title: Investigating the function of Fc-specific binding of IgM to Plasmodium falciparum erythrocyte membrane protein 1 mediating erythrocyte rosetting.
abstract: Acquired protection from Plasmodium falciparum malaria takes years to develop, probably reflecting the ability of the parasites to evade immunity. A recent example of this is the binding of the Fc region of IgM to VAR2CSA-type PfEMP1. This interferes with specific IgG recognition and phagocytosis of opsonized infected erythrocytes (IEs) without compromising the placental IE adhesion mediated by this PfEMP1 type. IgM also binds via Fc to several other PfEMP1 proteins, where it has been proposed to facilitate rosetting (binding of uninfected erythrocytes to a central IE). To further dissect the functional role of Fc -mediated IgM binding to PfEMP1, we studied the PfEMP1 protein HB3VAR06, which mediates rosetting and binds IgM. Binding of IgM to this PfEMP1 involved the Fc domains Cμ3-Cμ4 in IgM and the penultimate DBL domain (DBLζ2) at the C-terminus of HB3VAR06. However, IgM binding did not inhibit specific IgG labelling of HB3VAR06 or shield IgG-opsonized IEs from phagocytosis. Instead, IgM was required for rosetting, and each pentameric IgM molecule could bind two HB3VAR06 molecules. Together, our data indicate that the primary function of Fc -mediated IgM binding in rosetting is not to shield IE from specific IgG recognition and phagocytosis as in VAR2CSA-type PfEMP1. Rather, the function appears to be strengthening of IE-erythrocyte interactions. In conclusion, our study provides new evidence on the molecular details and functional significance of rosetting, a long-recognized marker of parasites that cause severe P. falciparum malaria.
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Liz
authors.initials: L
authors.lastname: Stevenson
authors.affiliation: Niels Bohr Institute, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Pie
authors.initials: P
authors.lastname: Huda
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Anine
authors.initials: A
authors.lastname: Jeppesen
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Erik
authors.initials: E
authors.lastname: Laursen
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, UK.
authors.forename: J Alexandra
authors.initials: JA
authors.lastname: Rowe
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, UK.
authors.forename: Alister
authors.initials: A
authors.lastname: Craig
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Werner
authors.initials: W
authors.lastname: Streicher
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Lea
authors.initials: L
authors.lastname: Barfod
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Hviid
mesh_terms: D000913:Antibodies, Protozoan / Q000378:metabolism*; D000953:Antigens, Protozoan / Q000378:metabolism*; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D007141:Immunoglobulin Fc Fragments; D007075:Immunoglobulin M / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000276:immunology*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000378:metabolism*
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D007141:Immunoglobulin Fc Fragments; D007075:Immunoglobulin M; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum