi is the etiologic agent of Chagas' disease, an illness that causes effect of chronic infection with this parasite is the development of cardiomyopathy. Because parasites are rarely found in the heart tissues of Chagas' patients who succumb to heart failure, an autoimmune mechanism has been proposed to be responsible for disease pathogenesis. Although not formally proven, this possibility has been supported by extensive experimentation in which immunologically cross- reactive T. cruzi and mammalian antigens have been identified and the development of pathology has been induced by the transfer of T cells from infected mice to naive recipient. In collaboration with Dr. Stephen Miller, an accomplished cellular autoimmunologist, applied for and received development and feasibility (D/F) funding through an Arthritis and Musculoskeletal Diseases Center Grant recently awarded to Northwestern University. The modest funding provided by the D/F Award has allowed us to begin to investigate the prospect that cardiac antigen-specific autoimmunity participates in the pathogenesis of Chagas' heart disease. As a first step, we directly tested for the presence of cardiac autoantibodies in T. cruzi-infected mice with heart disease and found that such mice produce autoantibodies to four cardiac antigens: the contractile protein myosin, the intermediate filament protein desmin, and two as yet unidentified proteins of 150-kDa and 37-kDa. The anti-myosin, anti-p150 and anti-desmin responses may be especially pertinent since they are found only in mice infected with a strain of T. cruzi that causes heart disease, and not in mice infected with a noncardiopathogenic T. cruzi strain. Anti-myosin and anti- desmin responses are found in immune cardiomyopathies induced by other agents as well and, perhaps most significant, immunization with purified cardiac myosin in complete Freund's adjuvant is sufficient ot induce severe myocarditis in certain strains of mice. The preliminary results obtained with the D/F Award form the basis for this R29 Grant Application. The participation of cardiac antigen-specific antibodies and T cells in th pathogenesis of murine Chagas' heart disease will be studied from two different, but complementary, perspectives. The apparent involvement of cellular autoimmune responses in Chagas' heart disease pathogenesis will be investigated through their suppression via the induction of antigen-specific peripheral tolerance. Abrogation of cardiomyopathy in T. cruzi-infected mice following tolerance induction would constitute formal proof of a role for cellular autoimmunity in Chagas' disease pathogenesis. The second aspect of the project will focus on the specific autoantigens described above, especially since CD4+ T cell reactivity to one of them-cardiac myosin-are fundamental to other experimental cardiomyopathies. Molecular techniques will be used for the cloning and generation of recombinant myosin, desmin, p150, p37, and fragments of these proteins, and used for studies of the humoral and cellular immune responses to the native proteins during murine T. cruzi infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Tropical Medicine and Parasitology Study Section (TMP)
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Northwestern University at Chicago
Schools of Dentistry
United States
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Bonney, Kevin M; Engman, David M (2015) Autoimmune pathogenesis of Chagas heart disease: looking back, looking ahead. Am J Pathol 185:1537-47
Tyler, K M; Engman, D M (2000) Flagellar elongation induced by glucose limitation is preadaptive for Trypanosoma cruzi differentiation. Cell Motil Cytoskeleton 46:269-78
Maldonado, R A; Mirzoeva, S; Godsel, L M et al. (1999) Identification of calcium binding sites in the trypanosome flagellar calcium-acyl switch protein. Mol Biochem Parasitol 101:61-70