Abstract
The protozoan parasite Trypanosoma cruzi, which causes human Chagas' disease, exerts a variety of effects on host extracellular matrix (ECM) including proteolytic degradation of collagens and dampening of ECM gene expression. Exposure of primary human dermal fibroblasts to live infective T. cruzi trypomastigotes or their shed/secreted products results in a rapid down-regulation of the fibrogenic genes collagenIα1, fibronectin and connective tissue growth factor (CTGF/CCN2). Here we demonstrate the ability of a secreted/released T. cruzi factor to antagonize ctgf/ccn2 expression in dermal fibroblasts in response to TGF-ß, lysophosphatidic acid or serum, where agonist-induced phosphorylation of the mitogen-activated protein (MAP) kinases Erk1/2, p38 and JNK was also inhibited. Global analysis of gene expression in dermal fibroblasts identified a discrete subset of TGF-ß-inducible genes involved in cell proliferation, wound repair, and immune regulation that are inhibited by T. cruzi secreted/released factors, where the genes exhibiting the highest sensitivity to T. cruzi are known to be regulated by MAP kinase-activated transcription factors. Consistent with this observation, the Ets-family transcription factor binding site in the proximal promoter region of the ctgf/ccn2 gene (−91 bp to −84 bp) was shown to be required for T. cruzi-mediated down-regulation of ctgf/ccn2 reporter expression. The cumulative data suggest a model in which T. cruzi-derived molecules secreted/released early in the infective process dampen MAP kinase signaling and the activation of transcription factors that regulate expression of fibroblast genes involved in wound repair and tissue remodelling, including ctgf/ccn2. These findings have broader implications for local modulation of ECM synthesis/remodelling by T. cruzi during the early establishment of infection in the mammalian host and highlight the potential for pathogen-derived molecules to be exploited as tools to modulate the fibrogenic response.
Highlights
The kinetoplastid protozoan parasite Trypanosoma cruzi causes Chagas’ disease in humans, a chronic and debilitating condition affecting several million individuals in Latin America
Connective tissue growth factor (CTGF/CCN2) expression is rapidly repressed in human dermal fibroblasts infected with the protozoan parasite, Trypanosoma cruzi, where the CTGF/CCN2repressive activity was shown to be associated with a secreted/ released trypanosome factor that is present in parasite-conditioned medium (PCM) [5] [7]
This study demonstrates that mammalian-infective forms of Trypanosoma cruzi release a factor that significantly impacts host cell signaling cascades, thereby altering the expression of a subset of genes involved in cell proliferation, wound repair and inflammation
Summary
The kinetoplastid protozoan parasite Trypanosoma cruzi causes Chagas’ disease in humans, a chronic and debilitating condition affecting several million individuals in Latin America. During its early interaction with mammalian host cells, trypomastigotes, the invasive forms of T. cruzi, trigger rapid changes in a number of cellular signaling pathways to facilitate the process of parasite entry into non-professional phagocytic cells (reviewed in [3,4]). While these early signaling events have been relatively well-studied in the context of T. cruzi invasion, little is known regarding the impact of these parasite-induced signaling cascades downstream of the invasion process. T. cruzi-dependent dampening of ctgf/ccn expression occurs at both the mRNA and protein levels and is mediated by a secreted/released parasite factor that is capable of antagonizing TGF-ß-mediated induction of ctgf/ccn2 [7]
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