Activation of transforming growth factor β by Trypanosoma cruzi

The anti-inflammatory cytokine, transforming growth factor beta (TGF beta), 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-TGF beta antibody inhibited T. cruzi infection of cardiomyocytes, demonstrating the requirement for active endogenous TGF beta. As TGF beta 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 TGF beta. To test this, we added recombinant latent TGF beta to a TGF beta-responsive reporter cell line in the presence of T. cruzi. We observed that T. cruzi was able to activate latent recombinant TGF beta in this cellular model. We then investigated the ability of T. cruzi to activate latent TGF beta in vitro. We found that live T. cruzi, or cytosolic extracts of T. cruzi, activated latent TGF beta in a dose- and temperature-dependent manner. The agent involved in TGF beta activation was shown to be thermolabile and hydrophobic. Taken together, our studies demonstrate that T. cruzi directly activates latent TGF beta. 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.