A monoclonal antibody selectively recognizing PfEMP1 proteins associated with cerebral malaria

The frequently fatal outcome of cerebral malaria has been linked to the adhesion and accumulation in the cerebral microvasculature of infected erythrocytes (IEs), which express a particular type of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). This type, found in the A and B/A subsets of PfEMP1, contains a particular structural motif (DBLβ_motif) and has dual affinity for the host vascular receptors ICAM-1 and EPCR. Here, we report the functional characterization of a mouse monoclonal antibody, mAb02, raised against eight different DBLβ_motif domains. The antibody selectively recognizes DBLβ_motif-positive PfEMP1 proteins and inhibits their binding to ICAM-1. It also recognizes IEs expressing DBLβ_motif-positive PfEMP1 proteins on their surface and inhibits their adhesion to ICAM-1. The mAb02 epitope is located in an unfolded linker region of the ICAM-1-binding site of DBLβ_motif and includes residues directly involved in the interaction between DBLβ_motif and ICAM-1, as well as residues that are important for the positioning of the interacting residues. Our study shows that mAb02 targets a broadly conserved epitope that is found in PfEMP1 proteins binding to ICAM-1 and EPCR and implicated in the pathogenesis of cerebral malaria (CM). This suggests the potential of mAb02 in the development of monoclonal antibody-based intervention against CM and for identification of IEs with capacity to causing CM.