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，由 被原生动物寄生虫锥虫克氏锥虫。超过1100万人感染，约1.2亿人感染 个人有感染这种疾病的风险。多达10万名来自流行国家的移民居住在 美国被认为感染了克鲁兹旋毛虫，对血液成分接受者来说是一个潜在的风险， 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。 目前还没有针对克氏锥虫的人类疫苗。 这项提案的总体目标是识别和验证主要的免疫优势抗原，这些抗原是 在哺乳动物栖息阶段的细胞表面广泛表达，为新的发育提供依据 预防或治疗恰加斯病的免疫治疗方法。要实现这一点，需要采取以下具体措施 建议的目标是： 特定目的#1.类鞭毛虫和胞内质膜的表达蛋白质组学 克氏毛滴虫的无鞭毛体。我们的主要目标是通过蛋白质组学分析确定主要的蛋白质和 不同系统发育谱系哺乳动物栖息期细胞表面糖蛋白的表达 和克氏锥虫的菌株。 特定目标#2.类鞭毛虫细胞表面和细胞内的功能蛋白质组学 克鲁兹毛滴虫的无鞭毛体形式，以识别和验证疫苗接种的新抗原靶点。我们将表演 对在特定目标1中发现的选定表面(糖蛋白)蛋白进行广泛的免疫学分析，以验证 作为实验性疫苗接种的抗原靶点。我们将鉴定出能够诱导 小鼠有效的体液和细胞免疫反应。最后，我们将进行实验性免疫 用两个最好的抗原靶，然后用克氏锥虫进行挑战，以评估对 寄生虫。 总体意义：我们相信这个项目将导致免疫优势的识别 克鲁兹毛滴虫哺乳动物栖息期细胞表面抗原靶标及其新的发育 预防和治疗恰加斯病的免疫治疗方法

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.