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: 6601533
• 负责人: BARBARA A BURLEIGH
• 金额: $ 40.75万
• 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/6601533
• 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（由申请方提供）：细胞内原生动物病原体克氏锥虫的慢性感染导致人类恰加斯病，这是拉丁美洲心力衰竭的主要原因。慢性炎症性心肌病的特征是伴随肥大和纤维化的慢性炎症。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，参与纤维形成和细胞外基质（ECM）重塑的宿主细胞基因的子集被T.克鲁兹这种限制性宿主细胞对T. Cruzi认为，在感染过程中，纤维化途径的抑制可能对寄生虫有利。特别感兴趣的是结缔组织生长因子（CTGF），其是一种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的纤维化细胞因子。T. cruzi分泌一种稳定的可溶性因子，该因子拮抗TGF β依赖性的CTGF基因表达诱导。在本研究中，T. Cruzi诱导的CTGF基因表达调节将被用作纤维化过程的敏感报告基因。分子、生物化学和细胞的方法将被用来确定参与T细胞过程中纤维化途径调节的信号成分。克氏感染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传导途径和受体。此外，我们还将对T.小鼠急性实验性感染期间宿主纤维化途径的cruzi依赖性调节。该系统提供了一个坚实的实验方法，将使我们能够连接T细胞在宿主细胞中触发的早期信号事件。cruzi对宿主细胞基因表达、感染建立和南美锥虫病发病机制的下游影响。在感染性疾病发病机制的背景下，纤维化反应的表征对不具有感染性病因的疾病状态中纤维化的分子机制具有更广泛的意义。当考虑到T。Cruzi感染是由稳定的可溶性寄生虫因子介导的，其可能对广泛的纤维化病症具有重要的治疗潜力。