title: Plasmodium falciparum expressing domain cassette 5 type PfEMP1 (DC5-PfEMP1) bind PECAM1.
abstract: Members of the Plasmodium falciparum Erythrocyte Membrane protein 1 (PfEMP1) family expressed on the surface of malaria-infected erythrocytes mediate binding of the parasite to different receptors on the vascular lining. This process drives pathologies, and severe childhood malaria has been associated with the expression of particular subsets of PfEMP1 molecules. PfEMP1 are grouped into subtypes based on upstream sequences and the presence of semi-conserved PfEMP1 domain compositions named domain cassettes (DCs). Earlier studies have indicated that DC5-containing PfEMP1 (DC5-PfEMP1) are more likely to be expressed in children with severe malaria disease than in children with uncomplicated malaria, but these PfEMP1 subtypes only dominate in a relatively small proportion of the children with severe disease. In this study, we have characterised the genomic sequence characteristic for DC5, and show that two genetically different parasite lines expressing DC5-PfEMP1 bind PECAM1, and that anti-DC5-specific antibodies inhibit binding of DC5-PfEMP1-expressing parasites to transformed human bone marrow endothelial cells (TrHBMEC). We also show that antibodies against each of the four domains characteristic for DC5 react with native PfEMP1 expressed on the surface of infected erythrocytes, and that some of these antibodies are cross-reactive between the two DC5-containing PfEMP1 molecules tested. Finally, we confirm that anti-DC5 antibodies are acquired early in life by individuals living in malaria endemic areas, that individuals having high levels of these antibodies are less likely to develop febrile malaria episodes and that the antibody levels correlate positively with hemoglobin levels.
authors.affiliation: Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, Copenhagen University Hospital (Rigshospitalet), University of Copenhagen, Copenhagen, Denmark. sansch@sund.ku.dk
authors.forename: Sanne S
authors.initials: SS
authors.lastname: Berger
authors.forename: Louise
authors.initials: L
authors.lastname: Turner
authors.forename: Christian W
authors.initials: CW
authors.lastname: Wang
authors.forename: Jens E V
authors.initials: JE
authors.lastname: Petersen
authors.forename: Maria
authors.initials: M
authors.lastname: Kraft
authors.forename: John P A
authors.initials: JP
authors.lastname: Lusingu
authors.forename: Bruno
authors.initials: B
authors.lastname: Mmbando
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Marquard
authors.forename: Dominique B A C
authors.initials: DB
authors.lastname: Bengtsson
authors.forename: Lars
authors.initials: L
authors.lastname: Hviid
authors.forename: Morten A
authors.initials: MA
authors.lastname: Nielsen
authors.forename: Thor G
authors.initials: TG
authors.lastname: Theander
authors.forename: Thomas
authors.initials: T
authors.lastname: Lavstsen
mesh_terms: D000913:Antibodies, Protozoan / Q000276:immunology / Q000378:metabolism; D000953:Antigens, Protozoan / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D016000:Cluster Analysis; D017124:Conserved Sequence; D042783:Endothelial Cells / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D005786:Gene Expression Regulation; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D016778:Malaria, Falciparum / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D010963:Plasmodium falciparum / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D007074:Immunoglobulin G; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum