Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

Abstract

SUMMARY Acute Trypanosoma cruzi infections can be asymptomatic, but chronically infected individuals can die of Chagas' disease. The transfer of the parasite mitochondrial kinetoplast DNA (kDNA) minicircle to the genome of chagasic patients can explain the pathogenesis of the disease; in cases of Chagas' disease with evident cardiomyopathy, the kDNA minicircles integrate mainly into retrotransposons at several chromosomes, but the minicircles are also detected in coding regions of genes that regulate cell growth, differentiation, and immune responses. An accurate evaluation of the role played by the genotype alterations in the autoimmune rejection of self-tissues in Chagas' disease is achieved with the cross-kingdom chicken model system, which is refractory to T. cruzi infections. The inoculation of T. cruzi into embryonated eggs prior to incubation generates parasite-free chicks, which retain the kDNA minicircle sequence mainly in the macrochromosome coding genes. Crossbreeding transfers the kDNA mutations to the chicken progeny. The kDNA-mutated chickens develop severe cardiomyopathy in adult life and die of heart failure. The phenotyping of the lesions revealed that cytotoxic CD45, CD8 + γδ, and CD8α + T lymphocytes carry out the rejection of the chicken heart. These results suggest that the inflammatory cardiomyopathy of Chagas' disease is a genetically driven autoimmune disease.

Parasite Induced Genetically Driven Autoimmune Chagas Heart Disease in the Chicken Model

“…Growth of Parasites 1. Grow trypomastigote forms of T. cruzi Berenice and the β-galactosidase-expressing Tulahuen T. cruzi MHOM/CH/00 C4 in murine muscle cell (L6) cultivated in Dulbecco minimal essential medium with 10% FSB, 100 IU/ml penicillin, 100 μg/ml streptomycin, and 250 nM L-glutamin (pH 7.2), 5% CO 2 at 37 °C.…”

“…Autoimmunity and parasite persistence are competing theories to explain the pathogenesis of Chagas disease 1,2 . To separate roles played by parasite persistence and autoimmunity in Chagas disease we inoculate the T. cruzi in the air chamber of fertilized eggs.…”

The importance of originality in scientific research on neglected tropical diseases

“…The treatment of Chagas heart disease has now been deciphered, and this scientifi c discovery brings hope for thousands of people. Although the studies on Chagas disease pathogenesis have received recognition after publications in prestigious scientifi c journals 3,[6][7][8][9] , the practical consequences of treating the autoimmune pathology require further progress on bone marrow transplantation immunology for matching histocompatible donors. Ideally, this can be accomplished alongside novel investigations to discover a nontoxic drug to eradicate T. cruzi in the candidate graft recipient 10 .…”

“…Progress has been made toward the treatment and partial prevention of several neglected diseases, but the worldwide spread of leishmaniases and Chagas disease is worrisome 1,2 . To contribute to the discussion on these neglected tropical diseases, the recorded levels of morbidity and mortality, which are now considered a global health problem requiring international solidarity, must be considered 3 .…”

Determinação do potencial tripanocida de derivados do ácido copálico

“…As complicações digestivas são caracterizadas pela dilatação do esôfago e colón, em consequência de lesões do sistema nervoso entérico, principalmente pela desnervação no plexo mioentérico de Auerbach (TEIXEIRA, 2011;RASSI et al, 2012). A desnervação induz à perda de coordenação motora e consequentemente, na acalasia dos esfíncteres, o que resulta no quadro patológico de megaesôfago e megacólon (RASSI et al, 2012).…”