CRL POLYMORPHISMS AND SUSCEPTIBILITY TO SEVERE MALARIA

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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.