Endothelin-1 receptors play a minor role in the protection against acute Trypanosoma cruzi infection in mice

Chagas' disease, caused by the protozoan Trypanosoma cruzi, is a major cause of cardiovascular disability in countries where it is endemic. Damage to the heart microvasculature has been proposed to be an important factor in the pathogenesis of heart dysfunction. Endothelin-1 (ET-1) is a potent vasoconstrictor and exerts its effects via specific ET A and ET B receptors. A few studies have suggested a role for ET-1 and its receptors in the pathogenesis of Chagas' disease. We investigated the effects of treatment with bosentan, an ET A/ET B receptor antagonist, on the course of T. cruzi infection (Y strain) in C57Bl/6 mice. Treatment with bosentan (100 mg kg-1 day-1) was given per os starting day 0 after infection until sacrifice. Bosentan significantly increased myocardial inflammation, with no effects on parasitemia. Although the total number of nests was similar, a lower number of intact amastigote nests was found in the heart of bosentan-treated animals. Bosentan failed to affect the infection-associated increase in the cardiac levels of the cytokines IFN-g and TNF-a and the chemokines CCL2/MCP-1, CCL3/MIP-1a and CCL5/RANTES. In vitro, pre-incubation with ET-1 (0.1 µM) 4 h before infection enhanced the uptake of the parasites by peritoneal macrophages, and this effect was abrogated when macrophages were pre-treated with bosentan (1 µM) 15 min before incubation with ET-1. However, ET-1 did not alter killing of intracellular parasites after 48 h of in vitro infection. Our data suggest that bosentan-treated mice have a delay in controlling parasitism which is compensated for exacerbated inflammation. Infection is eventually controlled in these animals and lethality is unchanged, demonstrating that ET-1 plays a minor role in the protection against acute murine T. cruzi infection

Relationship between granulocyte macrophage-colony stimulating factor, tumour necrosis factor-α and Trypanosoma cruzi infection of murine macrophages

Gamma interferon (IFN-γ)-activated macrophages control Trypanosoma cruzi infection via nitric oxide (NO), recently recognized as a major effector molecule. Granulocyte macrophage-colony stimulating factor (GM-CSF) is a multipotent cytokine secreted by macrophages and many other cells. It induces the production of tumour necrosis factor alpha (TNF-α), another cytokine also secreted by macrophages and involved in the control of T. cruzi infection. However, no data are available on the relationship between GM-CSF, TNF-α and NO produced by macrophages activated by IFN-γ and infected with T. cruzi. To highlight this relationship, mouse peritoneal macrophages (MPM) and two c-myc retrovirus-induced macrophage cell lines (9.1.1 and BMM8), respectively characterized by a constitutive and an inducible production of GM-CSF, were activated with IFN-γ and/or GM-CSF and infected with T, cruzi. Our results indicate that T. cruzi upregulates GM-CSF release from MPM and from the two macrophage cell lines, activated (or not) by IFN-γ. A high autocrine production of GM-CSF or an exogenous supply of GM-CSF is correlated with an enhanced release of TNF-α and NO, inducing an improved control of T. cruzi infection by IFN-γ-activated MPM.SCOPUS: ar.jFLWNAinfo:eu-repo/semantics/publishe

The cachexia associated with Trypanosoma cruzi acute infection in mice is attenuated by anti-TNF-a, but not by anti-IL-6 or anti-IFN-7 antibodies

BALB/c male mice acutely infected with Trypanosoma cruzi underwent a severe weight loss (around 20%, from day 18 to 31 post-infection), when compared to age-matched uninfected animals. Though mice regained weight later, when blood parasites were hardly detectable, wasting extended over the chronic phase of infection. The onset and the magnitude of weight loss were related to the mouse susceptibility to infection, since they were respectively earlier and higher in male mice which will die than in surviving ones, in males than in females, and in BALB/c than in B6D2 [(C57B1/6 x DBA/2)F1], a mouse strain more resistant to infection. Fat weight of infected mice (male BALB/c) was reduced by 60 to 80%, whereas lean mass was unaffected and water content rose by 6 to 10% in acute and chronic infection. Haematocrit was also decreased by 15-16% in acute infection. Animals failed to compensate their energetic loss since their food intake remained similar to that of uninfected animals. Injections of neutralizing anti-TNF-alpha monoclonal antibody into infected male mice, during the first two weeks but not later in infection, significantly attenuated the weight loss. Early administration of anti-IL-6 or anti-IFN-gamma MoAbs did not improve the mouse wasting. Taken together, these data show that TNF is a key agent of cachexia occurring in the acute T. cruzi infection in mice.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jFLWNAinfo:eu-repo/semantics/publishe

Role of Trypanosoma cruzi Autoreactive T Cells in the Generation of Cardiac Pathology

Chagas disease, caused by Trypanosoma cruzi, affects several million people in Central and South America. About 30% of chronic patients develop cardiomyopathy probably caused by parasite persistence and/or autoimmunity. While several cross-reactive antibodies generated during mammal T. cruzi infection have been described, very few cross-reactive T cells have been identified. We performed adoptive transfer experiments of T cells isolated from chronically infected mice. The results showed the generation of cardiac pathology in the absence of parasites. We also transferred cross-reactive SAPA-specific T cells and observed unspecific alterations in heart repolarization, cardiac inflammatory infiltration, and tissue damage.S