: Chagas disease is the most lethal endemic disease in the Western Hemisphere. Various hypotheses have been proposed to explain the pathogenesis of Chagas disease, ranging from degradation of the affected tissues by the presence of the parasite to the possibility of an autoimmune response that is not dependent on the persistence of live infection. It has been shown that kDNA integration into the vertebrate host genome occurs frequently. Furthermore, the KDNA integration that takes place in early embryonic life perpetuates through the germline of vertebrarte hosts. We hypothesise that kDNA mutations in the course of Chagas disease can be associated with the histopathology evident in the vertebrate host heart tissue. In this study, the chicken model will be utilized because chicks hatched from Trypanosoma cruzi-inoculated eggs are infection-free, even though PCR amplification with specific nested primer sets and Southern blots reveal kDNA-positive bands and absence of nuclear DNA. In this kDNA-positive animal model we will determine the phenotypic modification of mutated host cells that could trigger autoimmunity in Chagas disease. Novel chimeric protein encoded by ORFs formed by kDNA and host DNA juxtaposition, which carries the potential to induce the immune response will be detected, and its a.a. sequence determined by mass spectrometry. The chimeric protein sequence will be correlated with a potential ORF detected by Blast analyses of DNA sequences originated from kDNA mutated birds. Moreover, the role of immune competent cells in the production of heart lesions present in kDNA mutated chickens will be determined in the congenic MHC(B), BB (B12/B12) and CC (C4/C4) lineages. This will consist of histo-compatible donor heart graft into the subcutaneous tissue at the base of the neck of kDNA mutated chickens showing ECG alterations typical of Chagas disease. Control experiments will consist of control histo-compatible chicken heart graft into kDNA-negative recipients of the same congenic strain. The heart graft will be excised from the recipient chicken at various set-times, and the tissue will be subjected to histopathological exam. The phenotypes of the immune cells associated with the rejection of the target heart will be detected. This investigation will set the basis for explaining long-lasting asymptomatic infections in individuals with harmless kDNA mutation, and Chagas heart disease in cases showing deleterious kDNA mutations in some chromosomal sites. ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Research Grants (R03)
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Pathogenic Eukaryotes Study Section (PTHE)
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Wali, Tonu M
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University of Brasilia
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Teixeira, A R L; Nitz, N; Guimaro, M C et al. (2006) Chagas disease. Postgrad Med J 82:788-98