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

项目摘要 据估计，阿根廷有160万人患有恰加斯病。这种慢性残疾 疾病也是拉丁美洲的一个主要健康问题。它的病原体，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， 寄生虫不能进行唾液酸从头合成。TS转移唾液酸残基 从哺乳动物宿主蛋白质到寄生虫表面，从而防止其被血清组分溶解 并使寄生虫能够侵入细胞进行复制。这种毒力因子也会脱落到 在血流中发现环境，因此远离感染部位起作用。TS诱导多个 免疫系统的改变，包括细胞成分的凋亡和CD 4的调节 T细胞在它们的诱导和效应阶段。我们最近确定了寄生虫的分布 表面蛋白组分中的TS和粘蛋白，主要受体是唾液酸残基 转移，位于不同的域。其他不相关的蛋白质也是如此。 一些蛋白质利用收缩泡作为到达表面的途径，而另一些则不然。在这 项目，我们建议研究蛋白质的要求，使用这种贩运途径，或被排除在外 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构成寄生虫的中心毒力因子，我们将获得缺乏TS的寄生虫。 其表达以评估它们在哺乳动物中侵入细胞、复制和诱导发病的能力。 本文将结合近年来的研究成果，对TS调节TH 1/TH 2/TH 17平衡的能力进行分析。 我们实验室的发现可能解释了其他研究人员以前的结果， 感染的后果

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.