title: Identification of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) as the rosetting ligand of the malaria parasite P. falciparum.
abstract: Severe Plasmodium falciparum malaria is characterized by excessive sequestration of infected and uninfected erythrocytes in the microvasculature of the affected organ. Rosetting, the adhesion of P. falciparum-infected erythrocytes to uninfected erythrocytes is a virulent parasite phenotype associated with the occurrence of severe malaria. Here we report on the identification by single-cell reverse transcriptase PCR and cDNA cloning of the adhesive ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1). Rosetting PfEMP1 contains clusters of glycosaminoglycan-binding motifs. A recombinant fusion protein (Duffy binding-like 1-glutathione S transferase; Duffy binding-like-1-GST) was found to adhere directly to normal erythrocytes, disrupt naturally formed rosettes, block rosette reformation, and bind to a heparin-Sepharose matrix. The adhesive interactions could be inhibited with heparan sulfate or enzymes that remove heparan sulfate from the cell surface whereas other enzymes or similar glycosaminoglycans of a like negative charge did not affect the binding. PfEMP1 is suggested to be the rosetting ligand and heparan sulfate, or a heparan sulfate-like molecule, the receptor both for PfEMP1 binding and naturally formed erythrocyte rosettes.
authors.affiliation: Microbiology and Tumor Biology Center, Karolinska Institutet, the Swedish Institute for Infectious Disease Control, S-171 77 Stockholm, Sweden.
authors.forename: Q
authors.initials: Q
authors.lastname: Chen
authors.forename: A
authors.initials: A
authors.lastname: Barragan
authors.forename: V
authors.initials: V
authors.lastname: Fernandez
authors.forename: A
authors.initials: A
authors.lastname: Sundström
authors.forename: M
authors.initials: M
authors.lastname: Schlichtherle
authors.forename: A
authors.initials: A
authors.lastname: Sahlén
authors.forename: J
authors.initials: J
authors.lastname: Carlson
authors.forename: S
authors.initials: S
authors.lastname: Datta
authors.forename: M
authors.initials: M
authors.lastname: Wahlgren
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001798:Blood Proteins / Q000235:genetics / Q000502:physiology*; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004910:Erythrocyte Membrane / Q000469:parasitology*; D006025:Glycosaminoglycans / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D016778:Malaria, Falciparum / Q000097:blood / Q000469:parasitology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D015800:Protozoan Proteins / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012397:Rosette Formation
chemical_list: D001798:Blood Proteins; D017931:DNA Primers; D018076:DNA, Complementary; D006025:Glycosaminoglycans; D006497:Heparan Sulfate; D008024:Ligands; D008565:Membrane Proteins; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum