A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria |
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Authors: | Cockburn Ian A Mackinnon Margaret J O'Donnell Angela Allen Stephen J Moulds Joann M Baisor Moses Bockarie Moses Reeder John C Rowe J Alexandra |
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Affiliation: | Institute of Cell Animal and Population Biology, Ashworth Laboratories, King's Buildings, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, United Kingdom. |
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Abstract: | Parasitized red blood cells (RBCs) from children suffering from severe malaria often adhere to complement receptor 1 (CR1) on uninfected RBCs to form clumps of cells known as "rosettes." Despite a well documented association between rosetting and severe malaria, it is controversial whether rosetting is a cause or a correlate of parasite virulence. CR1-deficient RBC show greatly reduced rosetting; therefore, we hypothesized that, if rosetting is a direct cause of malaria pathology, CR1-deficient individuals should be protected against severe disease. In this study, we show that RBC CR1 deficiency occurs in up to 80% of healthy individuals from the malaria-endemic regions of Papua New Guinea. This RBC CR1 deficiency is associated with polymorphisms in the CR1 gene and, unexpectedly, with alpha-thalassemia, a common genetic disorder in Melanesian populations. Analysis of a case-control study demonstrated that the CR1 polymorphisms and alpha-thalassemia independently confer protection against severe malaria. We have therefore identified CR1 as a new malaria resistance gene and provided compelling evidence that rosetting is an important parasite virulence phenotype that should be a target for drug and vaccine development. |
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