CR1 Polymorphisms and Susceptibility to Severe Malaria

CR1 多态性与严重疟疾的易感性

• 批准号: 6545283
• 负责人: JOANN M MOULDS
• 金额: $ 26.43万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2004-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6545283
• 关键词: Africa; Asia; Plasmodium falciparum; antigen antibody reaction; blood group antigens; cellular immunity; clinical research; complement receptor; disease /disorder proneness /risk; erythrocytes; gene mutation; genetic polymorphism; genetic susceptibility; genotype; health surveys; host organism interaction; human genetic material tag; human subject; malaria; molecular pathology; nucleic acid sequence; pathologic process; phenotype; population genetics; receptor expression; serology /serodiagnosis; virulence

DESCRIPTION (provided by the applicant): Plasmodium falciparum malaria is one of the most important infectious diseases affecting the human population and is a multi-factorial process influenced by both parasite virulence factors and host genetic susceptibility. Rosetting and cytoadherence are believed to be the prime virulence factors involved in severe disease, and disruption of rosettes could be an important tool for treatment. The parasite ligand for rosette formation is a var gene product, PfEMP-1, that interacts with complement receptor one (CR1) on uninfected red cells. This proposal Will test the hypothesis that red cell CR1 is important in rosetting and malaria pathogenesis and that unique CR1-specific genetic polymorphisms have evolved in malaria endemic regions to confer resistance to severe disease. CR1 exhibits both quantitative (expression) and qualitative (Knops blood group) polymorphisms that differ significantly in frequency in malaria endemic vs. non-malarial regions. Red cells with low expression of CR1 have reduced rosetting while those negative for a Knops blood group antigen, Sla, formed fewer rosettes using PfEMP-1 expressing COS cells. Studies have shown that antibodies to rosettes are acquired with age and malaria immunity. Thus, any or all of these factors may protect from severe malaria. The molecular basis of the Knops antigens SIa, VII, McCa and MCCb were identified in order to genotype a large DNA database from malaria patients and correlate the Knops type with disease severity. However, the genotyping methods proved inadequate due to unforeseen variation in red cell CR1 expression resulting in discordant CR1 genotype and red cell phenotype. Thus, we propose to prospectively test patients whose red cells have normal CR1 levels but carry the Knops blood group polymorphisms to examine if they are functionally deficient and have a reduced avidity of binding between CR1 and its ligands (PfEMP-1). We will test patients with low red cell CR1 to determine if they are protected from syndromes involving micro-vascular obstruction (cerebral malaria) due to the inhibitory effect on rosetting. We will further determine if low red cell CR1 levels increase susceptibility to severe malaria anemia due to reduced protection of the red cells from complement damage. By defining the molecular basis and functional consequences of these CR1 polymorphisms we will have a better understanding of the host-parasite interactions in order to develop new therapeutics and provide better treatment.

描述（由申请人提供）：恶性疟原虫疟疾是影响人类最重要的传染病之一，是一个受寄生虫毒力因素和宿主遗传易感性共同影响的多因素过程。结簇和细胞粘附性被认为是涉及严重疾病的主要毒力因素，破坏结簇可能是治疗的重要工具。用于玫瑰花结形成的寄生虫配体是一种变异基因产物PfEMP-1，它与未感染红细胞上的补体受体1 （CR1）相互作用。这一提议将验证红细胞CR1在结花和疟疾发病机制中起重要作用的假设，以及在疟疾流行地区进化出独特的CR1特异性遗传多态性，从而赋予对严重疾病的抵抗力。CR1表现出定量（表达）和定性（Knops血型）多态性，在疟疾流行地区和非疟疾地区的频率有显著差异。低表达CR1的红细胞形成较少的玫瑰花，而那些Knops血型抗原Sla阴性的红细胞使用表达PfEMP-1的COS细胞形成较少的玫瑰花。研究表明，玫瑰病抗体是随着年龄增长和疟疾免疫而获得的。因此，这些因素中的任何一个或全部都可以预防严重疟疾。鉴定Knops抗原SIa、VII、McCa和MCCb的分子基础，以便对来自疟疾患者的大型DNA数据库进行基因分型，并将Knops型与疾病严重程度联系起来。然而，由于红细胞CR1表达的不可预见的变化导致CR1基因型和红细胞表型不一致，基因分型方法被证明是不充分的。因此，我们建议对红细胞中CR1水平正常但携带Knops血型多态性的患者进行前瞻性检测，以检查他们是否存在功能缺陷，以及CR1与其配体（PfEMP-1）之间的结合度是否降低。我们将对低红细胞CR1患者进行测试，以确定由于对结瘤的抑制作用，他们是否受到微血管阻塞综合征（脑型疟疾）的保护。我们将进一步确定低红细胞CR1水平是否会增加对严重疟疾贫血的易感性，原因是红细胞免受补体损伤的保护能力降低。通过定义这些CR1多态性的分子基础和功能后果，我们将更好地了解宿主与寄生虫的相互作用，从而开发新的治疗方法并提供更好的治疗。