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Title: Complement receptor one polymorphisms and susceptibility to severe malaria
Author: Cockburn, Ian
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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Rosetting – the binding of parasitized red blood cells to uninfected red cells to form “rosettes” has been associated with severe disease in many studies in Africa. However, a study in Papua New Guinea found no association between resetting and severe disease. It remains unclear whether resetting is a cause or correlate of parasite virulence. Rosetting is mediated by the interaction of at least one parasite protein: Plasmodium falciparum erythrocyte membrane protein one (PfEMP1) on the infected erythrocyte surface and a variety of host red cell surface receptors including complement receptor one (CR1). We reasoned that if resetting were a cause of severe disease we would be able to identify protective polymorphisms in the CR1 gene. Here we show that CR1 deficiency is extremely common among individuals from malaria endemic populations in Papua New Guinea. This deficiency is associated with previously reported polymorphisms in the CR1 gene and unexpectedly with alpha-thalassaemia, a red cell disorder that occurs in up to 90% of Melanesians. We tested the hypothesis that CR1 polymorphisms protect against severe malaria by genotyping samples from a case control study for polymorphisms in the CR1. We found that both CR1 deficiency alleles and alpha-thalassaemia protect against severe malaria. We wished to test the hypothesis that resetting was not associated with severe disease in Papua New Guinea because of widespread CR1 deficiency preventing the formation of rosettes strong enough to withstand sheer forces in the circulation. Studies on field isolates from Papua New Guinea showed that resetting was unusual in this population, rarely mediated by binding to CR1 and not associated with disease severity. This suggests that CR1 is essential for physiologically significant resetting associated with severe malaria. We have therefore identified a new malaria resistance gene and provided compelling evidence that CR1 mediated resetting is an important virulence phenotype and a potential target for drug vaccine development.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available