Characterization of Plasmodium GAPDH as a candidate for development of a malaria pre-erythrocytic vaccine

疟原虫 GAPDH 作为开发疟疾前红细胞疫苗候选物的表征

基本信息

批准号：
9228326
负责人：
MARCELO JACOBS-LORENA
金额：
$ 24.3万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9228326
关键词：
Antibodies Antigen Targeting Antigens Binding Biological Assay Bite Blood Circulation Blood Vessels Cell Communication Cell Surface Receptors Cells Communicable Diseases Culicidae Deposition Development Disease Economics Effectiveness Endothelial Cells Epitope Mapping Epitopes Erythrocytes Glyceraldehyde-3-Phosphate Dehydrogenases Glycolysis Glycosaminoglycans Hepatocyte Human Immune Immunity Immunization Immunize Immunofluorescence Immunologic In Vitro Individual Infection Insecticides Kupffer Cells Libraries Ligand Binding Ligands Liver Malaria Malaria Vaccines Mass Spectrum Analysis Measures Mediating Microbe Modeling Molecular Mus Parasites Pathogenicity Peptide Phage Display Library Peptide antibodies Peptides Persons Phage Display Pharmaceutical Preparations Plasmodium Plasmodium berghei Plasmodium falciparum Play Proteins Receptor Cell Recombinants Skin Sporozoites Surface Tertiary Protein Structure Testing Vaccine Antigen Vaccines Western Blotting Work cell type circumsporozoite protein experimental study fighting in vivo killings liver infection macrophage malaria infection novel phase III trial public health relevance receptor stellate cell vector mosquito weapons

项目摘要

DESCRIPTION (provided by applicant): Malaria remains one of the most devastating infectious diseases. It kills around a million people every year while causing immense suffering and economic losses worldwide. The two main weapons to fight the disease - insecticides that kill the mosquito vector and drugs that kill the parasites in infected individuals - significantly contribute to contain the disease. However, it is imperative that additional measures, such as vaccines, be developed for the elimination and eventual eradication of the disease. Human infection is initiated when during a bite by an infected mosquito, sporozoites are deposited in the skin of the bitten person. Next, sporozoites enter the circulation and must leave it in the liver t continue their cycle. Liver vessels are lined by two cell types - endothelial cells and Kupffer cels - and sporozoites exit the vessels by preferentially traversing Kupffer cells. Using a phage peptide display library we have identified three peptides - P39, P61 and P52 - that bind specifically to Kupffer cells and by doing so, inhibit sporozoite traversal both in vitro (Kupffer ell cultures) and in vivo (live mice). Further work determined that the peptides bind to the CD68 Kupffer cell surface receptor protein. Moreover, the peptides structurally mimic domains of Plasmodium berghei glyceraldehyde 3-phosphate dehydrogenase (PbGAPDH), a protein present on the surface of sporozoites. In addition, we have shown that the CD68 and PbGAPDH proteins interact directly. This project aims at identifying domains of the PbGAPDH protein that mediate interactions with the CD68 receptor. These protein domains will be used as antigens to immunize mice. It is expected that the antibodies of immune mice will interfere with sporozoite traversal of Kupffer cells and in this way, thwart liver infection. The antigens identified in this study may conceivably be used to enhance the effectiveness of the RTS,S pre-erythrocytic vaccine, which in phase III trials has proven to be partially effective.

描述（由申请人提供）：疟疾仍然是最具破坏性的传染病之一，它每年夺去大约一百万人的生命，同时在全世界范围内造成巨大的痛苦和经济损失。对抗这种疾病的两种主要武器是杀死蚊媒的杀虫剂和杀虫剂。杀死感染者体内寄生虫的药物对控制这种疾病有很大帮助，但是，必须开发疫苗等其他措施来消除并最终根除被蚊虫叮咬时引发的人类感染。受感染的蚊子，子孢子沉积在接下来，子孢子进入循环系统并必须留在肝脏中继续其循环。肝血管由两种细胞类型（内皮细胞和库普弗细胞）组成，并且子孢子优先穿过库普弗细胞离开血管。使用噬菌体肽展示库，我们鉴定了三种肽 - P39、P61 和 P52 - 与库普弗细胞特异性结合，并通过因此，在体外（Kupffer 细胞培养物）和体内（活体小鼠）抑制子孢子的穿越，进一步的研究确定该肽与 CD68 Kupffer 细胞表面受体蛋白结合，此外，该肽在结构上模拟伯氏疟原虫甘油醛 3- 的结构域。磷酸脱氢酶（PbGAPDH），一种存在于子孢子表面的蛋白质此外，我们还发现CD68。该项目旨在鉴定介导与 CD68 受体相互作用的 PbGAPDH 蛋白结构域，这些蛋白结构域将用作免疫小鼠的抗原，预计免疫小鼠的抗体将干扰子孢子的穿越。库普弗细胞并以这种方式阻止肝脏感染。这项研究可能会被用来增强 RTS,S 红细胞前疫苗的有效性，该疫苗在 III 期试验中已被证明是部分有效的。