Proceedings of the National Academy of Sciences · 2003 · 259 citations · 42 references
Life SciencesGeneticsMolecular GeneticsHuman GeneticsImmunogeneticsMedical GeneticsAnemiaBlood ParasitesComplement SystemInnate Immune Responses To ParasitesMalariaRed Blood Cell DisordersComplement System GenesMalaria ParasitesMalaria PathologyMalaria ResistanceMalaria SusceptibilityParasite Virulence FactorsPlasmodium FalciparumSevere Malaria
Parasitized red blood cells from children with severe malaria adhere to complement receptor 1 on uninfected RBCs, forming rosettes that are associated with severe disease but whose causal role remains uncertain. The study tests whether CR1 deficiency, which markedly reduces rosetting, confers protection against severe malaria. CR1 deficiency, linked to CR1 gene polymorphisms and α‑thalassemia, occurs in up to 80 % of healthy individuals in Papua New Guinea and independently protects against severe malaria, establishing CR1 as a new malaria resistance gene and confirming rosetting as a key virulence phenotype.
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 α-thalassemia, a common genetic disorder in Melanesian populations. Analysis of a case-control study demonstrated that the CR1 polymorphisms and α-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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