title: α2-Macroglobulin Can Crosslink Multiple Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) Molecules and May Facilitate Adhesion of Parasitized Erythrocytes.
abstract: Rosetting, the adhesion of Plasmodium falciparum-infected erythrocytes to uninfected erythrocytes, involves clonal variants of the parasite protein P. falciparum erythrocyte membrane protein 1 (PfEMP1) and soluble serum factors. While rosetting is a well-known phenotypic marker of parasites associated with severe malaria, the reason for this association remains unclear, as do the molecular details of the interaction between the infected erythrocyte (IE) and the adhering erythrocytes. Here, we identify for the first time a single serum factor, the abundant serum protease inhibitor α2-macroglobulin (α2M), which is both required and sufficient for rosetting mediated by the PfEMP1 protein HB3VAR06 and some other rosette-mediating PfEMP1 proteins. We map the α2M binding site to the C terminal end of HB3VAR06, and demonstrate that α2M can bind at least four HB3VAR06 proteins, plausibly augmenting their combined avidity for host receptors. IgM has previously been identified as a rosette-facilitating soluble factor that acts in a similar way, but it cannot induce rosetting on its own. This is in contrast to α2M and probably due to the more limited cross-linking potential of IgM. Nevertheless, we show that IgM works synergistically with α2M and markedly lowers the concentration of α2M required for rosetting. Finally, HB3VAR06+ IEs share the capacity to bind α2M with subsets of genotypically distinct P. falciparum isolates forming rosettes in vitro and of patient parasite isolates ex vivo. Together, our results are evidence that P. falciparum parasites exploit α2M (and IgM) to expand the repertoire of host receptors available for PfEMP1-mediated IE adhesion, such as the erythrocyte carbohydrate moieties that lead to formation of rosettes. It is likely that this mechanism also affects IE adhesion to receptors on vascular endothelium. The study opens opportunities for broad-ranging immunological interventions targeting the α2M--(and IgM-) binding domains of PfEMP1, which would be independent of the host receptor specificity of clinically important PfEMP1 antigens.
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Liz
authors.initials: L
authors.lastname: Stevenson
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen and 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, Center for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Cowan
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark; Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana.
authors.forename: Betty
authors.initials: B
authors.lastname: Bandoh
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Lea
authors.initials: L
authors.lastname: Barfod
authors.affiliation: Institute of Immunology and Infection Research, Center for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: David R
authors.initials: DR
authors.lastname: Cavanagh
authors.affiliation: Department of Molecular Biology and Genetics, University of Aarhus, Aarhus, Denmark.
authors.forename: Gregers R
authors.initials: GR
authors.lastname: Andersen
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Hviid
mesh_terms: D000818:Animals; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D016778:Malaria, Falciparum / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism*; D012397:Rosette Formation; D000511:alpha-Macroglobulins / Q000378:metabolism*
chemical_list: D015800:Protozoan Proteins; D000511:alpha-Macroglobulins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum