title: Structure-Guided Identification of a Family of Dual Receptor-Binding PfEMP1 that Is Associated with Cerebral Malaria.
abstract: Cerebral malaria is a deadly outcome of infection by Plasmodium falciparum, occurring when parasite-infected erythrocytes accumulate in the brain. These erythrocytes display parasite proteins of the PfEMP1 family that bind various endothelial receptors. Despite the importance of cerebral malaria, a binding phenotype linked to its symptoms has not been identified. Here, we used structural biology to determine how a group of PfEMP1 proteins interacts with intercellular adhesion molecule 1 (ICAM-1), allowing us to predict binders from a specific sequence motif alone. Analysis of multiple Plasmodium falciparum genomes showed that ICAM-1-binding PfEMP1s also interact with endothelial protein C receptor (EPCR), allowing infected erythrocytes to synergistically bind both receptors. Expression of these PfEMP1s, predicted to bind both ICAM-1 and EPCR, is associated with increased risk of developing cerebral malaria. This study therefore reveals an important PfEMP1-binding phenotype that could be targeted as part of a strategy to prevent cerebral malaria.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, OX1 3QU Oxford, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Lennartz
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Adams
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark.
authors.forename: Anja
authors.initials: A
authors.lastname: Bengtsson
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark.
authors.forename: Rebecca W
authors.initials: RW
authors.lastname: Olsen
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark.
authors.forename: Louise
authors.initials: L
authors.lastname: Turner
authors.affiliation: Faculté de Pharmacie, Institut de Recherche pour le Développement (IRD), COMUE Sorbonne Paris Cité, 75013 Paris, France; Faculté des Sciences de la Santé (FSS), Université d'Aboméy Calavi, 01 BP 526 Cotonou, Benin.
authors.forename: Nicaise T
authors.initials: NT
authors.lastname: Ndam
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark; Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana.
authors.forename: Gertrude
authors.initials: G
authors.lastname: Ecklu-Mensah
authors.affiliation: Faculté des Sciences de la Santé (FSS), Université d'Aboméy Calavi, 01 BP 526 Cotonou, Benin.
authors.forename: Azizath
authors.initials: A
authors.lastname: Moussiliou
authors.affiliation: Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Ofori
authors.affiliation: UMR_S1134, Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, 75013 Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Gamain
authors.affiliation: National Institute for Medical Research, Tanga Centre, 11101 Dar es Salaam, Tanzania.
authors.forename: John P
authors.initials: JP
authors.lastname: Lusingu
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark.
authors.forename: Jens E V
authors.initials: JE
authors.lastname: Petersen
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Wang
authors.affiliation: UMR_S1134, Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, 75013 Paris, France.
authors.forename: Sofia
authors.initials: S
authors.lastname: Nunes-Silva
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark.
authors.forename: Jakob S
authors.initials: JS
authors.lastname: Jespersen
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, OX1 3QU Oxford, UK.
authors.forename: Clinton K Y
authors.initials: CK
authors.lastname: Lau
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark.
authors.forename: Thor G
authors.initials: TG
authors.lastname: Theander
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lavstsen
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Hviid
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, OX1 3QU Oxford, UK. Electronic address: matthew.higgins@bioch.ox.ac.uk.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Higgins
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark. Electronic address: atrj@sund.ku.dk.
authors.forename: Anja T R
authors.initials: AT
authors.lastname: Jensen
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D002448:Cell Adhesion; D019295:Computational Biology; D018360:Crystallography, X-Ray; D000074283:Endothelial Protein C Receptor; D018503:Genome, Protozoan; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016779:Malaria, Cerebral / Q000469:parasitology*; D016778:Malaria, Falciparum / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000472:pathogenicity* / Q000502:physiology; D011485:Protein Binding; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D053838:Scattering, Small Angle; D017422:Sequence Analysis, DNA; D020349:Surface Plasmon Resonance; D037521:Virulence Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; D037521:Virulence Factors; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D018799:Intercellular Adhesion Molecule-1
keywords: EPCR; ICAM-1; PfEMP1; Plasmodium falciparum; cerebral malaria