RESUMO
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.
Assuntos
Cardiomiopatia Chagásica/tratamento farmacológico , Doença de Chagas/tratamento farmacológico , Fator de Crescimento Transformador beta/metabolismo , Animais , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/fisiopatologia , Doença de Chagas/parasitologia , Doença de Chagas/fisiopatologia , Desenho de Fármacos , Junções Comunicantes/parasitologia , Sistema de Condução Cardíaco/parasitologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/parasitologia , Transdução de Sinais/efeitos dos fármacos , Trypanosoma cruzi/isolamento & purificaçãoRESUMO
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.