Host fibrogenic response to Trypanosoma cruzi infection

宿主对克氏锥虫感染的纤维化反应

• 批准号: 6787197
• 负责人: BARBARA A BURLEIGH
• 金额: $ 41万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6787197
• 关键词: SDS polyacrylamide gel electrophoresis; Trypanosoma cruzi; biological signal transduction; connective tissue growth factor; enzyme linked immunosorbent assay; extracellular matrix; fibrosis; gene expression; host organism interaction; hypertrophy; immunocytochemistry; laboratory mouse; polymerase chain reaction; protozoal infection; receptor; recombinant proteins; trypanosomiasis; western blottings

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.

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会导致人类恰加斯病，这是拉丁美洲心力衰竭的主要原因。恰加斯心肌病的特征是慢性炎症并伴有肥厚和纤维化。我们实验室的初步研究结果揭示了令人惊讶的观察结果，即在感染过程的早期，参与纤维发生和细胞外基质 (ECM) 重塑的宿主细胞基因子集被克氏锥虫抑制。这种受限宿主细胞对克氏锥虫反应的选择性表明，抑制纤维生成途径可能有利于寄生虫在感染过程中。特别令人感兴趣的是结缔组织生长因子 (CTGF)，这是一种纤维生成细胞因子，可通过诱导胶原蛋白和纤连蛋白合成以及 ECM 沉积来促进伤口愈合。克氏锥虫的感染阶段会分泌一种稳定的可溶性因子，该因子可拮抗 TGFβ 依赖性诱导的 CTGF 基因表达。在这项拟议的研究中，克氏锥虫诱导的 CTGF 基因表达调节将被用作纤维形成过程的敏感报告基因。将利用分子、生化和细胞方法来鉴定克氏锥虫感染期间参与纤维形成途径调节的信号成分。这些包括介导该过程的特定寄生虫因子以及宿主细胞信号传导途径和受体。此外，我们将对小鼠急性实验感染期间克氏锥虫依赖性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下游对宿主细胞基因表达、感染的建立和恰加斯病的发病机制的影响联系起来。传染病发病机制中纤维化反应的表征对于无传染性病因的疾病状态下纤维化的分子机制具有更广泛的影响。考虑到克氏锥虫感染期间 CTGF 的抑制是由稳定的可溶性寄生虫因子介导的，该研究的潜在深远效益是显而易见的，这可能对广泛的纤维化疾病具有重要的治疗潜力。