title: A novel domain cassette identifies Plasmodium falciparum PfEMP1 proteins binding ICAM-1 and is a target of cross-reactive, adhesion-inhibitory antibodies.
abstract: Cerebral Plasmodium falciparum malaria is characterized by adhesion of infected erythrocytes (IEs) to the cerebral microvasculature. This has been linked to parasites expressing the structurally related group A subset of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of IE adhesion ligands and to IEs with affinity for ICAM-1. However, recent evidence has cast doubt on both these associations, tempering hopes of the feasibility of developing a vaccine based on ICAM-1-binding PfEMP1. In this study, we report the identification of a domain cassette (DC) present in group A var genes from six genetically distinct P. falciparum parasites. The three domains in the cassette, which we call DC4, had a high level of sequence identity and cluster together phylogenetically. Erythrocytes infected by these parasites and selected in vitro for expression of DC4 adhered specifically to ICAM-1. The ICAM-1-binding capacity of DC4 was mapped to the C-terminal third of its Duffy-binding-like β3 domain. DC4 was the target of broadly cross-reactive and adhesion-inhibitory IgG Abs, and levels of DC4-specific and adhesion-inhibitory IgG increased with age among P. falciparum-exposed children. Our study challenges earlier conclusions that group A PfEMP1 proteins are not central to ICAM-1-specific IE adhesion and support the feasibility of developing a vaccine preventing cerebral malaria by inhibiting cerebral IE sequestration.
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 1014, Denmark.
authors.forename: Anja
authors.initials: A
authors.lastname: Bengtsson
authors.forename: Louise
authors.initials: L
authors.lastname: Joergensen
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Rask
authors.forename: Rebecca W
authors.initials: RW
authors.lastname: Olsen
authors.forename: Marianne A
authors.initials: MA
authors.lastname: Andersen
authors.forename: Louise
authors.initials: L
authors.lastname: Turner
authors.forename: Thor G
authors.initials: TG
authors.lastname: Theander
authors.forename: Lars
authors.initials: L
authors.lastname: Hviid
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Higgins
authors.forename: Alister
authors.initials: A
authors.lastname: Craig
authors.forename: Alan
authors.initials: A
authors.lastname: Brown
authors.forename: Anja T R
authors.initials: AT
authors.lastname: Jensen
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000235:genetics / Q000378:metabolism*; D000953:Antigens, Protozoan / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D001666:Binding Sites, Antibody / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D017124:Conserved Sequence / Q000235:genetics / Q000276:immunology; D003429:Cross Reactions / Q000276:immunology; D004910:Erythrocyte Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D023281:Genomics / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016254:Mutagenesis, Insertional / Q000235:genetics / Q000276:immunology*; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D015800:Protozoan Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D051381:Rats
chemical_list: D019138:Antibodies, Blocking; D000953:Antigens, Protozoan; C573420:ICAM1 protein, human; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D018799:Intercellular Adhesion Molecule-1