**2.1.1 Life cycle of** *Trypanosoma cruzi*

When a reduviid bug feeds from an infected mammal, it takes up circulating trypomastigotes, which reach then the bug's gut. There, they differentiate to amastigotes, which proliferate and start to differentiate into epimastigotes. In this process, when amastigote is still sphere-shaped but has developed its flagellum, some authors call this stage spheromastigotes. Then, it elongates its cell body and flagellum, taking the classical epimastigote shape. At this stage, the parasite undergoes metacyclogenesis, differentiating in metacyclic trypomastigotes, the infective form for mammals. When the bug feeds again,

CCC is manifested by a chronic, diffuse, progressive fibrosing myocarditis that involves not only the working myocardium but also the atrioventricular (AV) conduction system, autonomic nervous system and microcirculation (Andrade, 1985, Marin-Neto, et al., 2007, Milei, et al., 1991b). This leads to cardiomegaly, cardiac failure, arrhythmias, thromboembolism, and death (Milei, et al., 1991b). Colon and esophagus are also commonly affected by Chagas' disease, being megacolon with constipation and megaesofagus with

Milei et al. proposed a combined theory that could explain the pathogenic mechanism in chronic chagasic myocarditis (Milei, et al., 1996a, Storino & Milei, 1994). This theory is based on three ingredients: the parasite, host immune system and fibrosis. These ingredients are proposed as being the primary causative agents of damage on myocardial tissue, conduction

The role of *T. cruzi* in the chronic phase has been previously underestimated due to the fact that its presence was believed to be scarce and unrelated to the inflammatory infiltrate present at this stage. Nowadays, the involvement of the parasite in the chronic phase has been well documented. Using dissimilar methods, different authors demonstrated either the persistence of *T. cruzi* or parasite antigens in mice (Younées-Chennoufi, et al., 1988), the parasite DNA sequence amplified by the polymerase chain reaction (PCR) (Jones, et al., 1993, Schijman, et al., 2004), *T. cruzi* antigens from inflammatory lesions in human chagasic cardiomyopathy (Higuchi, Brito et al. 1993), or the immunohistochemical finding of the parasite in endomyocardial biopsies with PCR confirmation (Añez, Carrasco et al. 1999). This would suggest a direct role for the parasite in the perpetuation of myocardial inflammation. In other words, the antigen stimulation would persist throughout the chronic stage, even though the parasites are not morphologically detectable by light microscopy

The role of parasitemia is more controversial. High parasitemia correlated with severity of disease in one report (Basquiera, et al., 2003), but showed no association in another (Castro

Interestingly, it has been observed that immunosuppression reactivates rather than ameliorates the disease, as seen in patients receiving immunosuppressive therapy to prevent transplant rejection and in AIDS patients. Accordingly, many experimental models where strains of genetically manipulated mice lacking various immune functions showed

When a reduviid bug feeds from an infected mammal, it takes up circulating trypomastigotes, which reach then the bug's gut. There, they differentiate to amastigotes, which proliferate and start to differentiate into epimastigotes. In this process, when amastigote is still sphere-shaped but has developed its flagellum, some authors call this stage spheromastigotes. Then, it elongates its cell body and flagellum, taking the classical epimastigote shape. At this stage, the parasite undergoes metacyclogenesis, differentiating in metacyclic trypomastigotes, the infective form for mammals. When the bug feeds again,

increased susceptibility to develop the disease (Tarleton & Zhang, 1999).

achalasia also features of the disease (Rassi, et al., 2010).

system, autonomic ganglia and nerves and microvasculature.

**2. Pathogenesis of Chagas' myocarditis** 

**2.1 First ingredient: the parasite** 

**2.1.1 Life cycle of** *Trypanosoma cruzi* 

(Andrade 1992).

C., et al., 2005).

it excretes trypomastigotes with feces, which in turn reach blood torrent through bug's wound. Trypomastigotes can infect a wide variety of host cells, within them it differentiate into amastigotes and proliferate. Then, they can differentiate into trypomastigotes again, reach circulation and infect new cells. If an uninfected bug feeds from the animal in the moment of parasitemia, cycle starts again (Tyler & Engman, 2001).

Fig. 1. Life cycle of *Trypanosoma cruzi.* 
