A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria.
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.
Cockburn
Ian A
IA
Institute of Cell Animal and Population Biology, Ashworth Laboratories, King's Buildings, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, United Kingdom.
Mackinnon
Margaret J
MJ
O'Donnell
Angela
A
Allen
Stephen J
SJ
Moulds
Joann M
JM
Baisor
Moses
M
Bockarie
Moses
M
Reeder
John C
JC
Rowe
J Alexandra
JA
D000328:Adult; D000483:Alleles; D000818:Animals; D002648:Child; D004912:Erythrocytes / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D016778:Malaria, Falciparum / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D010219:Papua New Guinea; D010963:Plasmodium falciparum / Q000276:immunology* / Q000472:pathogenicity*; D011110:Polymorphism, Genetic; D011951:Receptors, Complement / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D012397:Rosette Formation; D014774:Virulence; D017085:alpha-Thalassemia / Q000235:genetics / Q000276:immunology
D011951:Receptors, Complement