title: Hemoglobin C modulates the surface topography of Plasmodium falciparum-infected erythrocytes.
abstract: There is a well-established clinical association between hemoglobin genotype and innate protection against Plasmodium falciparum malaria. In contrast to normal hemoglobin A, mutant hemoglobin C is associated with substantial reductions in the risk of severe malaria in both heterozygous AC and homozygous CC individuals. Irrespective of hemoglobin genotype, parasites may induce knob-like projections on the erythrocyte surface. The knobs play a major role in the pathogenesis of severe malaria by serving as points of adherence for P. falciparum-infected erythrocytes to microvascular endothelia. To evaluate the influence of hemoglobin genotype on knob formation, we used a combination of atomic force and light microscopy for concomitant topographic and wide-field fluorescence imaging. Parasitized AA, AC, and CC erythrocytes showed a population of knobs with a mean width of approximately 70 nm. Parasitized AC and CC erythrocytes showed a second population of large knobs with a mean width of approximately 120 nm. Furthermore, spatial knob distribution analyses demonstrated that knobs on AC and CC erythrocytes were more aggregated than on AA erythrocytes. These data support a model in which large knobs and their aggregates are promoted by hemoglobin C, reducing the adherence of parasitized erythrocytes in the microvasculature and ameliorating the severity of a malaria infection.
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Arie
authors.forename: Rick M
authors.initials: RM
authors.lastname: Fairhurst
authors.forename: Nathaniel J
authors.initials: NJ
authors.lastname: Brittain
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wellems
authors.forename: James A
authors.initials: JA
authors.lastname: Dvorak
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D048430:Cell Shape; D004730:Endothelium, Vascular; D004912:Erythrocytes / Q000469:parasitology* / Q000473:pathology; D005838:Genotype; D006444:Hemoglobin C / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood / Q000209:etiology; D008833:Microcirculation; D018625:Microscopy, Atomic Force; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D013499:Surface Properties
chemical_list: D006444:Hemoglobin C