The TcI and TcII Trypanosoma cruzi experimental infections induce distinct immune responses and cardiac fibrosis in dogs

Trypanosoma cruzi infection may be caused by different strains with distinct discrete typing units (DTUs) that can result in variable clinical forms of chronic Chagas disease. The present study evaluates the immune response and cardiac lesions in dogs experimentally infected with different T. cruzi strains with distinct DTUs, namely, the Colombian (Col) and Y strains of TcI and TcII DTU, respectively. During infection with the Col strain, increased levels of alanine aminotransferase, erythrocytes, haematocrit and haemoglobin were observed. In addition, CD8+ T-lymphocytes isolated from the peripheral blood produced higher levels of interleukin (IL)-4. The latter suggests that during the acute phase, infection with the Col strain may remain unnoticed by circulating mononuclear cells. In the chronic phase, a significant increase in the number of inflammatory cells was detected in the right atrium. Conversely, infection with the Y strain led to leucopoenia, thrombopoenia, inversion of the ratio of CD4+/CD8+ T-lymphocytes and alterations in monocyte number. The Y strain stimulated the production of interferon-γ by CD4+ and CD8+ T-lymphocytes and IL-4 by CD8+ T-cells. In the chronic phase, significant heart inflammation and fibrosis were observed, demonstrating that strains of different DTUs interact differently with the host.

Induction of chagasic-like arrhythmias in the isolated beating hearts of healthy rats perfused with Trypanosoma cruzi-conditioned medium

Chagas' myocardiopathy, caused by the intracellular protozoan Trypanosoma cruzi, is characterized by microvascular alterations, heart failure and arrhythmias. Ischemia and arrythmogenesis have been attributed to proteins shed by the parasite, although this has not been fully demonstrated. The aim of the present investigation was to study the effect of substances shed by T. cruzi on ischemia/reperfusion-induced arrhythmias. We performed a triple ischemia-reperfusion (I/R) protocol whereby the isolated beating rat hearts were perfused with either Vero-control or Vero T. cruzi-infected conditioned medium during the different stages of ischemia and subsequently reperfused with Tyrode's solution. ECG and heart rate were recorded during the entire experiment. We observed that triple I/R-induced bradycardia was associated with the generation of auricular-ventricular blockade during ischemia and non-sustained nodal and ventricular tachycardia during reperfusion. Interestingly, perfusion with Vero-infected medium produced a delay in the reperfusion-induced recovery of heart rate, increased the frequency of tachycardic events and induced ventricular fibrillation. These results suggest that the presence of parasite-shed substances in conditioned media enhances the arrhythmogenic effects that occur during the I/R protocol.

Antichagásicos potenciais: busca racional de compostos com ação seletiva pela cruzaína / Potential antichagasic agents: rational design of compounds with selective action in cruzain

A doença de Chagas, parasitose endêmica causada pelo Trypanosoma cruzi, se apresenta como grande causa de morbimortalidade, afetando cerca de 18 milhões de pessoas no continente americano e causando 21.000 mortes, a cada ano. Atualmente, estima-se que 100 milhões de pessoas estejam sob risco de contaminação nos 18 países da área endêmica da doença. A quimioterapia contra a tripanossomíase americana é constituída por apenas dois fármacos, nifurtimox e benznidazol, que não apresentam ação adequada na fase crônica da doença. Por estas razões, é premente a necessidade de novas e mais eficazes alternativas terapêuticas. A cruzaína, mais abundante cisteíno-protease do parasita, é enzima essencial em todos os estágios de modificação celular do parasita e está, também, presente no processo de invasão e modificação do sistema imune do hospedeiro. Além disso, apresenta diferenças em relação a enzimas dessa categoria no hospedeiro. Trata-se, pois, de excelente alvo bioquímico para a pesquisa de novos agentes contra o T. cruzi. Face ao exposto e tendo-se em vista a especificidade da cruzaína, considera-se de grande interesse a compreensão do mecanismo de interação de compostos com essa enzima com o intuito de planejar derivados com atividade antichagásica potencial. O presente trabalho teve o objetivo de elucidar a afinidade de diferentes classes de compostos pela enzima, na busca racional de novos tripanomicidas. Assim, pró-fármacos peptidicos recíprocos, derivados de primaquina(PQ) e de nitrofural(NF), anteriormente sintetizados, e pró-fármacos peptidicos duplos do hidroximetilnitrofural (NFOH) planejados, e cuja síntese foi estudada, foram submetidos a estudos de modelagem molecular e de docking...

