Trypanosoma cruzi reinfections in mice determine the severity of cardiac damage

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Abstract

In two murine models we studied Trypanosoma cruzi reinfection in the acute and chronic phase of experimental Chagas' disease in order to elucidate the relevance of reinfections in determining the variability of cardiac symptoms and the irreversible cardiac damage. They were followed for 120 and 600 days post infection (p.i.) for the acute and chronic model, respectively. Reinfected mice reached higher parasitaemia levels than infected mice. The survival was 33 and 21% in the chronic phase for mice reinfected in the acute phase and 13% for mice reinfected in the chronic stage at the end of the experiments. Sixty-six percent of the infected group presented electrocardiographic abnormalities (heart frequency, prolonged PQ segment or QRS complex) in the chronic stage whereas 100% of the reinfected animals exhibited electric cardiac dysfunction since 90 and 390 days p.i. for the acute and chronic reinfected model, respectively (P<0.01). Heart histopathological studies showed fibrosis and necrosis areas and mononuclear infiltrates supporting the view that parasite persistence is a major factor in continuing the tissue inflammation. This work shows that T. cruzi reinfections could be related to the variability and severity of the clinical course of Chagas' disease and that parasite persistence is involved in exacerbation of the disease.

Introduction

Chagas' disease, the parasitic infection caused by Trypanosoma cruzi, affects nearly 20 million people throughout South and Central America (World Health Organization, 1995, World Health Organization, 1991, Schofield and Dias, 1999). This disease represents the fourth cause of incapacity and loss of healthy years among all infectious diseases in the region (World Bank, 1993). The frequent form of transmission is through a blood sucking triatomine bug represented by different species of reduviid insects (e.g. Triatoma infestans).

There are three stages in the human disease (Tanowitz et al., 1992).The acute phase is sometimes severe in young infants (Sgambatti de Andrade et al., 1998), and the infected patients suffer a short period with or without symptomatology. The intermediate phase is generally symptomless, and may last from 10 to 20 years. In the chronic phase, approximately 30% of infected people develop cardiac Chagas' disease (Laguens et al., 1999, Andrade, 1999). Symptom diversity and severity range from a mild electrocardiographic alteration to sudden death. This great variability and severity in cardiac Chagas' disease symptoms may be due to many factors, such as: parasite strain (Montamant et al., 1996, Espinoza et al., 1998, Vago et al., 2000), the number of T. cruzi that infected the host (Fernández et al., 1996), host immunity (Koberle, 1968, Kalil and Cunha-Neto, 1996, Tomlinson and Raper, 1998), nutritional aspects of the host at the time of infection and possible reinfections. The role of reinfections in the evolution of Chagas' disease has been evaluated in rats (Revelli et al., 1990), showing that reinfections produce greater cardiac lesions. Controversially, Machado et al., 2001 found that infected or reinfected dogs developed the indeterminate form of Chagas' disease, which was independent of the number of infections.

People living in endemic areas are exposed to infections and reinfections at any time, therefore we have concentrated our efforts on studying this factor as a matter that could determine the severity of cardiac damage.

Here, we used an acute and chronic murine model, to study the effects of T. cruzi reinfections carried out in the acute and chronic phases of experimental Chagas' disease, in order to elucidate their consequences on the variability of cardiac symptoms and the irreversible damage characteristic of Chagas' disease.

Section snippets

Source of parasites

Bloodstream trypomastigotes of T. cruzi, Tulahuen strain, were obtained from infected mice. Infected heparinised blood was used for the assays described below without parasite purification.

Infection

Albino Swiss female mice weighing 30±1 g (n=282) were inoculated with 50 trypomastigote forms of T. cruzi, by i.p. injection. The number of parasites/ml of blood was determined in each group using a Neubauer haemocytometer. The blood (0.1 ml) was diluted in physiological solution and 30% BSA (V fraction) in

Parasitaemia

The levels of parasitaemia found in infected animals (Group 1) and mice reinfected in the acute phase with 50 (Group 2) and 500 (Group 3) parasites can be observed in Fig. 1A. It shows that in Group 1 and Group 2 parasitaemia rose in similar values except by day 21 p.i. when Group 2 presented parasitaemias significantly higher (P<0.01) than Group 1. Group 3 presented parasitaemia levels significantly higher (P<0.01) than Group 1 and Group 2 by day 28 p.i. reaching 307±32 parasites/μl. The

Discussion

Two hypotheses have been proposed as mechanisms for pathogenesis in Chagas' disease: persistence of T. cruzi at specific sites in the infected host or that T. cruzi infection induces immune responses that are responsible for the cardiac damages (Kalil and Cunha-Neto, 1996, Zhang and Tarleton, 1999, Kierszenbaum, 1999, Tarleton, 2001, Leon and Engman, 2001). The link among T. cruzi presence, levels of parasites and disease severity is really strong (Tarleton, 2001, Leon and Engman, 2001).

In the

Acknowledgements

This work was supported by grants from the Agencia Córdoba Ciencia and Secretarı́a de Ciencia y Técnica (SECYT) from Universidad Nacional de Córdoba.

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