title: Multiple Plasmodium falciparum Erythrocyte Membrane Protein 1 Variants per Genome Can Bind IgM via Its Fc Fragment Fcμ.
abstract: The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) adhesive proteins expressed on the surfaces of infected erythrocytes (IEs) are of key importance in the pathogenesis of P. falciparum malaria. Several structurally and functionally defined PfEMP1 types have been associated with severe clinical manifestations, such as cerebral malaria in children and placental malaria in pregnant women. PfEMP1 that can bind the Fc part of IgM (Fcμ) characterizes one such type, although the functional significance of this IgM binding to PfEMP1 remains unclear. In this study, we report the identification and functional analysis of five IgM-binding PfEMP1 proteins encoded by P. falciparum NF54. In addition to the VAR2CSA-type PFL0030c protein, already known to bind Fcμ and to mediate chondroitin sulfate A (CSA)-specific adhesion of IEs in the placenta, we found four PfEMP1 proteins not previously known to bind IgM this way. Although they all contained Duffy binding-like ε (DBLε) domains similar to those in VAR2CSA-type PfEMP1, they did not mediate IE adhesion to CSA, and IgM binding did not shield IEs from phagocytosis of IgG-opsonized IEs. In this way, these new IgM-binding PfEMP1 proteins resemble the rosette-mediating and IgM-binding PfEMP1 HB3VAR06, but none of them mediated formation of rosettes. We could map the capacity for Fc-specific IgM binding to DBLε domains near the C terminus for three of the four PfEMP1 proteins tested. Our study provides new evidence regarding Fc-dependent binding of IgM to PfEMP1, which appears to be a common and multifunctional phenotype.
authors.affiliation: Centre for Medical Parasitology, University of Copenhagen and Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Anine
authors.initials: A
authors.lastname: Jeppesen
authors.affiliation: Centre for Medical Parasitology, University of Copenhagen and Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Sisse Bolm
authors.initials: SB
authors.lastname: Ditlev
authors.affiliation: Centre for Medical Parasitology, University of Copenhagen and Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Vladyslav
authors.initials: V
authors.lastname: Soroka
authors.affiliation: Centre for Medical Parasitology, University of Copenhagen and Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Liz
authors.initials: L
authors.lastname: Stevenson
authors.affiliation: Centre for Medical Parasitology, University of Copenhagen and Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Louise
authors.initials: L
authors.lastname: Turner
authors.affiliation: Department of Microbiology and Molecular Genetics, The Institute for Medical Research Israel-Canada, The Kuvin Center for the Study of Infectious and Tropical Diseases, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Dzikowski
authors.affiliation: Centre for Medical Parasitology, University of Copenhagen and Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Lars
authors.identifier: http://orcid.org/0000-0002-1698-4927
authors.initials: L
authors.lastname: Hviid
authors.affiliation: Centre for Medical Parasitology, University of Copenhagen and Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark lbarfod@sund.ku.dk.
authors.forename: Lea
authors.identifier: http://orcid.org/0000-0001-6510-495X
authors.initials: L
authors.lastname: Barfod
mesh_terms: D000913:Antibodies, Protozoan / Q000235:genetics / Q000276:immunology*; D018503:Genome, Protozoan; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology*; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology*; D016778:Malaria, Falciparum / Q000235:genetics / Q000276:immunology / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D012397:Rosette Formation
chemical_list: D000913:Antibodies, Protozoan; D007141:Immunoglobulin Fc Fragments; D007075:Immunoglobulin M; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum