title: Hemoglobinopathic erythrocytes affect the intraerythrocytic multiplication of Plasmodium falciparum in vitro.
abstract: BACKGROUND
  The mechanisms by which α-thalassemia and sickle cell traits confer protection from severe Plasmodium falciparum malaria are not yet fully elucidated. We hypothesized that hemoglobinopathic erythrocytes reduce the intraerythrocytic multiplication of P. falciparum, potentially delaying the development of life-threatening parasite densities until parasite clearing immunity is achieved.
  
  
  METHODS
  We developed a novel in vitro assay to quantify the number of merozoites released from an individual schizont, termed the "intraerythrocytic multiplication factor" (IMF).
  
  
  RESULTS
  P. falciparum (3D7 line) schizonts produce variable numbers of merozoites in all erythrocyte types tested, with median IMFs of 27, 27, 29, 23, and 23 in control, HbAS, HbSS, and α- and β-thalassemia trait erythrocytes, respectively. IMF correlated strongly (r(2) = 0.97; P < .001) with mean corpuscular hemoglobin concentration, and varied significantly with mean corpuscular volume and hemoglobin content. Reduction of IMFs in thalassemia trait erythrocytes was confirmed using clinical parasite isolates with different IMFs. Mathematical modeling of the effect of IMF on malaria progression indicates that the lower IMF in thalassemia trait erythrocytes limits parasite density and anemia severity over the first 2 weeks of parasite replication.
  
  
  CONCLUSIONS
  P. falciparum IMF, a parasite heritable virulence trait, correlates with erythrocyte indices and is reduced in thalassemia trait erythrocytes. Parasite IMF should be examined in other low-indices erythrocytes.
authors.affiliation: Program in Physical Biology, Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Glushakova
authors.affiliation: Program in Physical Biology, Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health.
authors.forename: Amanda
authors.initials: A
authors.lastname: Balaban
authors.affiliation: Mathematical and Statistical Computing Laboratory, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health.
authors.forename: Philip G
authors.initials: PG
authors.lastname: McQueen
authors.affiliation: Laboratory of Cellular Imaging and Macromolecular Biophysics, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health.
authors.forename: Rosane
authors.initials: R
authors.lastname: Coutinho
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Miller
authors.affiliation: Program in Physical Biology, Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health.
authors.forename: Ralph
authors.initials: R
authors.lastname: Nossal
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Fairhurst
authors.affiliation: Program in Physical Biology, Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health.
authors.forename: Joshua
authors.initials: J
authors.lastname: Zimmerberg
mesh_terms: D004912:Erythrocytes / Q000469:parasitology*; D006453:Hemoglobinopathies; D006801:Humans; D052940:Merozoites / Q000254:growth & development*; D008962:Models, Theoretical; D059208:Parasite Load; D010963:Plasmodium falciparum / Q000254:growth & development*
keywords: Plasmodium falciparum; hemoglobinopathy; malaria; sickle hemoglobin; thalassemia