10779/crick.12657086.v1 Cécile Crosnier Cécile Crosnier Zamin Iqbal Zamin Iqbal Ellen Knuepfer Ellen Knuepfer Sorina Maciuca Sorina Maciuca Abigail J Perrin Abigail J Perrin Gathoni Kamuyu Gathoni Kamuyu David Goulding David Goulding Leyla Y Bustamante Leyla Y Bustamante Alistair Miles Alistair Miles Shona C Moore Shona C Moore Gordon Dougan Gordon Dougan Anthony A Holder Anthony A Holder Dominic P Kwiatkowski Dominic P Kwiatkowski Julian C Rayner Julian C Rayner Richard J Pleass Richard J Pleass Gavin J Wright Gavin J Wright Binding of Plasmodium falciparum merozoite surface proteins DBLMSP and DBLMSP2 to human immunoglobulin M is conserved amongst broadly diverged sequence variants The Francis Crick Institute 2020 genetic polymorphism host-pathogen interaction immunoglobulin M (IgM) merozoite parasite plasmodium protein-protein interaction Animals Antigens, Protozoan Humans Immunoglobulin M Plasmodium falciparum Protein Binding Protozoan Proteins Holder FC001097 06 Biological Sciences 11 Medical and Health Sciences 03 Chemical Sciences Biochemistry & Molecular Biology 2020-07-17 16:27:41 Journal contribution https://crick.figshare.com/articles/journal_contribution/Binding_of_Plasmodium_falciparum_merozoite_surface_proteins_DBLMSP_and_DBLMSP2_to_human_immunoglobulin_M_is_conserved_amongst_broadly_diverged_sequence_variants/12657086 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.