Several studies indicate that the activity of
cruzipain, the main lysosomal
cysteine peptidase of Trypanosoma cruzi, contributes to parasite infectivity. In addition, the parasitic invasion process of mammalian host cells is described to be dependent on the activation of the host TGF-β signaling pathway by T. cruzi. Here, we tested the hypothesis that
cruzipain could be an important activator of latent TGF-β and thereby trigger TGF-β-mediated events crucial for the development of
Chagas disease. We found that live epimastigotes of T. cruzi, parasite lysates and purified
cruzipain were able to activate latent TGF-β in vitro. This activation could be inhibited by the
cysteine peptidase inhibitor Z-Phe-Ala-FMK. Moreover, transfected parasites overexpressing chagasin, a potent endogenous
cruzipain inhibitor, prevented latent TGF-β activation. We also observed that T. cruzi invasion, as well as parasite intracellular growth, were inhibited by the administration of
Z-Phe-Ala-FMK or anti-TGF-β
neutralizing antibody to Vero cell cultures. We further demonstrated that addition of purified
cruzipain enhanced the invasive activity of trypomastigotes and that this effect could be completely inhibited by addition of a neutralizing anti-TGF-β antibody. Taken together, these results demonstrate that the activities of
cruzipain and TGF-β in the process of cell invasion are functionally linked. Our data suggest that
cruzipain inhibition is an interesting chemotherapeutic approach for
Chagas disease not only because of its trypanocidal activity, but also due to the inhibitory effect on TGF-β activation.