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Original Article

^a Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, CEP 21990-400 Rio de Janeiro, Brazil
^b Department of Cell Biology and Genetics, Universidade do Estado do Rio de Janeiro, Rio de Janeiro 20550-013, Brazil
^c Department of Biophysics, Escola Paulista de Medicina-Universidade Federal de São Paolo, São Paulo 04044-000, Brazil
^d Institute for Biochemistry II, University of Frankfurt Medical School, D-60590 Frankfurt, Germany
Instituto de Biofísica Carlos Chagas Filho, Centro de Ciencias de Saude, Universidade Federal do Rio de Janeiro, Cidade Universitária, CEP 21990-400 Rio de Janeiro, Brazil;55-21-280-819355-21-280-2718

The parasitic protozoan Trypanosoma cruzi employs multiple molecular strategies to invade a broad range of nonphagocytic cells. Here we demonstrate that the invasion of human primary umbilical vein endothelial cells (HUVECs) or Chinese hamster ovary (CHO) cells overexpressing the B₂ type of bradykinin receptor (CHO-B₂R) by tissue culture trypomastigotes is subtly modulated by the combined activities of kininogens, kininogenases, and kinin-degrading peptidases. The presence of captopril, an inhibitor of bradykinin degradation by kininase II, drastically potentiated parasitic invasion of HUVECs and CHO-B₂R, but not of mock-transfected CHO cells, whereas the B₂R antagonist HOE 140 or monoclonal antibody MBK3 to bradykinin blocked these effects. Invasion competence correlated with the parasites' ability to liberate the short-lived kinins from cell-bound kininogen and to elicit vigorous intracellular free calcium ([Ca²⁺]_i) transients through B₂R. Invasion was impaired by membrane-permeable cysteine proteinase inhibitors such as Z-(SBz)Cys-Phe-CHN₂ but not by the hydrophilic inhibitor 1-trans-epoxysuccinyl-L-leucyl-amido-(4-guanidino) butane or cystatin C, suggesting that kinin release is confined to secluded spaces formed by juxtaposition of host cell and parasite plasma membranes. Analysis of trypomastigote transfectants expressing various cysteine proteinase isoforms showed that invasion competence is linked to the kinin releasing activity of cruzipain, herein proposed as a factor of virulence in Chagas' disease.

Key Words: Trypanosoma cruzi • bradykinin • cruzipain • cysteine proteinases • kinin receptors

© 2000 The Rockefeller University Press

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