CRL POLYMORPHISMS AND SESCEPTIBILITY TO SEVERE MALARIA

在四种疟原虫中，恶性疟原虫造成的影响最大 发病率和死亡率最高，仍然是一个主要的世界卫生问题 有问题。有人提出，疾病的严重程度可能与 感染的红细胞在小静脉中隔离的能力 各种器官。自动减支似乎依赖于旋钮 在感染的红细胞表面产生，介导 依附于内皮细胞。结节阳性的红细胞也可以形成 具有未感染细胞的玫瑰花环；玫瑰花环是为数不多的已知玫瑰花环之一 与严重疟疾有关的毒力因素。然而，特定的配体- 参与这一机制的受体相互作用不是很好。 明白了。最近，一种恶性疟原虫var基因产物被 鉴定为配体(Duffy结合，如结构域或DBL-1)和 补体受体1(CR1)及其在体外玫瑰花环中的可能受体 队形。CR1以3种方式表现出遗传多态：分子 体重、克诺普斯血型和表达水平的差异 红血球。CR1和KNOPS血中CR1的低表达 组表型，Sl(a-)，降低了形成花环的能力。这个 在非洲人中检测到SL(a-)表型的频率很高 但在非疟疾地区的人群中很少见。这 增加了CR1基因多态赋予选择性 优势在于减少了P. 感染和未感染恶性疟原虫的红细胞。因此，这 提案将研究CR1的遗传多态如何与 重症恶性疟原虫花环形成及病理生理研究 疟疾。为了实现这一点，我们将确定分子基础 CR1基因多态性在非洲裔人群中出现频率更高 利用RT-PCR、异源双链筛选、DNA克隆和DNA测序 来自抗原阳性和阴性献血者的分析。采用这种方式 信息，他们的遗传相关性将通过筛选大的 以聚合酶链式反应为基础的疟疾DNA数据库。的功能相关性 这些多态将通过利用CR1缺失进行检查 构建来识别宿主-寄生虫相互作用的区域和 用抗CR1和/或的单抗阻断这些相互作用 重组可溶性CR1。因此，这项研究应该被视为 开发新的化疗药物的第一步 预防与严重疟疾相关的病理。

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.