A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria.

Journal article

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.

Authors: Cockburn, I; Mackinnon, M; O'Donnell, A; Allen, S; Moulds, J

• Publication status: Published
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Volume: 101
• Issue: 1
• Pages: 272-277
• Publication date: 2004-01-01
• DOI: 10.1073/pnas.0305306101
• EISSN: 1091-6490
• ISSN: 0027-8424
• Language: English
• Keywords: Polymorphism, Genetic; Malaria, Falciparum; Adult; Plasmodium falciparum; Erythrocytes; Receptors, Complement; Child; Virulence; Rosette Formation; Papua New Guinea; alpha-Thalassemia; Animals; Alleles; Humans