Plasmodium vivax Erythrocyte Invasion Mechanisms and Humoral Immune Response in Duffy Negative Africans

项目总结 间日疟原虫红细胞入侵机制与体液免疫 达菲阴性非洲人的反应 非洲血统的人被认为受到间日疟原虫的保护 因为他们的红细胞表面缺乏Duffy抗原的表达 间日疟原虫不能入侵它们的红细胞。然而，越来越多的间日疟原虫 非洲各地和达菲阴性患者报告的病例对此提出了挑战 传统教条，增加了一些间日疟原虫谱系进化为 使用Duffy结合蛋白以外的配体进行红细胞侵袭。内在的 达菲阴性个体对间日疟原虫的入侵机制和免疫应答 很大程度上是未知的。在本应用程序中，我们将研究该表达式和函数 达菲阴性间日疟原虫红细胞结合基因及其抗体反应的研究 达菲阴性个体对间日疟原虫抗原的反应。有三个具体目标：1) 鉴定Duffy阳性和Duffy阴性P. 用RNA-seq；2)测定间日疟原虫的体外结合和侵袭活性 Duffy阴性红细胞的候选配基蛋白；3)体内检测 达菲地区间日疟原虫靶向抗原抗体水平与红细胞侵袭相关 阴性患者。这项拟议的研究将在埃塞俄比亚进行，那里的疟疾 一个主要的公共卫生问题和120万确诊疟疾病例中的约30% 是间日疟原虫。由于我们的研究站点有大量的间日疟病例和 相当大比例的达菲阴性个体，我们有一个独特的机会 研究间日疟原虫在非洲的入侵机制。我们有一个协作团队 以及用于样品采集和处理的物流。我们已建立的实验室文化 设施关闭卫生中心，并成功获得间日疟原虫转录组数据 从培养的裂殖体中分离出来，证明了这项研究的可行性。比较 达菲阴性和达菲阳性个体间日疟原虫转录本的比较 体外和体内样本将提供第一个关于基因和功能的描述 间日疟原虫允许感染Duffy阴性红细胞的属性。这项研究 将大大提高对间日疟原虫在达菲地区入侵机制的了解。 并为分子和生化特征的研究奠定了基础 间日疟原虫的配体-受体相互作用。间日疟原虫入侵机制的知识 宿主免疫反应将对间日疟原虫疫苗产生重要影响 非洲内外的发展和间日疟风险评估。

PROJECT SUMMARY Title: Plasmodium vivax Erythrocyte Invasion Mechanisms and Humoral Immune Response in Duffy Negative Africans Individuals of African ancestry were thought to be protected from Plasmodium vivax because they lack Duffy antigen expression on the surface of their erythrocytes rendering P. vivax unable to invade their red blood cells. However, an increasing number of P. vivax cases reported across Africa and in Duffy-negative individuals challenges this conventional dogma, raising the possibility that some P. vivax lineages have evolved to use ligands other than Duffy Binding Protein for erythrocyte invasion. The intrinsic invasion mechanism and immune response of Duffy-negative individuals to P. vivax are largely unknown. In this application, we will investigate the expression and function of erythrocyte binding genes in Duffy-negative P. vivax and the antibody response of Duffy-negative individuals to P. vivax antigens. There are three specific aims: 1) to identify genes with differential expression between Duffy-positive and Duffy-negative P. vivax by RNA-seq; 2) to determine in vitro binding and invasion activities of P. vivax candidate ligand proteins to Duffy-negative red blood cells; and 3) to examine in vivo antibody levels to targeted P. vivax antigens associated with erythrocyte invasion in Duffy- negative patients. The proposed research will be conducted in Ethiopia, where malaria is a major public health problem and about 30% of the 1.2 million confirmed malaria cases were P. vivax. As our study sites have a large number of P. vivax cases and a significant proportion of Duffy-negative individuals, we have a unique opportunity to study the invasion mechanisms of P. vivax in Africa. We have a collaborative team and logistics in place for sample collection and processing. Our established lab culture facility closes to the health centers and successful P. vivax transcriptome data obtained from cultured schizonts have demonstrated the feasibility of this research. Comparison of P. vivax transcriptomes between Duffy-negative and Duffy-positive individuals from both in vitro and in vivo samples will provide the first description of genetic and functional attributes of P. vivax that permit infection of Duffy-negative erythrocytes. This research will significantly enhance the understanding of invasion mechanism of P. vivax in Duffy- negative individuals and lay a foundation for molecular and biochemical characterizations of P. vivax ligand-receptor interactions. Knowledge of P. vivax invasion mechanisms and host immune responses will have important implications for P. vivax vaccine development and vivax malaria risk assessment both within and outside Africa.