Identification and Validation of Novel Antigenic Targets in Trypanosoma cruzi

恰加斯病是美洲大陆最致命的传染病之一， 被原生寄生虫克氏锥虫感染超过1100万人被感染， 个人都有患上这种疾病的危险。多达100 000名来自流行国家的移民生活在 美国被认为感染了T. Cruzi，并且代表血液成分接受者的潜在风险， 和器官。目前，只有一种部分有效的药物可用于治疗恰加斯病。 目前还没有针对T.克鲁兹 该提案的总体目标是鉴定和验证主要的免疫显性抗原， 广泛表达于T. cruzi为新的发展 预防或治疗恰加斯病的免疫方法。为实现这一目标，以下具体 提出的目标是： 具体目标1。锥鞭毛体质膜和细胞内表达蛋白质组学研究 无鞭毛型T.克鲁兹我们的主要目标是通过蛋白质组学分析鉴定主要蛋白质， 不同系统发育谱系中哺乳动物居住阶段细胞表面表达的糖蛋白 和T.克鲁兹 具体目标#2。锥鞭毛体细胞表面和细胞内功能蛋白质组学研究 无鞭毛型T. cruzi以鉴定和验证用于疫苗接种的新抗原靶标。我们将执行 对特定目标#1中发现的选定表面（糖）蛋白进行广泛的免疫学分析，以验证 它们作为实验性疫苗接种的抗原靶点。我们将鉴定出能够诱导 有效的体液和细胞免疫应答。最后，我们将进行实验性免疫 用两种最佳抗原靶点，然后用T. cruzi来评估对 寄生虫 总体意义：我们相信，本项目将导致免疫显性的鉴定 T.哺乳动物阶段细胞表面的抗原靶标。cruzi和在新的发展 预防和治疗南美锥虫病的免疫学方法。

Chagas' disease is one of the most deadly infectious diseases in the American continent, and is caused by the protozoan parasite Trypanosoma cruzi. Over 11 million people are infected, and about 120 million individuals are at risk of acquiring the disease. Up to 100,000 migrants from endemic countries living in the U.S. are thought to be infected with T. cruzi, and represent a latent risk for recipients of blood components, and organs. Currently, only one partially effective drug is available for the treatment of Chagas' disease. There is no human vaccine against T. cruzi. The overall goal of this proposal is to identify and validate major immunodominant antigens that are ubiquitously expressed on the cell surface of mammal-dwelling stages of T. cruzi for the development of new immunotherapeutic approaches to prevent or treat Chagas' disease. To achieve this, the following specific aims are proposed: Specific aim # 1. Expression proteomics of the plasma membrane of trypomastigote and intracellular amastigote forms of T. cruzi. Our primary goal is to identify by proteomic analysis the major proteins and glycoproteins expressed on the cell surface of the mammal-dwelling stages in different phylogenetic lineages and strains of T. cruzi. Specific aim # 2. Functional proteomics of the cell surface of trypomastigote and intracellular amastigote forms of T. cruzi to identify and validate novel antigenic targets for vaccination. We will perform an extensive immunological analysis of selected surface (glyco)proteins found in specific aim # 1, to validate them as antigenic targets for experimental vaccination. We will identify proteins that are able to induce efficient humoral and celullar immune responses in mice. Finally, we will perform experimental immunization with the two best antigenic targets, followed by challenge with T. cruzi to evaluate the protection against the parasite. Overall significance: We believe that this project will result in the identification of immunodominant antigenic targets on the cell surface of mammal-dwelling stages of T. cruzi and in the development of new immunotherapeutic approaches for prevention and treatment of Chagas' disease.