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.

项目概要 据估计，阿根廷有 1,600,000 人患有恰加斯病。这种慢性致残 该疾病也是拉丁美洲的一个主要健康问题。它的病原体是原生动物 鞭毛虫克氏锥虫表达一种称为转唾液酸酶 (TS) 的毒力因子，可覆盖 寄生虫无法从头合成唾液酸。 TS转移唾液酸残基 从哺乳动物宿主蛋白到寄生虫表面，从而防止其被血清成分裂解 并使寄生虫能够侵入细胞进行复制。这种毒力因子也传播到 在血液中发现环境，因此远离感染部位。 TS诱发多种 免疫系统的改变，包括细胞成分的凋亡和 CD4 的调节 T 细胞处于诱导阶段和效应阶段。我们最近定义了寄生虫的分布 表面蛋白成分，其中 TS 和粘蛋白，唾液酸残基的主要受体 已转移，位于不同的域中。其他不相关的蛋白质也会发生类似的情况。 一些蛋白质使用收缩液泡作为到达表面的途径，而另一些则不然。在这个 项目中，我们建议研究使用这种贩运途径的蛋白质需求，否则就被排除在外 从中，以及与它们在寄生虫表面不同区域的最终命运相关的过程。 因为 TS 构成了寄生虫的中心毒力因子，所以我们将获得不含 TS 的寄生虫。 其表达可评估其在哺乳动物中侵入细胞、复制和诱导发病机制的能力。 TS对TH1/TH2/TH17平衡的调节能力将根据最近的情况进行分析 我们实验室的发现可能可以解释其他研究人员之前的结果并与之相关 随着感染的结果。