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Cruzipain Activates Latent TGF-β from Host Cells during T. cruzi Invasion.

Abstract
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.
AuthorsPatrícia Mello Ferrão, Claudia Masini d'Avila-Levy, Tania Cremonini Araujo-Jorge, Wim Maurits Degrave, Antônio da Silva Gonçalves, Luciana Ribeiro Garzoni, Ana Paula Lima, Jean Jacques Feige, Sabine Bailly, Leila Mendonça-Lima, Mariana Caldas Waghabi
JournalPloS one (PLoS One) Vol. 10 Issue 5 Pg. e0124832 ( 2015) ISSN: 1932-6203 [Electronic] United States
PMID25938232 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies
  • Cysteine Proteinase Inhibitors
  • Dipeptides
  • Ketones
  • Protozoan Proteins
  • Transforming Growth Factor beta
  • chagasin, Trypanosoma
  • MDL 201053
  • Cysteine Endopeptidases
  • cruzipain
Topics
  • Animals
  • Antibodies (pharmacology)
  • Chlorocebus aethiops
  • Cysteine Endopeptidases (pharmacology)
  • Cysteine Proteinase Inhibitors (pharmacology)
  • Dipeptides
  • Host-Parasite Interactions (drug effects)
  • Ketones
  • Parasites (drug effects)
  • Protozoan Proteins (pharmacology)
  • Transfection
  • Transforming Growth Factor beta (immunology, metabolism)
  • Trypanosoma cruzi (drug effects, growth & development, physiology)
  • Vero Cells

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