Enhanced phagocytosis of ring-parasitized mutant erythrocytes: a common mechanism that may explain protection against falciparum malaria in sickle trait and beta-thalassemia trait

Blood. 2004 Nov 15;104(10):3364-71. doi: 10.1182/blood-2003-11-3820. Epub 2004 Jul 27.


High frequency of erythrocyte (red blood cell [RBC]) genetic disorders such as sickle cell trait, thalassemia trait, homozygous hemoglobin C (Hb-C), and glucose-6-phosphate dehydrogenase (G6PD) deficiency in regions with high incidence of Plasmodium falciparum malaria and case-control studies support the protective role of those conditions. Protection has been attributed to defective parasite growth or to enhanced removal of the parasitized RBCs. We suggested enhanced phagocytosis of rings, the early intraerythrocytic form of the parasite, as an alternative explanation for protection in G6PD deficiency. We show here that P falciparum developed similarly in normal RBCs and in sickle trait, beta- and alpha-thalassemia trait, and HbH RBCs. We also show that membrane-bound hemichromes, autologous immunoglobulin G (IgG) and complement C3c fragments, aggregated band 3, and phagocytosis by human monocytes were remarkably higher in rings developing in all mutant RBCs considered except alpha-thalassemia trait. Phagocytosis of ring-parasitized mutant RBCs was predominantly complement mediated and very similar to phagocytosis of senescent or damaged normal RBCs. Trophozoite-parasitized normal and mutant RBCs were phagocytosed similarly in all conditions examined. Enhanced phagocytosis of ring-parasitized mutant RBCs may represent the common mechanism for malaria protection in nonimmune individuals affected by widespread RBC mutations, while individuals with alpha-thalassemia trait are likely protected by a different mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anemia, Sickle Cell / immunology*
  • Animals
  • Anion Exchange Protein 1, Erythrocyte / metabolism
  • Complement C3c / metabolism
  • Erythrocyte Membrane / immunology
  • Erythrocyte Membrane / metabolism
  • Erythrocyte Membrane / parasitology
  • Erythrocytes / immunology
  • Erythrocytes / metabolism
  • Erythrocytes / parasitology*
  • Female
  • Hemeproteins / metabolism
  • Humans
  • Immunoglobulin G / metabolism
  • Malaria, Falciparum / immunology*
  • Male
  • Middle Aged
  • Phagocytosis / immunology*
  • Plasmodium falciparum / growth & development*
  • Plasmodium falciparum / immunology
  • beta-Thalassemia / immunology*


  • Anion Exchange Protein 1, Erythrocyte
  • Hemeproteins
  • Immunoglobulin G
  • hemichrome
  • Complement C3c