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Background  α-thalassemia results from decreased production of α-globin chains that make up part of hemoglobin tetramers (Hb; α 2 β 2 ) and affects up to 50% of individuals in some regions of sub-Saharan Africa. Heterozygous (−α/αα) and homozygous (−α/−α) genotypes are associated with reduced risk of severe  Plasmodium falciparum  malaria, but the mechanism of this protection remains obscure. We hypothesized that α-thalassemia impairs the adherence of parasitized red blood cells (RBCs) to microvascular endothelial cells (MVECs) and monocytes – two interactions that are centrally involved in the pathogenesis of severe disease.    Methods and Findings  We obtained  P. falciparum  isolates directly from Malian children with malaria and used them to infect αα/αα (normal), −α/αα and −α/−α RBCs. We also used laboratory-adapted  P. falciparum  clones to infect −/−α RBCs obtained from patients with HbH disease. Following a single cycle of parasite invasion and maturation to the trophozoite stage, we tested the ability of parasitized RBCs to bind MVECs and monocytes. Compared to parasitized αα/αα RBCs, we found that parasitized −α/αα, −α/−α and −/−α RBCs showed, respectively, 22%, 43% and 63% reductions in binding to MVECs and 13%, 33% and 63% reductions in binding to monocytes. α-thalassemia was associated with abnormal display of  P. falciparum  erythrocyte membrane protein 1 (PfEMP1), the parasite’s main cytoadherence ligand and virulence factor, on the surface of parasitized RBCs.    Conclusions  Parasitized α-thalassemic RBCs show PfEMP1 display abnormalities that are reminiscent of those on the surface of parasitized sickle HbS and HbC RBCs. Our data suggest a model of malaria protection in which α-thalassemia ameliorates the pro-inflammatory effects of cytoadherence. Our findings also raise the possibility that other unstable hemoglobins such as HbE and unpaired α-globin chains (in the case of β-thalassemia) protect against life-threatening malaria by a similar mechanism.

α-Thalassemia Impairs the Cytoadherence of Plasmodium falciparum-Infected Erythrocytes