Role in pathogenesis and parasite cell biology of the trans-sialidase from Trypanosoma cruzi, the agent of Chagas Disease

克氏锥虫（恰加斯病的病原体）转唾液酸酶在发病机制和寄生虫细胞生物学中的作用

• 批准号: 10394268
• 负责人: Oscar Eduardo Campetella
• 金额: $ 13.5万
• 依托单位: INSTITUTE/RESEARCH/BIOTECHNOLOGY FDN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394268
• 关键词: Affect; Apoptosis; Argentina; Biology; Blood Circulation; CD4 Positive T Lymphocytes; Cells; Cellular biology; Chagas Disease; Chronic; Cytolysis; Disease Outcome; Equilibrium; Genes; Genetic; Glycobiology; Health; Immune system; Infection; Invaded; Knowledge; Latin America; Light; Mammals; Mastigophora; Membrane; Membrane Proteins; Mucins; Outcome; Parasites; Pathogenesis; Pathway interactions; Persons; Phenotype; Physiology; Play; Process; Proteins; Research Personnel; Role; Serum; Sialic Acids; Site; Surface; T-Lymphocyte; Trypanosoma cruzi; Trypanosoma cruzi trans-sialidase; Vacuole; Virulence Factors; disabling disease; prevent; protein distribution; protein transport; trafficking; trans-sialidase

Project Summary Chagas disease affects an estimate of 1,600,000 people in Argentina. This chronic disabling disease also constitutes a major health issue in Latin America. Its causative agent, the protozoan flagellate Trypanosoma cruzi, expresses a virulence factor known as trans-sialidase (TS) that cover the inability of the parasite to perform sialic acids synthesis de novo. TS transfer the sialyl residue from the mammal host proteins to the parasite surface, thus preventing its lysis by serum components and enabling the parasite to invade cells where to replicate. This virulence factor is also shed to the milieu being found in the bloodstream thus acting far from the infectious site/s. TS induce several alterations on the immune system including apoptosis of cellular components and modulation of CD4 T cells both at their elicitation and effector stages. We recently defined the distribution of the parasite surface protein components where the TS and mucins, the main acceptor of the sialyl residue transferred, are located in separate domains. Similarly happens with other unrelated proteins. Some proteins use the contractile vacuole as a pathway to reach the surface while others not. In this project, we propose to study the protein requirements to use this trafficking pathway, or been excluded from it, and the process associated with their final fate on different domains at the parasite surface. Because the TS constitute a central virulence factor of the parasite we will obtain parasites devoid of its expression to assess their ability to invade cells, replicate and induce pathogenesis in mammals. The ability of TSs to modulate the TH1/TH2/TH17 balance will be analyzed at the light of recent findings from our lab that might explain previous results from other researchers and been associated with the outcome of the infection.

项目摘要 查加斯病影响阿根廷的估计值160万人。这种慢性残疾 疾病在拉丁美洲也是一个重大健康问题。它的病因剂，原生动物 鞭毛锥虫克鲁齐（Cruzi 寄生虫无法执行唾液酸合成。 TS转移siAlyl残留物 从哺乳动物宿主蛋白到寄生虫表面，从而防止了血清成分的裂解 并使寄生虫能够入侵要复制的细胞。这种毒力也被放到 在血液中发现了环境，因此远离感染部位。 TS诱导了几个 免疫系统的改变，包括细胞成分的凋亡和CD4的调节 T细胞在其启发和效应子阶段均处于。我们最近定义了寄生虫的分布 表面蛋白质成分，其中TS和粘蛋白，siAllyl残基的主要受体 转移，位于单独的域中。类似地发生在其他无关蛋白质中。 一些蛋白质使用收缩液泡作为到达表面的途径，而另一些则没有。在这个 项目，我们建议研究使用此贩运途径或被排除的蛋白质要求 从中及其在寄生虫表面的不同域上的最终命运相关的过程。 由于TS构成寄生虫的中心毒力因子，因此我们将获得没有的寄生虫 它的表达是评估其侵入细胞，复制和诱导哺乳动物发病机理的能力。 TSS调节TH1/TH2/TH17余额的能力将根据最近的方式进行分析 我们实验室的发现可能解释了其他研究人员以前的结果并有关联 随着感染的结果。