title: α-Thalassemia impairs the cytoadherence of Plasmodium falciparum-infected erythrocytes.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Krause
authors.forename: Seidina A S
authors.initials: SA
authors.lastname: Diakite
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Lopera-Mesa
authors.forename: Chanaki
authors.initials: C
authors.lastname: Amaratunga
authors.forename: Takayuki
authors.initials: T
authors.lastname: Arie
authors.forename: Karim
authors.initials: K
authors.lastname: Traore
authors.forename: Saibou
authors.initials: S
authors.lastname: Doumbia
authors.forename: Drissa
authors.initials: D
authors.lastname: Konate
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Keefer
authors.forename: Mahamadou
authors.initials: M
authors.lastname: Diakite
authors.forename: Rick M
authors.initials: RM
authors.lastname: Fairhurst
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D004912:Erythrocytes / Q000469:parasitology* / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D016778:Malaria, Falciparum / Q000235:genetics*; D008302:Mali; D018625:Microscopy, Atomic Force; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009000:Monocytes / Q000502:physiology; D010963:Plasmodium falciparum / Q000502:physiology*; D015800:Protozoan Proteins / Q000378:metabolism*; D017085:alpha-Thalassemia / Q000235:genetics / Q000503:physiopathology*
chemical_list: D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum