Molecular analysis of erythrocyte invasion in malaria isolates from Senegal

塞内加尔疟疾分离株红细胞侵袭的分子分析

基本信息

批准号：
7760921
负责人：
Manoj T Duraisingh
金额：
$ 3.44万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7760921
关键词：
Address Affinity Affinity Chromatography Alleles Antibodies Antigens Apical Binding Proteins Biochemical Biochemical Genetics C-terminal Cells Charge Chimera organism Chimeric Proteins Collaborations Complement Consultations Cytoplasmic Tail Data Development Disease Doctor of Philosophy Drug resistance Epidemiology Erythrocytes Event Family Family member Future Gene Deletion Gene Family Generations Genetic Genetic Polymorphism Geographic Locations Goals Grant Head Homologous Gene Hospitals Human Immune Immune response Immune system Immunity In Vitro Infection Institution Integral Membrane Protein Invaded Knock-out Knowledge Label Laboratories Laboratory culture Lead Ligands Malaria Measures Membrane Methodology Methods Molecular Molecular Analysis Multigene Family Mutate Nature Organelles Parasites Parents Pathology Pathway interactions Patients Pharmaceutical Preparations Plasmodium Plasmodium falciparum Plasmodium vivax Play Population Process Protein Binding Proteins Public Health Schools Relative (related person)Research Research Infrastructure Reticulocytes Role Sampling Scientist Senegal Serum Signal Transduction Staging Students Surface Tail Testing Text Training Transcript Transmembrane Domain Universities Vaccine Design Variant Virulence Work Writing Yeasts base chymotrypsin clinical research site combat design erythrocyte receptor experience field study functional outcomes immunogenicity in vivo insight international center member mutant novel paralogous gene parasite invasion parent grant positional cloning professor protein complex public health relevance receptor response rhoptry stem trafficking transmission process vaccine development yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): The human malaria parasite, P. falciparum, utilizes multiple ligand-receptor pathways, known as invasion pathways, for the invasion of human erythrocytes. This allows the malaria parasite to respond to polymorphisms in erythrocyte receptors and/or evade the immune system and may be a determinant of virulence. This research will be done primarily in Dakar, Senegal at the University of Cheikh Anta Diop in collaboration with Dr. Ousmane Sarr, Prof. Souleymane Mboup and Mr. Ambroise Ahouidi, as an extension of the Fogarty International Center grant (D43 TW0011503). Previously, we have identified the common usage of multiple invasion pathways in Senegalese isolates and the expression of multiple paralogs of the PfRh family. We will test the hypothesis that sequence and expression polymorphism in members of the PfRh family are driven by the humoral immune response. Importantly, this proposal focuses on uncultured field isolates from regions of different malaria endemicity within Senegal. To accomplish these goals our specific aims are as follows: 1) We will analyze in detail the extent of expression variation and sequence polymorphism of parasite invasion ligands of the PfRh family that have been implicated in erythrocyte invasion in isolates obtained directly from patients in Senegal. 2) We will measure humoral immune responses to specific domains of the PfRh proteins. We will assess the invasion inhibition potential of antibodies derived from exposed patient sera using PfRh-knockout parasite lines. An understanding of the relationship between the use of multiple invasion ligands and the development of protective immunity is a pre-requisite to their inclusion in the development of a vaccine. PUBLIC HEALTH RELEVANCE: In collaboration with the University of Cheikh Anta Diop, we propose to analyze in detail the extent of variation in levels of expression and sequence of the PfRh family of invasion ligands, an uncharacterized family of molecules that are postulated to play a role in both virulence of the parasite and immunity. The present proposal presents two novel aspects that have developed from previous work in Senegal. Firstly, we will consider in depth, the nature of expression and sequence polymorphisms of members of the PfRh family. Secondly, we will measure immune recognition of this important family that has not been previously studied at all. The data we obtain will have important implications for the inclusion of these molecules in the development of vaccines against malaria.

描述（由申请人提供）：恶性疟原虫的人类疟疾寄生虫使用多种配体受体途径，称为入侵途径，用于侵袭人红细胞。这使疟疾寄生虫能够对红细胞受体中的多态性反应和/或逃避免疫系统，并且可能是毒力的决定因素。这项研究将主要在Cheikh Anta Diop大学的塞内加尔达卡（Dakar）与Ousmane Sarr博士，Souleymane Mboup教授和Ambroise Ahouidi先生合作，作为Fogarty International Center Grant（D43 TW0011503）的扩展。以前，我们已经确定了塞内加尔分离株中多种入侵途径的常见用法以及PFRH家族的多个旁系同源物的表达。我们将检验以下假设：PFRH家族成员的序列和表达多态性是由体液免疫反应驱动的。重要的是，该提案重点是塞内加尔不同疟疾地区的未养殖场分离株。为了实现这些目标，我们的具体目的如下：1）我们将详细分析PFRH家族的寄生虫入侵配体的表达变化和序列多态性的程度，这些程度与直接从塞内加尔患者获得的分离株中有关的红细胞浸润涉及。 2）我们将测量对PFRH蛋白特定域的体液免疫反应。我们将使用PFRH-KNOCKOUT寄生虫线来评估从暴露的患者血清中衍生出的抗体的侵袭抑制潜力。对使用多种入侵配体的使用与保护性免疫的发展之间的关系是它们包含在疫苗开发中的先决条件。公共卫生相关性：与Cheikh Anta Diop大学合作，我们建议详细分析PFRH入侵配体的表达水平和序列的变化程度，PFRH侵袭配体家族是一种未表征的分子家族，这些分子家族被认为在寄生虫和免疫性的两种毒力中都起着作用。本提案介绍了塞内加尔以前的工作发展的两个新方面。首先，我们将深入考虑PFRH家族成员的表达和序列多态性的性质。其次，我们将衡量对以前尚未研究过这个重要家庭的免疫识别。我们获得的数据将对这些分子在针对疟疾的疫苗开发中包含有重要意义。