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 microM) 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 microM) 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.

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 æM) 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 æM) 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.

Absence of interferon-gamma-inducible gene IGTP does not significantly alter the development of chagasic cardiomyopathy in mice infected with Trypanosoma cruzi (Brazil strain).

Interferon-gamma (IFN-gamma) contributes to host resistance during acute infection with Trypanosoma cruzi, the causative agent of Chagas' disease. Inducibly expressed guanosine triphosphatase (IGTP), a 48-kDa guanosine triphosphatase (GTPase), is a member of a family of GTPase proteins inducibly expressed by IFN-gamma. The expression pattern of IGTP suggests that it may mediate IFN-gamma-induced responses in a variety of cell types. IGTP has been demonstrated to be important for control of Toxoplasma gondii infection but not for resistance against Listeria monocytogenes. We evaluated the role of IGTP in development of chronic chagasic cardiomyopathy in IGTP null mice and C57X129sv (wild type [WT]) mice infected with the Brazil strain for 6 mo. There was no significant difference in parasitemia or cardiac histopathology between null and WT mice. Right ventricular remodeling was observed in infected IGTP null mice, suggesting that IGTP does not significantly alter the course of T. cruzi infection.

Fas-FasL interaction modulates nitric oxide production in Trypanosoma cruzi-infected mice.

During acute Trypanosoma cruzi infection in mice, many leucocytes undergo apoptosis. Although apoptosis has been ascribed to increased levels of nitric oxide (NO) and Fas-FasL interaction, the importance of this phenomenon in modulating the host response against T. cruzi is unknown. Herein, the role of NO- and Fas-FasL-induced apoptosis in modulating the immune response to T. cruzi was evaluated using mice deficient in Fas expression (MRL/MpJ-Fas lpr) and inducible nitric oxide synthase (iNOS) knockout mice (iNOS-/-). The results showed that besides decreasing apoptosis induction after infection, impairment of the Fas-FasL interaction resulted in decreased NO production, as a consequence of enhanced T helper 2 (Th2) cytokine production. Differently, blockage of NO-induced apoptosis resulted in uncontrolled cytokine production, rather than a biased Th2 cytokine pattern. Together, these results suggested that Fas and FasL-induced apoptosis could be implied in modulation of the immune response against T. cruzi by interfering with cytokine and NO production during the acute phase of the infection.

Conduction defects and arrhythmias in Chagas' disease: possible role of gap junctions and humoral mechanisms.

The protozoan parasite Trypanosoma cruzi causes Chagas' disease, a major cause of cardiac dysfunction in Latin Americans. Chagas' disease exhibits both acute and chronic phases, and each may be characterized by cardiac conduction disturbances. In acutely infected cultures of rodent heart cells, synchronized spontaneous beating becomes less regular, and coupling between cells is reduced. The basis of this decreased conduction is apparently in localization of the gap junction protein (Cx43) inside infected cells. Although total Cx43 is normal in infected cells, little is recognizable at appositional membranes. Electrophysiological properties are also altered by this infection. Action potentials are shortened, resting Ca2+ levels are elevated, and response to alpha-adrenergic agonists was altered, compared to controls. Humoral factors may contribute to the conduction defects in chronic Chagas' disease. Sera from chronically infected rabbits produced ECG abnormalities in Langendorff-perfused rabbit hearts. These findings indicate that chagasic infection may modify ion channel function in the heart, and we suggest that these changes may be manifested in the conduction disturbances that characterize this disease.

Taeniasis and cysticercosis.

This article focuses on clinical issues of taeniasis and cysticercosis, including a comprehensive review of the clinical data, standard and latest chemotherapy, modern concepts of pathogenesis, conventional and advanced diagnostic tests, current epidemiology, and effective means of control. Fundamental parasitology is covered to familiarize physicians and scientists with the latest concepts of parasites.

Imported malaria in the Bronx: review of 51 cases recorded from 1986 to 1991.

The cases of 51 patients with malaria seen at the Albert Einstein College of Medicine hospitals from January 1986 to June 1991 are reviewed. Thirty-five patients acquired infection on journeys to their country of origin. Of these 35 patients, 83% of whom had lived in the United States for > or = 2 years, only 17% received antimalarial prophylaxis. Ten of the 51 patients were born and raised in the United States, and 70% received prophylaxis (P < .01). Six of the 51 patients were visitors to the United States from areas endemic for malaria. Overall, 64% of patients acquired malaria in West Africa, south of the Sahara; 20% in Asia; 8% in Ecuador; 6% in Haiti; and 4% in the Middle East. The majority of infections were due to Plasmodium falciparum. Six patients traveled to a zone endemic for malaria while pregnant, and none received prophylaxis. In nine of 13 patients who received prophylaxis, there was inadequate dosing or poor compliance. Individuals born in regions endemic for malaria are at high risk of acquiring malaria on return to their countries of origin and are less aware of the need for malaria prophylaxis than are other travelers.

Protection against fatal murine Chagas' disease with a Leishmania braziliensis panamensis stock.

Past attempts to immunize mice against a fatal Trypanosoma cruzi infection utilizing related hemoflagellates have been unsuccessful. In the present study, C57BL/6 mice received a footpad inoculation of 10(7) promastigotes of Leishmania braziliensis panamensis. Six and 9 weeks subsequent to this inoculation mice were infected intraperitoneally with the Tulahuen strain of T. cruzi. All immunized mice survived infection over the 6-month period of observation whereas control mice regularly died. There was an early transient T. cruzi parasitemia in the immunized mice. Culture of blood and organs as well as histopathological examination of various organs 6 months post-challenge failed to yield any evidence of T. cruzi. Heat-killed and freeze-thawed extracts of promastigotes did not confer any protection. These observations raise the possibility that certain leishmanial species might confer natural protection against a T. cruzi infection and that this information could be useful in the development of a vaccine.