CRL POLYMORPHISMS AND SESCEPTIBILITY TO SEVERE MALARIA

CRL 多态性和对严重疟疾的敏感性

• 批准号: 2462899
• 负责人: JOANN M MOULDS
• 金额: $ 29.22万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2462899
• 关键词: African; Plasmodium falciparum; antigen antibody reaction; blood group antigens; cellular immunity; complement receptor; disease /disorder proneness /risk; erythrocytes; gene mutation; genetic polymorphism; health surveys; host organism interaction; human subject; immune adherence reaction; malaria; molecular cloning; molecular pathology; monoclonal antibody; nucleic acid sequence; pathologic process; polymerase chain reaction; receptor expression; serology /serodiagnosis; tissue /cell culture; virulence; western blottings

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.

在四种疟原虫中，恶性疟原虫的致死率最高