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160万人感染恰加斯病。这是一种慢性残疾 在拉丁美洲，疾病也是一个主要的健康问题。它的病原体，原生动物 鞭毛虫克氏锥虫表达一种称为反唾液酸酶(TS)的毒力因子，该因子覆盖 寄生虫不能从头合成唾液酸。TS转移唾液酸基残基 从哺乳动物宿主蛋白到寄生虫表面，从而阻止其通过血清成分裂解 并使寄生虫能够入侵细胞进行复制。这种毒力因素也被释放到 在血液中发现环境，从而远离感染部位/S。TS导致几个 免疫系统的变化，包括细胞成分的凋亡和CD4的调节 T细胞处于诱导期和效应期。我们最近确定了这种寄生虫的分布 表面蛋白质组分中TS和粘蛋白是唾液酸基残基的主要受体 转移，位于不同的域中。类似的情况也发生在其他无关的蛋白质上。 一些蛋白质使用可收缩的液泡作为到达表面的途径，而另一些则不是。在这 项目中，我们建议研究使用这种转运途径的蛋白质需求，否则将被排除在外 从它，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，所以我们将获得没有 它的表达来评估它们入侵细胞、复制和诱导哺乳动物发病的能力。 TSS调节TH1/TH2/TH17平衡的能力将根据最近的 我们实验室的发现可能解释了其他研究人员之前的结果，并与 感染的结果。

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.