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

达菲阴性非洲人间日疟原虫红细胞侵袭机制和体液免疫反应

• 批准号: 10569567
• 负责人: Eugenia Lo
• 金额: $ 63.83万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-09 至 2023-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10569567
• 关键词: Africa; African; African ancestry; Age; Antibodies; Antibody Response; Antigens; Binding; Binding Proteins; Biochemical; Biological Assay; Candidate Disease Gene; Case Study; Cells; Classification; Copy Number Polymorphism; DNA biosynthesis; Data; Diagnosis; Disease; Enrollment; Epidemic; Erythrocytes; Ethiopia; Flow Cytometry; Foundations; Gender; Gene Dosage; Gene Expression; Genes; Genetic; Genetic Transcription; Genotype; Health; Immune response; Immunize; Immunoassay; Immunoglobulin G; In Vitro; Individual; Infection; Invaded; Knowledge; Ligand Binding; Ligands; Logistics; Malaria; Measures; Molecular; Mutation; Oryctolagus cuniculus; Outcome; Parasites; Patients; Phenotype; Plasma; Plasmids; Plasmodium vivax; Plasmodium vivax vaccine; Population; Process; Proteins; Public Health; RNA; Recombinant Proteins; Reporting; Research; Reticulocytes; Risk Assessment; Sampling; Site; Surface; Time; Transfection; Variant; Vivax Malaria; Whole Blood; antigen binding; candidate identification; comparative; density; differential expression; feasibility research; genomic signature; in vivo; inhibiting antibody; parasite invasion; receptor; residence; sample collection; transcriptome; transcriptome sequencing; vaccine development; vector

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.

项目摘要 间日疟原虫红细胞侵袭机制与体液免疫 达菲阴性非洲人的反应 非洲血统的个体被认为可以免受间日疟原虫的侵害 因为他们的红细胞表面缺乏达菲抗原表达，导致 P.间日疟原虫无法侵入红细胞然而，越来越多的间日疟原虫 非洲各地报告的病例和达菲阴性个体挑战了这一点 传统的教条，提高了一些P的可能性。间日疟原虫谱系已经进化到 使用Duffy结合蛋白以外的配体进行红细胞侵入。本征 Duffy阴性个体对间日疟原虫的入侵机制和免疫应答， 大部分未知。在这个应用程序中，我们将研究的表达和功能 Duffy阴性间日疟原虫红细胞结合基因的表达及抗体应答 Duffy阴性个体对间日疟原虫抗原的反应。具体目标有三个：1） 鉴定Duffy阳性和Duffy阴性P. 通过RNA-seq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体蛋白;和3）体内检测 Duffy中与红细胞侵袭相关的靶向间日疟原虫抗原的抗体水平， 阴性患者这项拟议中的研究将在埃塞俄比亚进行，那里的疟疾是 这是一个重大的公共卫生问题，在120万确诊疟疾病例中， 是间日疟原虫。由于我们的研究中心有大量的间日疟原虫病例， 很大一部分达菲阴性个体，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。我们有一个合作的团队 以及样品收集和处理的后勤保障。我们建立的实验室文化 设施靠近卫生中心，并成功获得间日疟原虫转录组数据 从养殖的小龙虾中提取的蛋白质证明了这项研究的可行性。比较 P. Duffy阴性和Duffy阳性个体之间的间日疟原虫转录组 体外和体内样品将首次描述基因和功能 间日疟原虫允许感染达菲阴性红细胞的属性。本研究 将显著提高对间日疟原虫入侵达菲- 阴性个体，并为分子和生化表征奠定基础 间日疟原虫配体-受体相互作用。间日疟原虫入侵机制的认识 和宿主免疫应答对间日疟原虫疫苗的研究具有重要意义 在非洲内外开展了发展和间日疟风险评估。