Títulos de anticuerpos antisulfátido en pacientes con cardiopatía chagásica crónica y con otras formas de cardiopatía / Antisulfatide antibody titers in patients with chronic Chagas heart disease and other forms of heart disease

Aún no se ha podido encontrar un tratamiento específico para la enfermedad de Chagas, a pesar de su endemicidad en extensas zonas de la Región de las Américas. En estudios anteriores se ha propuesto la posibilidad de que el galactocerebrósido sulfatado presente en Trypanosoma cruzi podría actuar como inmunógeno para producir las concentraciones elevadas de anticuerpos antisulfátido que se han encontrado en pacientes con infección crónica por ese parásito. Ese fenómeno podría ser importante en la patogenia de los síntomas cardíacos o del sistema nervioso periférico que caracteriza a la enfermedad de Chagas, que es la primera causa de miocarditis en Centroamérica y América del Sur y la segunda causa de insuficiencia cardíaca en algunos países de esas subregiones. El presente estudio se realizó con objeto de determinar si había diferencia entre pacientes con la enfermedad de Chagas y otros pacientes sin la enfermedad con respecto a la presencia de anticuerpos antisulfátido y describe las concentraciones de anticuerpos antisulfátido que se encontraron en 124 pacientes (74 hombres y 50 mujeres) de 15 a 94 años de edad hospitalizados en el Servicio de Cardiología del Hospital Vargas de Caracas, durante el período del 1 de julio de 1993 al 30 de junio de 1995. Los títulos de anticuerpos antisulfátido se midieron con la técnica del inmunoensayo enzimático (ELISA) usando como antígeno cerebrósido sulfatado obtenido de cerebro de bovino. De los 124 pacientes estudiados, 39 (31,5 por ciento) eran chagásicos y mostraron títulos de anticuerpos antisulfátido más altos que los 85 no chagásicos (P= 0,0298) y que un grupo control de 28 sujetos aparentemente sanos (P = 0,0035). Las concentraciones séricas de anticuerpos antisulfátido en pacientes con otras formas de cardiopatía también se compararon con las del grupo control y se encontraron títulos significativamente altos en sujetos con cardiopatía isquémica aguda (P = 0,0049), cardiopatía valvular reumática (P = 0,0075), cardiopatía isquémica crónica (P = 0,0464) y bradiarritmias (P = 0,0157) y valores significativamente bajos en sujetos con cardiopatía hipertensiva (P = 0,0367). Las concentraciones de dichos anticuerpos no se correlacionaron con variables clínicas o paraclínicas indicadoras del grado de afección cardíaca. Los resultados corroboran que los anticuerpos antisulfátido podrían desempeñar algún papel en la patogenia de la cardiomiopatía chagásica

A specific treatment for Chagas' disease has not yet been discovered, even though the condition is endemic in large parts of the Region of the Americas. Earlier studies have addressed the possibility that the sulfatide galactocerebroside in Trypanosoma cruzi behaves as an immunogen involved in the production of the high antisulfatide antibody levels found in patients with chronic infestation with the parasite. This may be an important factor in the pathogenesis of the cardiac symptoms and peripheral neuropathy seen in Chagas' disease, which is the most important cause of myocarditis in Central and South America and the second most important cause of heart failure in several of the countries located in these subregions. The present study was conducted in order to ascertain whether patients with Chagas' disease and other patients not afflicted with the ailment differ insofar as the presence of antibodies against sulfatide is concerned, and it describes antisulfatide antibody levels in 124 hospital patients (74 men and 50 women) between the ages of 15 and 94 who were in the cardiology unit of Vargas Hospital in Caracas from 1 July to 30 June 1995. Antisulfatide antibody titers were determined by means of enzyme-linked immunosorbent assays (ELISA), and the antigen employed was sulfatide cerebroside obtained from bovine brain tissue. Of the 124 patients under study, 39 (31,5%) suffered from Chagas' disease and had antisulfatide antibody levels higher than those detected in patients without Chagas (P = 0,0298) and in 28 seemingly healthy controls (P = 0,0035). Serum levels of antisulfatide antibodies in patients with other forms of heart disease were also compared with those seen in the control group, and significantly higher levels were found in patients with acute ischemic heart disease (P = 0,0049), rheumatic valvular heart disease (P = 0,0075), chronic ischemic heart disease (P = 0,0464) and bradiarrythmias (P = 0,0157), and significantly lower ones in subjects with hypertensive heart disease (P = 0,0367). These antibody levels showed no correlation with clinical or paraclinical variables indicative of the degree of cardiac compromise. Our results support the notion that antibodies against sulfatide may play a role in the pathogenesis of Chagas' cardiomyopathy and other forms of heart disease and should be further studied in an effort to determine their potential role in these processes