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.
Highlights
From the ‡Cell Surface Signalling Laboratory, the §Malaria Programme, and the **Microbial Pathogenesis Laboratory, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom, the ¶Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom, the ʈFrancis Crick Institute, Mill Hill Laboratory, London NW7 1AA, United Kingdom, the ‡‡Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom, and the §§Warwick Systems Biology Centre, Senate House, University of Warwick, Coventry CV4 7AL, United Kingdom
Whereas other MSP3 family members (MSP3, MSP6, H101, and MSP11) and Duffy binding-like (DBL)-containing merozoite surface proteins (EBA140, EBA175, and EBA181) reacted, as expected, with only the exposed sera, DBLMSP and DBLMSP2 showed strong immunoreactivity to both the unexposed control and exposed sera (Fig. 1B). This suggested that recombinant DBLMSP and DBLMSP2 bound immunoglobulins present in normal serum from individuals without prior exposure to the malaria parasite
We showed that DBLMSPcoated beads but not control beads incubated in normal human serum purified bands with masses there were consistent with the heavy and light chain of IgM (Fig. 1E), and their identities were subsequently confirmed by mass spectrometry
Summary
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 dblmsp, which encode Duffy binding-like (DBL) domain-containing proteins located on the merozoite surface but whose function remains unknown. We used whole genome sequence data from over 400 African and Asian P. falciparum isolates to show that dblmsp and dblmsp 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.
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