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Infection and Immunity, September 2002, p. 5115-5123, Vol. 70, No. 9
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.9.5115-5123.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Increased Trypanosoma cruzi Invasion and Heart Fibrosis Associated with High Transforming Growth Factor ß Levels in Mice Deficient in ₂-Macroglobulin

Laboratório de Biologia Celular,¹ Laboratório de Ultra-estrutura Celular,³ Instituto Oswaldo Cruz, FIOCRUZ and Universidade Federal Fluminense, Rio de Janeiro, Brazil,² EMI 01-05, Department of Cellular Response and Dynamics,CEA-G, Grenoble,⁴ Unite d'Immunochimie Analytique, Institut Pasteur and CNRS URA 1960, Paris, France,⁵ Experimental Genetics Group, Department of Human Genetics, KULeuven, Leuven, Belgium⁶

Received 8 January 2002/ Returned for modification 26 March 2002/ Accepted 22 May 2002

Trypanosoma cruzi proteinases are involved in host cell invasion in human patients and in mouse models. In mice, murine ₂-macroglobulin (MAM) and murinoglobulin are circulating plasma proteinase inhibitors that also have important roles in inflammation and immune modulation. To define their role in experimental Chagas disease, we investigated the susceptibility to T. cruzi infection of mice that are deficient only in 2-macroglobulins (AM-KO) or in both MAM and monomeric murinoglobulin-1 (MM-KO), relative to the wild type (WT). Despite the high parasite load, parasitemia was lower in AM-KO and MM-KO mice than in WT mice. Nevertheless, we observed a significantly higher parasite load in the hearts of AM-KO and MM-KO mice, i.e., more amastigote nests and inflammatory infiltrates than in WT mice. This result demonstrates a protective role for MAM in the acute phase of murine T. cruzi infection. We further demonstrated in vitro that human 2-macroglobulins altered the trypomastigote morphology and motility in a dose-dependent way, and that also impaired T. cruzi invasion in cardiomyocytes. Finally, we demonstrated that the levels of transforming growth factor ß in AM-KO mice increased significantly in the third week postinfection, concomitant with high amastigote burden and important fibrosis. Combined, these in vivo and in vitro findings demonstrate that the MAM contribute to the resistance of mice to acute myocarditis induced by experimental T. cruzi infection.

Editor: J. M. Mansfield

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