CR1 Polymorphisms and Susceptibility to Severe Malaria

描述(由申请人提供)：恶性疟疾是影响人类人口的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影响的多因素过程。玫瑰花结和细胞黏附被认为是严重疾病的主要致病因子，破坏玫瑰花环可能是治疗的重要工具。形成花环的寄生虫配体是一种var基因产物PfEMP-1，它与未感染的红细胞上的补体受体1(CR1)相互作用。这一提议将检验一种假设，即红细胞CR1在花环和疟疾发病机制中具有重要作用，并且在疟疾流行地区进化出独特的CR1特异性基因多态，以增强对严重疾病的抵抗力。在疟疾流行地区和非疟疾流行地区，CR1表现出数量(表达)和质量(诺普斯血型)的多态，其频率显著不同。CR1低表达的红细胞玫瑰花环减少，而那些Knops血型抗原SLA阴性的红细胞使用PfEMP-1表达COS细胞形成的玫瑰花环较少。研究表明，对玫瑰花环的抗体是随着年龄和疟疾免疫力的提高而获得的。因此，这些因素中的任何一个或所有因素都可以预防严重疟疾。为了对疟疾患者的大型DNA数据库进行基因分型，并将其与疾病严重程度相关联，对Knops抗原Sia、Vi、MCCa和MCCb的分子基础进行了鉴定。然而，由于红细胞CR1表达的不可预见的变化导致CR1基因和红细胞表型不一致，因此基因分型方法被证明是不充分的。因此，我们建议对红细胞CR1水平正常但携带Knop血型多态的患者进行前瞻性测试，以检查他们是否存在功能缺陷，以及CR1与其配体(PfEMP-1)的结合亲和力是否降低。我们将测试低红细胞CR1的患者，以确定他们是否受到保护，免受由于抑制玫瑰花环的作用而导致的微血管阻塞(脑性疟疾)综合征的发生。我们将进一步确定低水平的红细胞CR1是否由于降低了对红细胞免受补体损伤的保护而增加了对严重疟疾贫血的易感性。通过确定这些CR1基因多态性的分子基础和功能后果，我们将更好地了解宿主-寄生虫的相互作用，以便开发新的治疗方法和提供更好的治疗。

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.