Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America.
PLoS One. 2011;6(9):e23482. doi: 10.1371/journal.pone.0023482. Epub 2011 Sep 8.
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.
原生动物寄生虫克氏锥虫，引起人类恰加斯病，对宿主细胞外基质（ECM）施加多种影响，包括胶原蛋白的蛋白水解降解和 ECM 基因表达的抑制。暴露于活的感染性克氏锥虫锥虫或其脱落/分泌产物的原代人真皮成纤维细胞导致纤维原基因胶原 Iα1、纤连蛋白和结缔组织生长因子（CTGF/CCN2）的快速下调。在这里，我们证明了一种分泌/释放的克氏锥虫因子能够拮抗真皮成纤维细胞中 CTGF/CCN2 的表达，以响应 TGF-β、溶血磷脂酸或血清，其中激动剂诱导的丝裂原激活蛋白（MAP）激酶 Erk1/2、p38 和 JNK 的磷酸化也被抑制。真皮成纤维细胞中基因表达的全基因组分析确定了一小部分 TGF-β诱导的基因，这些基因参与细胞增殖、伤口修复和免疫调节，被克氏锥虫分泌/释放的因子抑制，其中对克氏锥虫最敏感的基因已知受 MAP 激酶激活的转录因子调节。与这一观察结果一致，在 CTGF/CCN2 基因的近端启动子区域（-91bp 至-84bp）中发现了 Ets 家族转录因子结合位点，该位点对于 T. cruzi 介导的 CTGF/CCN2 报告基因表达的下调是必需的。累积的数据表明了一种模型，即感染过程早期分泌/释放的克氏锥虫衍生分子抑制 MAP 激酶信号传导和转录因子的激活，这些转录因子调节参与伤口修复和组织重塑的成纤维细胞基因的表达，包括 CTGF/CCN2。这些发现对克氏锥虫在哺乳动物宿主中早期感染过程中对 ECM 合成/重塑的局部调节具有更广泛的意义，并强调了病原体衍生分子作为调节纤维生成反应的工具的潜力。
