Abstract
Binding of host immunoglobulin is a common immune evasion mechanism demonstrated by microbial pathogens. Previous work showed that the malaria parasite Plasmodium falciparum binds the Fc-region of human IgM molecules, resulting in a coating of IgM on the surface of infected erythrocytes. IgM binding is a property of P. falciparum strains showing virulence-related phenotypes such as erythrocyte rosetting. The parasite ligands for IgM binding are members of the diverse P. falciparum Erythrocyte Membrane Protein One (PfEMP1) family. However, little is known about the amino acid sequence requirements for IgM binding. Here we studied an IgM binding domain from a rosette-mediating PfEMP1 variant, DBL4ζ of TM284var1, and found that the minimal IgM binding region mapped to the central region of the DBL domain, comprising all of subdomain 2 and adjoining parts of subdomains 1 and 3. Site-directed mutagenesis of charged amino acids within subdomain 2, predicted by molecular modelling to form the IgM binding site, showed no marked effect on IgM binding properties. Overall, this study identifies the minimal IgM binding region of a PfEMP1 domain, and indicates that the existing homology model of PfEMP1-IgM interaction is incorrect. Further work is needed to identify the specific interaction site for IgM within the minimal binding region of PfEMP1.
Highlights
Many pathogens have evolved to bind to a common site on the Fc portion of immunoglobulin, the consequences of such interactions are largely unexplored [1]
Binding occurs during the asexual stage of the parasite life cycle on the surface of infected Red Blood Cells to a parasitederived ligand called P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) [2], which is a variant surface antigen encoded by the var gene family
We previously showed that recombinant TM284var1 DBL4 containing 16 cysteine residues binds to human IgM [2]
Summary
Many pathogens have evolved to bind to a common site on the Fc portion of immunoglobulin, the consequences of such interactions are largely unexplored [1]. Plasmodium falciparum, the major cause of severe malaria, is an example of such a pathogen that has been shown to bind to the Fc region of human IgM [2]. Binding occurs during the asexual stage of the parasite life cycle on the surface of infected Red Blood Cells (iRBCs) to a parasitederived ligand called P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) [2], which is a variant surface antigen encoded by the var gene family. PfEMP1 molecules are made up of cysteine-rich adhesion domains called Duffy Binding Like (DBL) and Cysteine-rich Inter-Domain Regions (CIDR) that bind to a range of host receptors including CD36, Chondroitin Sulphate A (CSA), InterCellular Adhesion Molecule-1 and Endothelial Protein C Receptor [4]. The molecular basis of IgM binding by PfEMP1 is not fully understood, but current data suggest that most IgM binding sites lie within specific DBL and DBL domains [2,9,10,11]
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