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Abstract. We tested four isolates of Trypanosoma cruzi to assess parasite virulence and ability to cause myocarditis, cardiac sympathetic denervation, and histopathologic alterations in organs of the digestive system. The susceptibility of rats depends on the population of T. cruzi, with the ABC strain and the CL-Brener clone killing all animals, regardless of the parasitemic pattern. All tested T. cruzi populations caused acute myocarditis, but failed to induce histologic alterations in the intestine. The Cl-Brener and ABC isolates caused esophageal myositis. The myocarditis caused by the ABC, CL-Brener, and Y isolates was severe, but resolution started at the end of the acute phase. In contrast, the Col 1.7G2 clone induced mild and sustained myocarditis. Our results also showed that T. cruzi populations able to induce severe acute myocarditis caused marked sympathetic denervation, but recovery of normal cardiac histology and innervation occurred. The sustained myocarditis induced by Col 1.7 G2 clone failed to cause sustained denervation.

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Micronutrient malnutrition is usually highly prevalent in areas endemic for Chagas disease. Nevertheless, the contribution of micronutrient deficiency to the immunopathology of this infection is often overlooked. In the present work, we assessed the effects of vitamin E deficiency on acute Trypanosoma cruzi (Y strain) infection of Holtzman rats. At 20 days post infection, vitamin E deficiency induced changes in leukocyte levels and exacerbated the myocarditis and sympathetic denervation of ventricular hearts. Vitamin E-deficient infected rats displayed significant leukopenia, evidenced by the decline in the numbers of CD45RA(+)CD3(-) B-cells and CD3(+)CD4(+) T-lymphocytes in the peripheral blood compared with infected control rats. In contrast, vitamin E deficiency induced monocytosis as well as an increased differentiation rate of monocytes to macrophages, as revealed by immunohistochemical analysis.

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SummaryAt the site of infection, pro-inflammatory cytokines locally produced by macrophages infected with Trypanosoma cruzi can activate surrounding nonprofessional phagocytes such as fibroblasts, epithelial and endothelial cells, which can be further invaded by the parasite. The effect of secreted soluble factors on the invasion of these cells remains, however, to be established. We show here that two epithelial cell lines become significantly susceptible to the infection by the Y strain of T. cruzi after tumour necrosis factor (TNF) treatment. The increase in the invasion was correlated with the increasing concentration of recombinant TNF added to cultures of HEK293T or LLC-MK2 cells. Supernatants taken from PMA-differentiated human monocytes infected with T. cruzi also increased the permissiveness of epithelial cells to subsequent infection with the parasite, which was inhibited by a TNF monoclonal antibody. Furthermore, the permissiveness induced by TNF was inhibited by TPCK, and led to significant decrease in the number of intracellular parasites, providing evidence that activation of NF-kB induced by TNF favours the invasion of the epithelial cell lines by T. cruzi through yet an unidentified mechanism. Our data indicate that soluble factors released from macrophages early in the infection favours T. cruzi invasion of non-professional phagocytic cells.

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Chagas' disease is caused by the intracellular protozoan Trypanosoma cruzi. Here we have investigated the role of endothelin-1 in T. cruzi acute infection in rats, using the orally active ET(A) receptor antagonist BSF-461314. Treatment with BSF-461314 markedly increased parasitaemia, but animals managed to control the infection by day 15. Histopathological analysis of heart tissue at the end of the acute phase showed greater numbers of parasite nests in BSF-461314-treated animals. The perfusion of isolated rat hearts from infected animals with bradykinin failed to induce an increase, and actually reduced, coronary blood flow. Pretreatment with BSF-461314 prevented changes in coronary flow induced by T. cruzi infection. Together these results demonstrate that endothelin-1, through ET(A) receptor activation, contributes to the protective immune response against acute T. cruzi infection. Moreover, these data suggest that endothelin-1 is a mediator of impaired endothelium-dependent vasomotion in the coronary microcirculation associated with acute T. cruzi infection.