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Inhibition of host connective tissue growth factor expression: a novel Trypanosoma cruzi-mediated response

Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA

¹Correspondence: Department of Immunology and Infectious Diseases, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115, USA. E-mail: bburleig{at}hsph.harvard.edu

Connective tissue growth factor (CTGF) is a secreted cytokine that plays a fundamental role in the development of tissue fibrosis by mediating many of the profibrotic effects of TGF-ß. We present the novel finding that the intracellular pathogen Trypanosoma cruzi elicits immediate and sustained repression of basal CTGF expression in dermal fibroblasts, followed by down-regulation of the extracellular matrix proteins, fibronectin, and collagen I 1. To address mechanisms underlying this response, the major CTGF-regulating pathways were investigated. We report that both T. cruzi trypomastigotes and secreted parasite factor(s) antagonize TGF-ß-dependent induction of CTGF in fibroblasts. Of the TGF-ß-dependent signaling pathways required for CTGF expression, we demonstrate that T. cruzi interferes with cellular Erk1/2 phosphorylation but not Smad3 signaling. While increased stimulation of Erk phosphorylation alone was insufficient to override the parasite-mediated repression of CTGF, stimulation of fibroblasts with increased concentrations of TGF-ß, which activates both Smad3 and Erk1/2, completely abrogated this inhibition. Together with the finding that T. cruzi-mediated down-regulation of CTGF expression requires de novo host cell protein synthesis, our data indicate that the unique ability of T. cruzi to interfere with the host fibrogenic response is a complex process requiring input from multiple host cell signaling pathways.—Unnikrishnan, M., Burleigh, B. A. Inhibition of host connective tissue growth factor expression: a novel Trypanosoma cruzi-mediated response.

Key Words: parasite • extracellular matrix • infection • mitogen-activated kinases

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