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1.
PLoS One ; 8(6): e65820, 2013.
Article in English | MEDLINE | ID: mdl-23776551

ABSTRACT

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects several million people in Latin America. Myocarditis, observed during both the acute and chronic phases of the disease, is characterized by an inflammatory mononuclear cell infiltrate that includes CD4(+) T cells. It is known that Th1 cytokines help to control infection. The role that Treg and Th17 cells may play in disease outcome, however, has not been completely elucidated. We performed a comparative study of the dynamics of CD4(+) T cell subsets after infection with the T. cruzi Y strain during both the acute and chronic phases of the disease using susceptible BALB/c and non-susceptible C57BL/6 mice infected with high or low parasite inocula. During the acute phase, infected C57BL/6 mice showed high levels of CD4(+) T cell infiltration and expression of Th1 cytokines in the heart associated with the presence of Treg cells. In contrast, infected BALB/c mice had a high heart parasite burden, low heart CD4(+) T cell infiltration and low levels of Th1 and inflammatory cytokines, but with an increased presence of Th17 cells. Moreover, an increase in the expression of IL-6 in susceptible mice was associated with lethality upon infection with a high parasite load. Chronically infected BALB/c mice continued to present higher parasite burdens than C57BL/6 mice and also higher levels of IFN-γ, TNF, IL-10 and TGF-ß. Thus, the regulation of the Th1 response by Treg cells in the acute phase may play a protective role in non-susceptible mice irrespective of parasite numbers. On the other hand, Th17 cells may protect susceptible mice at low levels of infection, but could, in association with IL-6, be pathogenic at high parasite loads.


Subject(s)
CD4-Positive T-Lymphocytes/metabolism , Chagas Disease/immunology , Chagas Disease/metabolism , Cytokines/metabolism , Trypanosoma cruzi/physiology , Animals , CD4-Positive T-Lymphocytes/immunology , Female , Flow Cytometry , Fluorescent Antibody Technique , Interferon-gamma/metabolism , Interleukin-10/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Real-Time Polymerase Chain Reaction , Transforming Growth Factor beta/metabolism , Trypanosoma cruzi/immunology
2.
Ann N Y Acad Sci ; 1107: 434-44, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17804572

ABSTRACT

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.


Subject(s)
Chagas Disease/immunology , Chagas Disease/pathology , T-Lymphocytes/immunology , Trypanosoma cruzi/immunology , Animals , Autoimmunity/immunology , Chagas Disease/parasitology , Epitopes/immunology , Humans , Molecular Mimicry/immunology
3.
J Med Chem ; 49(3): 892-9, 2006 Feb 09.
Article in English | MEDLINE | ID: mdl-16451055

ABSTRACT

There is no effective treatment for the prevalent chronic form of Chagas' disease in Latin America. Its causative agent, the protozoan parasite Trypanosoma cruzi, has an essential requirement for ergosterol, and ergosterol biosynthesis inhibitors, such as the antifungal drug posaconazole, have potent trypanocidal activity. The antiarrhythmic compound amiodarone, frequently prescribed for the symptomatic treatment of Chagas' disease patients, has also recently been shown to have antifungal activity. We now show here for the first time that amiodarone has direct activity against T. cruzi, both in vitro and in vivo, and that it acts synergistically with posaconazole. We found that amiodarone, in addition to disrupting the parasites' Ca(2+) homeostasis, also blocks ergosterol biosynthesis, and that posaconazole also affects Ca(2+) homeostasis. These results provide logical explanations for the synergistic activity of amiodarone with azoles against T. cruzi and open up the possibility of novel, combination therapy approaches to the treatment of Chagas' disease using currently approved drugs.


Subject(s)
Amiodarone/pharmacology , Triazoles/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Acute Disease , Amiodarone/chemistry , Amiodarone/therapeutic use , Animals , Calcium/metabolism , Chagas Disease/drug therapy , Chlorocebus aethiops , Crystallography, X-Ray , Drug Synergism , Ergosterol/biosynthesis , Intramolecular Transferases/antagonists & inhibitors , Intramolecular Transferases/chemistry , Mice , Models, Molecular , Molecular Structure , Triazoles/chemistry , Triazoles/therapeutic use , Trypanocidal Agents/chemistry , Trypanocidal Agents/therapeutic use , Trypanosoma cruzi/metabolism , Vero Cells
4.
Antimicrob Agents Chemother ; 48(7): 2379-87, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15215084

