Host fibrogenic response to Trypanosoma cruzi infection

描述(由申请人提供)：细胞内原生动物病原体克氏锥虫的慢性感染导致人类查加斯病，这是拉丁美洲心力衰竭的主要原因。查格斯克性心肌病以慢性炎症为特征，并伴有肥大和纤维化。我们实验室的初步发现揭示了一个令人惊讶的观察结果，即在感染过程的早期，参与纤维化形成和细胞外基质(ECM)重塑的宿主细胞基因的子集被T.ruzi抑制。这种受限制的宿主细胞对克氏锥虫的反应的选择性表明，在感染过程中抑制纤维化途径可能对寄生虫有利。尤其令人感兴趣的是结缔组织生长因子(CTGF)，这是一种纤维化细胞因子，通过诱导胶原和纤维连接蛋白的合成以及细胞外基质的沉积来促进伤口愈合。克氏毛滴虫感染阶段能分泌一种稳定的、可溶的因子，该因子能拮抗TGFβ依赖的CTGF基因表达的诱导。在这项提出的研究中，克氏支原体诱导的CTGF基因表达的调节将被用作纤维化过程的敏感报告。分子、生物化学和细胞方法将被用来确定在克氏毛滴虫感染过程中参与调节纤维化途径的信号成分。这些包括介导这一过程的特定寄生虫因子以及宿主细胞信号通路和受体(S)。此外，我们还将对小鼠急性实验性感染过程中克氏毛滴虫依赖的宿主纤维形成途径的调节进行详细的分子表征。该系统提供了一种可靠的实验方法，使我们能够将克氏锥虫在宿主细胞中触发的早期信号事件与宿主细胞基因表达、感染建立和恰加斯病发病机制的下游效应联系起来。在传染病发病机制的背景下表征纤维化反应对于没有感染病因学的疾病状态下潜在的纤维化的分子机制具有更广泛的意义。考虑到克氏毛滴虫感染过程中CTGF的抑制是由一种稳定的可溶性寄生虫因子介导的，这项研究的潜在深远好处是显而易见的，这可能对广泛的纤维性疾病具有重要的治疗潜力。

DESCRIPTION (provided by the applicant): Chronic infections with the intracellular protozoan pathogen, Trypanosoma cruzi, lead to Chagas' disease in humans, the principal cause of heart failure in Latin America. Chagasic cardiomyopathy is characterized by chronic inflammation with associated hypertrophy and fibrosis. Preliminary findings from our laboratory have revealed the surprising observation that early in the infective process, a subset of host cell genes involved in fibrogenesis and extracellular matrix (ECM) remodeling is repressed by T. cruzi. The selectivity of this restricted host cell response to T. cruzi suggests that repression of the fibrogenic pathway may be advantageous to the parasite during the infectious process. Of particular interest is connective tissue growth factor (CTGF), a fibrogenic cytokine that promotes wound healing by inducing collagen and fibronectin synthesis and ECM deposition. Infective stages of T. cruzi were shown to secrete a stable, soluble factor that antagonizes TGFbeta-dependent induction of CTGF gene expression. In this pro posed study, T. cruzi-induced modulation of CTGF gene expression will be used as a sensitive reporter for the fibrogenic process. Molecular, biochemical and cellular approaches will be utilized to identify the signaling components involved in the modulation of the fibrogenic pathway during T. cruzi infection. These include specific parasite factors that mediate this process as well as host cell signaling pathways and receptor(s). Furthermore, we will carry out a detailed molecular characterization of T. cruzi-dependent modulation of the host fibrogenic pathway during acute experimental infections in mice. This system provides a solid experimental approach that will enable us to connect early signaling events triggered in host cells by T. cruzi to downstream effects on host cell gene expression, establishment of infection and pathogenesis of Chagas' disease. Characterization of the fibrogenic response in the context of infectious disease pathogenesis has broader implications for molecular mechanisms underlying fibrosis in disease states that do not have an infectious etiology. The potential far-reaching benefits of this research are apparent when considering that repression of CTGF during T. cruzi infection is mediated by a stable soluble parasite factor, which may have important therapeutic potential for a broad range of fibrotic disorders.