title: Binding of Plasmodium falciparum Merozoite Surface Proteins DBLMSP and DBLMSP2 to Human Immunoglobulin M Is Conserved among Broadly Diverged Sequence Variants.
abstract: Diversity at pathogen genetic loci can be driven by host adaptive immune selection pressure and may reveal proteins important for parasite biology. Population-based genome sequencing of Plasmodium falciparum, the parasite responsible for the most severe form of malaria, has highlighted two related polymorphic genes called dblmsp and dblmsp2, which encode Duffy binding-like (DBL) domain-containing proteins located on the merozoite surface but whose function remains unknown. Using recombinant proteins and transgenic parasites, we show that DBLMSP and DBLMSP2 directly and avidly bind human IgM via their DBL domains. We used whole genome sequence data from over 400 African and Asian P. falciparum isolates to show that dblmsp and dblmsp2 exhibit extreme protein polymorphism in their DBL domain, with multiple variants of two major allelic classes present in every population tested. Despite this variability, the IgM binding function was retained across diverse sequence representatives. Although this interaction did not seem to have an effect on the ability of the parasite to invade red blood cells, binding of DBLMSP and DBLMSP2 to IgM inhibited the overall immunoreactivity of these proteins to IgG from patients who had been exposed to the parasite. This suggests that IgM binding might mask these proteins from the host humoral immune system.
authors.affiliation: Cell Surface Signalling Laboratory, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom; Malaria Programme, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom.
authors.forename: Cécile
authors.initials: C
authors.lastname: Crosnier
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom.
authors.forename: Zamin
authors.initials: Z
authors.lastname: Iqbal
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, United Kingdom.
authors.forename: Ellen
authors.initials: E
authors.lastname: Knuepfer
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom.
authors.forename: Sorina
authors.initials: S
authors.lastname: Maciuca
authors.affiliation: Cell Surface Signalling Laboratory, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom; Malaria Programme, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom.
authors.forename: Abigail J
authors.initials: AJ
authors.lastname: Perrin
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom.
authors.forename: Gathoni
authors.initials: G
authors.lastname: Kamuyu
authors.affiliation: Microbial Pathogenesis Laboratory, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Goulding
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom.
authors.forename: Leyla Y
authors.initials: LY
authors.lastname: Bustamante
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom; Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom.
authors.forename: Alistair
authors.initials: A
authors.lastname: Miles
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom; Warwick Systems Biology Centre, Senate House, University of Warwick, Coventry CV4 7AL, United Kingdom.
authors.forename: Shona C
authors.initials: SC
authors.lastname: Moore
authors.affiliation: Microbial Pathogenesis Laboratory, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom.
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, United Kingdom.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Holder
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom; Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Rayner
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Pleass
authors.affiliation: Cell Surface Signalling Laboratory, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom; Malaria Programme, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom. Electronic address: gw2@sanger.ac.uk.
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Wright
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000378:metabolism*; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000378:metabolism*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000378:metabolism*
chemical_list: D000953:Antigens, Protozoan; D007075:Immunoglobulin M; D015800:Protozoan Proteins; C077028:merozoite major surface antigen, Plasmodium
keywords: genetic polymorphism; host-pathogen interaction; immunoglobulin M (IgM); merozoite; parasite; plasmodium; protein-protein interaction