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Infection and Immunity, October 2004, p. 5892-5902, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5892-5902.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

A New Cruzipain-Mediated Pathway of Human Cell Invasion by Trypanosoma cruzi Requires Trypomastigote Membranes

Isabela M. Aparicio, Julio Scharfstein, and Ana Paula C. A. Lima*

Instituto de Biofísica Carlos Chagas Filho, Bloco G, CCS, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, Brazil

Received 19 October 2003/ Returned for modification 17 January 2004/ Accepted 24 June 2004

The intracellular protozoan Trypanosoma cruzi causes Chagas' disease, a chronic illness associated with cardiomyopathy and digestive disorders. This pathogen invades mammalian cells by signaling them through multiple transduction pathways. We previously showed that cruzipain, the main cysteine protease of T. cruzi, promotes host cell invasion by activating kinin receptors. Here, we report a cruzipain-mediated invasion route that is not blocked by kinin receptor antagonists. By testing different strains of T. cruzi, we observed a correlation between the level of cruzipain secreted by trypomastigotes and the capacity of the pathogen to invade host cells. Consistent with a role for cruzipain, the cysteine protease inhibitor N-methylpiperazine-urea-Phe-homophenylalanine-vinylsulfone-benzene impaired the invasion of human smooth muscle cells by strains Dm28c and X10/6 but not by the G isolate. Cruzipain-rich supernatants of Dm28c trypomastigotes enhanced the infectivity of isolate G parasites twofold, an effect which was abolished by the cysteine protease inhibitor L-trans-epoxysuccinyl-leucylamido-(4-guanidino)butane and by thapsigargin, a drug that induces depletion of the intracellular Ca2+ stores. The enhancement due to Dm28 supernatants was abolished upon cruzipain immunodepletion, and the activity was restored by purified cruzipain. In contrast, supernatants from isolate G trypomastigotes (with low levels of cruzipain) or supernatants from Dm28c epimastigotes or purified cruzipain alone did not enhance parasite invasion, indicating that the protease is required but not sufficient to engage this invasion pathway. We provide evidence that activation of this pathway requires cruzipain-mediated processing of a trypomastigote molecule associated with parasite-shed membranes. Our results couple cruzipain to host cell invasion through a kinin-independent route and further suggest that high-level cruzipain expression may contribute to parasite infectivity.

* Corresponding author. Mailing address: Instituto de Biofísica Carlos Chagas Filho, Bloco G, CCS, UFRJ, Ilha do Fundão, Rio de Janeiro, RJ, CEP 21-944-900 Brazil. Phone: (55)(21)(2562-6709). Fax: (55)(21)2280-8193. E-mail: anapaula{at}biof.ufrj.br.

Editor: J. F. Urban, Jr.

Infection and Immunity, October 2004, p. 5892-5902, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5892-5902.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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