No abstract

The cytokine-mediated stimulation of the hypothalamuspituitary-adrenal (HPA) axis is relevant for survival during bacterial endotoxemia and certain viral infections. However, only limited information is available regarding the effects of endogenous glucocorticoids on parasite diseases. We have studied this issue using, as a model, C57Bl/6 and Balb/c mice infected with Trypanosoma cruzi, the causal agent of Chagas' disease. These two mouse strains differ in the susceptibility to infection with the parasite. An intense stimulation of the HPA-axis was observed 3 weeks after infection in both strains, but glucocorticoid levels were already increased two-to threefold in the less susceptible Balb/c strain during the first week. Blockade of glucocorticoid receptors with the glucocorticoid antagonist RU486, starting on day 10 after infection, partially reversed the thymic atrophy and decreased the number of CD4 C CD8 C thymocytes without affecting parasitemia and the number of inflammatory foci in the heart. However, tumor necrosis factor-a blood levels were increased in infected mice of both strains treated with RU486. Furthermore, the blockade of glucocorticoid receptors accelerated death in C57Bl/6J mice and increased lethality to 100% in Balb/c mice. The results obtained represent the first evidence that an endocrine host response that is coupled to the immune process can strongly affect the course of a parasite infection.

SUMMARY Inoculation of Trypanosoma cruzi, Tulahuén strain, into C57BL/6 and BALB/c mice led to an acute infection characterized by marked parasitaemia, myocardial inflammation and thymocyte depletion. While C57BL/6 mice showed a progressive and lethal disease, BALB/c mice partly recovered. To characterize these murine models more effectively, we studied the parasite burden, serum levels of major infection outcome‐related cytokines, the in vitro features of T. cruzi infection in peritoneal macrophages and the immunophenotype of thymic cells. The greater disease severity of T. cruzi‐infected C57BL/6 mice was not linked to an increased parasite load, as parasitaemia, myocardial parasite nests and amastigote counts in peritoneal macrophages were not different from those in BALB/c mice. Cortical thymocyte loss was accompanied by the presence of apoptotic bodies and fragmented nuclear DNA, whereas fluorocytometric analysis at 17 days postinfection (p.i.) revealed a more pronounced loss of CD4+ CD8+ cells in C57BL/6 mice. This group displayed higher levels of TNF‐α on days 14 and 21 p.i., in the presence of lower IL‐1β and IL‐10 concentrations by days 14 and 21, and days 7 and 14 p.i., respectively. Day‐21 evaluation showed higher concentrations of nitrate and TNF‐α soluble receptors in C57BL/6 mice with no differences in IFN‐γ levels, with respect to the BALB/c group. Increased morbidity of C57BL/6 T. cruzi‐infected mice does not seem to result from an aggravated infection but from an unbalanced relationship between pro‐ and anti‐inflammatory mediators.

The data presented revealed the presence of low-frequency MSI (MSI-L) at the 1p and 9p regions in both MDN and CMM. Whether the MSI-L pattern reflects a defect in mismatch repair genes is still to be determined.

Oral transmission of Chagas disease has been documented in Latin American countries. Nevertheless, significant studies on the pathophysiology of this form of infection are largely lacking. The few studies investigating oral route infection disregard that inoculation in the oral cavity (Oral infection, OI) or by gavage (Gastrointestinal infection, GI) represent different infection routes, yet both show clear-cut parasitemia and heart parasitism during the acute infection. Herein, BALB/c mice were subjected to acute OI or GI infection using 5x104 culture-derived Trypanosoma cruzi trypomastigotes. OI mice displayed higher parasitemia and mortality rates than their GI counterparts. Heart histopathology showed larger areas of infiltration in the GI mice, whereas liver lesions were more severe in the OI animals, accompanied by higher Alanine Transaminase and Aspartate Transaminase serum contents. A differential cytokine pattern was also observed because OI mice presented higher pro-inflammatory cytokine (IFN-γ, TNF) serum levels than GI animals. Real-time PCR confirmed a higher TNF, IFN-γ, as well as IL-10 expression in the cardiac tissue from the OI group compared with GI. Conversely, TGF-β and IL-17 serum levels were greater in the GI animals. Immunolabeling revealed macrophages as the main tissue source of TNF in infected mice. The high mortality rate observed in the OI mice paralleled the TNF serum rise, with its inhibition by an anti-TNF treatment. Moreover, differences in susceptibility between GI versus OI mice were more clearly related to the host response than to the effect of gastric pH on parasites, since infection in magnesium hydroxide-treated mice showed similar results. Overall, the present study provides conclusive evidence that the initial site of parasite entrance critically affects host immune response and disease outcome. In light of the occurrence of oral Chagas disease outbreaks, our results raise important implications in terms of the current view of the natural disease course and host-parasite relationship.