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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Hall, B Fenton
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mcp Hahnemann University
Schools of Medicine
United States
Zip Code
Gonzalez, A M; Cabrera, V M; Larruga, J M et al. (2006) Mitochondrial DNA variation in Mauritania and Mali and their genetic relationship to other Western Africa populations. Ann Hum Genet 70:631-57
Thomas, B N; Donvito, B; Cockburn, I et al. (2005) A complement receptor-1 polymorphism with high frequency in malaria endemic regions of Asia but not Africa. Genes Immun 6:31-6
Thathy, Vandana; Moulds, JoAnn M; Guyah, Bernard et al. (2005) Complement receptor 1 polymorphisms associated with resistance to severe malaria in Kenya. Malar J 4:54
Moulds, J M; Thomas, B J; Doumbo, O et al. (2004) Identification of the Kna/Knb polymorphism and a method for Knops genotyping. Transfusion 44:164-9
Zimmerman, P A; Fitness, J; Moulds, J M et al. (2003) CR1 Knops blood group alleles are not associated with severe malaria in the Gambia. Genes Immun 4:368-73
Rowe, J A; Raza, A; Diallo, D A et al. (2002) Erythrocyte CR1 expression level does not correlate with a HindIII restriction fragment length polymorphism in Africans; implications for studies on malaria susceptibility. Genes Immun 3:497-500
Moulds, J M; Zimmerman, P A; Doumbo, O K et al. (2002) Expansion of the Knops blood group system and subdivision of Sl(a). Transfusion 42:251-6
Moulds, J M (2001) Ethnic diversity of class III genes in autoimmune disease. Front Biosci 6:D986-91
Moulds, J M; Zimmerman, P A; Doumbo, O K et al. (2001) Molecular identification of Knops blood group polymorphisms found in long homologous region D of complement receptor 1. Blood 97:2879-85
Moulds, J M; Kassambara, L; Middleton, J J et al. (2000) Identification of complement receptor one (CR1) polymorphisms in west Africa. Genes Immun 1:325-9

Showing the most recent 10 out of 13 publications