Host cell invasion by Trypanosoma cruzi is potentiated by activation of bradykinin B2 receptors

doi:10.1084/jem.192.9.1289

Published online 6 November 2000.

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© The Rockefeller University Press, 0022-1007/2000/11/1289/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 9, November 6, 2000 1289-1300

Original Article

Host cell invasion by Trypanosoma cruzi is potentiated by activation of bradykinin B₂ receptors

Julio Scharfstein^a, Veronica Schmitz^a, Veronica Morandi^b, Marcia M. A. Capella^a, Ana Paula C. A. Lima^a, Alexandre Morrot^a, Luiz Juliano^c, and Werner Müller-Esterl^d
^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

Correspondence to: Julio Scharfstein, 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; Tel:55-21-280-2718 Fax:55-21-280-8193

The parasitic protozoan Trypanosoma cruzi employs multiple molecularstrategies to invade a broad range of nonphagocytic cells. Herewe demonstrate that the invasion of human primary umbilicalvein 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 thecombined activities of kininogens, kininogenases, and kinin-degradingpeptidases. The presence of captopril, an inhibitor of bradykinindegradation by kininase II, drastically potentiated parasiticinvasion of HUVECs and CHO-B₂R, but not of mock-transfectedCHO cells, whereas the B₂R antagonist HOE 140 or monoclonalantibody MBK3 to bradykinin blocked these effects. Invasioncompetence correlated with the parasites' ability to liberatethe short-lived kinins from cell-bound kininogen and to elicitvigorous intracellular free calcium ([Ca²⁺]_i) transients throughB₂R. Invasion was impaired by membrane-permeable cysteine proteinaseinhibitors such as Z-(SBz)Cys-Phe-CHN₂ but not by the hydrophilicinhibitor 1-trans-epoxysuccinyl-L-leucyl-amido-(4-guanidino)butane or cystatin C, suggesting that kinin release is confinedto secluded spaces formed by juxtaposition of host cell andparasite plasma membranes. Analysis of trypomastigote transfectantsexpressing various cysteine proteinase isoforms showed thatinvasion competence is linked to the kinin releasing activityof cruzipain, herein proposed as a factor of virulence in Chagas'disease.

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

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