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Published on: January 3, 2012
A monoclonal antibody selectively recognizing PfEMP1 proteins associated with cerebral malaria
Nanna Dalgaard1, Rebecca W Olsen1, Yvonne Adams1
1Centre for Translational Medicine and Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Abstract:
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 (DBLβmotif) 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 DBLβmotif domains. The antibody selectively recognizes DBLβmotif-positive PfEMP1 proteins and inhibits their binding to ICAM-1. It also recognizes IEs expressing DBLβmotif-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 DBLβmotif and includes residues directly involved in the interaction between DBLβmotif 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.
Insights
A new antibody, mAb02, targets a key protein (PfEMP1) on malaria-infected red blood cells. This antibody blocks parasite adhesion in the brain, offering potential for cerebral malaria (CM) treatment and diagnosis.
Area of Science:
- Immunology
- Infectious Diseases
- Molecular Biology
Background:
- Cerebral malaria (CM) is often fatal, linked to infected red blood cells (IEs) adhering to brain blood vessels.
- Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) on IEs mediates this adhesion via specific motifs (DBLβmotif).
- This PfEMP1 type binds to host receptors ICAM-1 and EPCR, contributing to CM pathogenesis.
Purpose of the Study:
- To functionally characterize a novel monoclonal antibody, mAb02, targeting the DBLβmotif of PfEMP1.
- To assess mAb02's ability to inhibit PfEMP1 binding to ICAM-1 and IE adhesion.
- To investigate the epitope recognized by mAb02 and its implications for CM intervention.
Main Methods:
- Generation of a mouse monoclonal antibody (mAb02) against DBLβmotif domains.
- Testing mAb02's recognition of DBLβmotif-positive PfEMP1 proteins and IEs.
- Evaluating mAb02's inhibition of PfEMP1-ICAM-1 binding and IE adhesion.
- Epitope mapping of mAb02 on the DBLβmotif structure.
Main Results:
- mAb02 selectively recognizes DBLβmotif-positive PfEMP1 proteins and IEs.
- mAb02 effectively inhibits PfEMP1 binding to ICAM-1 and IE adhesion to ICAM-1.
- The antibody's epitope is in a conserved linker region crucial for DBLβmotif-ICAM-1 interaction.
- mAb02 targets a broadly conserved epitope implicated in CM pathogenesis.
Conclusions:
- mAb02 targets a conserved PfEMP1 epitope involved in cerebral malaria pathogenesis.
- This antibody shows potential for developing new monoclonal antibody-based interventions against CM.
- mAb02 can identify infected red blood cells capable of causing cerebral malaria.
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