ABSTRACT

Chagas' disease is a serious public health problem in Latin America, and no treatment is available for the prevalent chronic stage. Its causative agent, Trypanosoma cruzi, requires specific endogenous sterols for survival, and we have recently demonstrated that squalene synthase (SQS) is a promising target for antiparasitic chemotherapy. E5700 and ER-119884 are quinuclidine-based inhibitors of mammalian SQS that are currently in development as cholesterol- and triglyceride-lowering agents in humans. These compounds were found to be potent noncompetitive or mixed-type inhibitors of T. cruzi SQS with K(i) values in the low nanomolar to subnanomolar range in the absence or presence of 20 microM inorganic pyrophosphate. The antiproliferative 50% inhibitory concentrations of the compounds against extracellular epimastigotes and intracellular amastigotes were ca. 10 nM and 0.4 to 1.6 nM, respectively, with no effects on host cells. When treated with these compounds at the MIC, all of the parasite's sterols disappeared from the parasite cells. In vivo studies indicated that E5700 was able to provide full protection against death and completely arrested the development of parasitemia when given at a concentration of 50 mg/kg of body weight/day for 30 days, while ER-119884 provided only partial protection. This is the first report of an orally active SQS inhibitor that is capable of providing complete protection against fulminant, acute Chagas' disease.


Subject(s)
Enzyme Inhibitors/pharmacology , Farnesyl-Diphosphate Farnesyltransferase/antagonists & inhibitors , Pyridines/pharmacology , Quinuclidines/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/enzymology , Animals , Cell Division/drug effects , Farnesyl-Diphosphate Farnesyltransferase/isolation & purification , Female , Kinetics , Lipid Metabolism , Mice
5.
Int J Antimicrob Agents ; 21(1): 27-38, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12507835

ABSTRACT

Ravuconazole is an experimental triazole derivative with potent and broad-spectrum antifungal activity and a remarkably long half-life in humans. In this work, we investigated the in vitro and in vivo activities of this compound against Trypanosoma cruzi. Ravuconazole showed very potent in vitro anti-T. cruzi activity with minimal inhibitory concentrations (MIC) of 300 and 1 nM against the extracellular epimastigote and intracellular amastigote forms, respectively. As with other azole derivatives, ravuconazole at the MIC led to an essentially complete depletion of the epimastigotes' endogenous C4,14-desmethyl sterols and their replacement by di- and tri-methylated sterols. In murine acute models of acute Chagas disease, it was found that ravuconazole treatment led to high levels of parasitological cures, but only when given twice a day (b.i.d.), consistent with its short terminal half-life in mice (4 h). Furthermore, it was found that this curative activity was restricted towards nitrofuran/nitroimidazole-susceptible (CL) and partially drug-resistant (Y) strains of T. cruzi, with no curative activity in animals infected with the fully drug-resistant Colombiana strain. No curative activity occurred in a chronic model of the disease. No toxic side effects were observed resulting from treatment with the triazole. Ravuconazole is a very potent and specific anti-T. cruzi agent in vitro but its in vivo activity in mice is limited, probably due to its unfavourable pharmacokinetic properties in this animal model. However, these results do not necessarily rule out the potential utility of ravuconazole in the treatment of human T. cruzi infections.


Subject(s)
Thiazoles/pharmacology , Triazoles/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Chagas Disease/drug therapy , Dose-Response Relationship, Drug , Drug Resistance , Female , Mice
6.
Int J Antimicrob Agents ; 21(1): 39-48, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12507836

ABSTRACT

We investigated the activity of TAK-187, an experimental antifungal triazole with a long terminal half-life in several experimental animals, against Trypanosoma cruzi. In vitro studies showed that the minimal inhibitory concentration (MIC) against the (extracellular) epimastigote form was 0.3-1 microM, while the corresponding concentration against clinically relevant intracellular amastigotes was 1 nM. At the MIC the endogenous epimastigote C4,14-desmethyl sterols were replaced by di- and tri-methylated sterols, supporting the notion that the primary target of TAK-187 is the parasite's sterol C14alpha demethylase. We investigated the in vivo activity of the compound in a murine model of acute Chagas disease, using T. cruzi strains with different susceptibilities to the drugs currently used clinically (nitrofurans and nitroimidazoles). It was found that TAK-187 given orally at 20 mg/kg induced complete protection against death and high levels (60-100%) of parasitological cures, independently of the infecting strain and even when administered every other day (e.o.d.), consistent with its long terminal half-life in mice. Other experiments, using longer treatment periods were carried out in both acute and chronic models of the disease and showed that TAK-187 given at 10-20 mg/kg e.o.d. induced 80-100% survival with 80-100% of parasitological cures of survivors in both models. No toxic side effects were observed in any of the experimental protocols. TAK-187 is a potent anti-T. cruzi compound with trypanocidal activity in vivo and should be considered for further studies as a potential specific treatment of human Chagas disease.


Subject(s)
Chagas Disease/drug therapy , Triazoles/therapeutic use , Trypanocidal Agents/therapeutic use , Acute Disease , Animals , Chagas Disease/parasitology , Chronic Disease , Dose-Response Relationship, Drug , Drug Resistance , Female , Mice
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