Identification of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) as the rosetting ligand of the malaria parasite P. falciparum.
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.
Chen
Q
Q
Microbiology and Tumor Biology Center, Karolinska Institutet, the Swedish Institute for Infectious Disease Control, S-171 77 Stockholm, Sweden.
Barragan
A
A
Fernandez
V
V
Sundström
A
A
Schlichtherle
M
M
Sahlén
A
A
Carlson
J
J
Datta
S
S
Wahlgren
M
M
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
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