The TGF-ß pathway as an emerging target for Chagas disease therapy.

Transforming growth factor-ß (TGF-ß) influences the development of myocardiopathy in Chagas disease through regulation of (i) parasite invasion of heart cells, (ii) an intracellular parasite cycle, (iii) inflammation and immune response, (iv) heart fibrosis and remodeling, and (v) gap junction modulation and heart conduction. In this review, we discuss the rationale for developing TGF-ß signaling-interfering therapies as adjuvant approaches for the management of the cardiac alterations of Chagas disease-affected patients.

Activation of transforming growth factor beta by Trypanosoma cruzi.

The anti-inflammatory cytokine, transforming growth factor beta (TGFbeta), plays an important role in Chagas disease, which is caused by the protozoan parasite Trypanosoma cruzi. In the current study, we show that the addition of an anti-TGFbeta antibody inhibited T. cruzi infection of cardiomyocytes, demonstrating the requirement for active endogenous TGFbeta. As TGFbeta is synthesized as a biologically inactive precursor, which is proteolytically processed to yield a mature, active homodimer, we hypothesized that T. cruzi could activate latent TGFbeta. To test this, we added recombinant latent TGFbeta to a TGFbeta-responsive reporter cell line in the presence of T. cruzi. We observed that T. cruzi was able to activate latent recombinant TGFbeta in this cellular model. We then investigated the ability of T. cruzi to activate latent TGFbetain vitro. We found that live T. cruzi, or cytosolic extracts of T. cruzi, activated latent TGFbeta in a dose- and temperature-dependent manner. The agent involved in TGFbeta activation was shown to be thermolabile and hydrophobic. Taken together, our studies demonstrate that T. cruzi directly activates latent TGFbeta. This activation is required for parasite entry into the mammalian cells and is likely to play an important role in modulating the outcome of T. cruzi infection.

Increased Trypanosoma cruzi invasion and heart fibrosis associated with high transforming growth factor beta levels in mice deficient in alpha(2)-macroglobulin.

Trypanosoma cruzi proteinases are involved in host cell invasion in human patients and in mouse models. In mice, murine alpha(2)-macroglobulin (MAM) and murinoglobulin are circulating plasma proteinase inhibitors that also have important roles in inflammation and immune modulation. To define their role in experimental Chagas disease, we investigated the susceptibility to T. cruzi infection of mice that are deficient only in alpha2-macroglobulins (AM-KO) or in both MAM and monomeric murinoglobulin-1 (MM-KO), relative to the wild type (WT). Despite the high parasite load, parasitemia was lower in AM-KO and MM-KO mice than in WT mice. Nevertheless, we observed a significantly higher parasite load in the hearts of AM-KO and MM-KO mice, i.e., more amastigote nests and inflammatory infiltrates than in WT mice. This result demonstrates a protective role for MAM in the acute phase of murine T. cruzi infection. We further demonstrated in vitro that human alpha2-macroglobulins altered the trypomastigote morphology and motility in a dose-dependent way, and that also impaired T. cruzi invasion in cardiomyocytes. Finally, we demonstrated that the levels of transforming growth factor beta in AM-KO mice increased significantly in the third week postinfection, concomitant with high amastigote burden and important fibrosis. Combined, these in vivo and in vitro findings demonstrate that the MAM contribute to the resistance of mice to acute myocarditis induced by experimental T. cruzi infection.