CRL POLYMORPHISMS AND SUSCEPTIBILITY TO SEVERE MALARIA

在四种疟原虫中，恶性疟原虫引起的疟疾发病率最高， 发病率和死亡率最高，仍然是世界卫生组织的一个主要问题。 问题.有人认为，疾病的严重程度可能与 感染的红细胞在微静脉中隔离的能力 各种器官。隔离似乎取决于旋钮 在受感染的红细胞表面产生， 附着于内皮。Knob阳性红细胞也可形成 用未感染的细胞进行玫瑰花结;玫瑰花结是少数已知的 与严重疟疾有关的毒力因子。但是，特定的配体- 参与该机制的受体相互作用并不好 明白最近，恶性疟原虫变种基因产物已被 鉴定为配体（Duffy结合样结构域或DBL-1）， 补体受体1（CR 1）及其体外玫瑰花结中的假定受体 阵CR 1在3个方面表现出遗传多态性：分子 体重，Knops血型和表达水平差异 红细胞CR 1的低表达和Knops血液中的一种 组表型，S1（a-），降低了形成罗丹明的能力。的 Sl（a-）表型在非洲来源的 但在非疟疾流行地区的人群中很少见。这 提出了CR 1多态性赋予选择性 通过降低P. 感染和未感染的红细胞。因此本 这项提案将研究CR 1的遗传多态性如何与 花结形成与重症恶性疟原虫的病理生理 疟疾为了做到这一点，我们将确定的分子基础， CR 1多态性在非洲人群中更常见 利用RT-PCR、异源双链筛选、DNA克隆和DNA序列测定 来自抗原阳性和阴性供体的分析。采用这种 信息，它们的遗传相关性将通过筛选大型 疟疾DNA数据库的PCR为基础的技术。功能相关性 这些多态性将通过使用CR 1缺失来检查 构建体以鉴定宿主-寄生虫相互作用的区域， 阻断这些与CR 1单克隆抗体的相互作用，和/或 重组可溶性CR 1。因此，这项研究应被视为 这是开发新化疗剂的第一步， 预防与严重疟疾相关的病理学。

Of the four species of Plasmodium, P. falciparum causes the greatest morbidity and highest mortality and remains a major world health problem. It has been suggested that severity of disease may relate to the ability of infected erythrocytes to sequester in the venules of various organs. Sequestration appears to be dependent upon knobs produced on the surface of infected erythrocytes which mediate attachment to the endothelium. Knob positive erythrocytes can also form rosettes with uninfected cells; rosetting being one of the few known virulence factors related to severe malaria. However, specific ligand- receptor interactions involved in this mechanism are not well understood. Recently, a P. falciparum var gene product has been identified as the ligand (Duffy binding like domain or DBL-1) and complement receptor one (CR1) its putative receptor in in vitro rosette formation. CR1 exhibits genetic polymorphism in 3 ways: molecular weight, the Knops blood group and expression level differences on erythrocytes. The low expression of CR1 and one of the Knops blood group phenotypes, Sl(a-), reduces the ability to form rosettes. The Sl(a-) phenotype is detected at high frequency in African-derived populations but is rare in populations from non-malarious regions. This raises the possibility that CR1 polymorphism confers a selective advantage by reducing the potential for rosette formation between P. falciparum-infected and uninfected erythrocytes. Therefore, this proposal will study how the genetic polymorphisms of CR1 relate to rosette formation and the pathophysiology of severe P.falciparum malaria. To accomplish this we will identify the molecular basis of the CR1 polymorphisms found more frequently in African-derived population using RT-PCR, heteroduplex screening, DNA cloning and DNA sequence analysis from antigen positive and negative donors. Employing this information, their genetic relevance will be tested by screening large malaria DNA databases by PCR-based techniques. Functional relevance of these polymorphisms will be examined by utilizing CR1 deletion constructs to identify the regions of host-parasite interaction and blocking these interactions with monoclonal antibodies to CR1 and/or recombinant soluble CR1. Therefore, this research should be viewed as a first step in the development of new chemotherapeutic agents that prevent pathology associated with severe malaria.