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PLoS One. 2015 May 4;10(5):e0124832. doi: 10.1371/journal.pone.0124832. eCollection 2015.

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

Author information

1
Laboratório de Genômica Funcional e Bioinformática, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil; Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil.
2
Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil.
3
Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil.
4
Laboratório de Genômica Funcional e Bioinformática, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil.
5
Laboratório de Biotecnologia e Fisiologia de Infecções Virais, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil.
6
Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil; Programa Integrado de doença de Chagas, Fiocruz, Rio de Janeiro, Brazil.
7
Laboratório de Bioquímica e Biologia Molecular de Peptidases, Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil.
8
INSERM, Unité 1036, Grenoble, F-38054, France; Université Grenoble-Alpes-Grenoble, F-38041, France; CEA, DSV,iRTSV, Laboratory of Biology of Cancer and Infection, Grenoble, F-38054, France.
9
Laboratório de Genômica Funcional e Bioinformática, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil; Programa Integrado de doença de Chagas, Fiocruz, Rio de Janeiro, Brazil.

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.

PMID:
25938232
PMCID:
PMC4418758
DOI:
10.1371/journal.pone.0124832
[Indexed for MEDLINE]
Free PMC Article

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