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Updated: May 12, 2026
Measuring Naturally Acquired Phagocytosis-Inducing Antibodies to Plasmodium falciparum Parasites by a Flow Cytometry-Based Assay
Published on: August 6, 2020
Structure-function-immunogenicity studies of PfEMP1 domain DBL2βPF11_0521, a malaria parasite ligand for ICAM-1
Justin Gullingsrud1, Tracy Saveria, Emily Amos
1Seattle Biomedical Research Institute, Seattle, Washington, USA.
Abstract:
Plasmodium falciparum virulence has been ascribed to its ability to sequester in deep vascular beds, mediated by the variant surface antigen family PfEMP1 binding endothelial receptors like ICAM-1. We previously observed that naturally-acquired antibodies that block a PfEMP1 domain, DBL2β of PF11_0521 allele, from binding to the human ICAM1 receptor, reduce the risk of malaria hospitalization in children. Here, we find that DBL2βPF11_0521 binds ICAM-1 in the low nM range and relate the structure of this domain with its function and immunogenicity. We demonstrate that the interaction with ICAM-1 is not impaired by point mutations in the N-terminal subdomain or in the flexible Loop 4 of DBL2βPF11_0521, although both substructures were previously implicated in binding ICAM-1. These data will help to refine the existing model of DBLβ::ICAM-1 interactions. Antibodies raised against full-length DBL2βPF11_0521, but not truncated forms lacking the N terminal fragment, block its interaction with ICAM-1. Our data suggest that full length domain is optimal for displaying functional epitopes and has a broad surface of interaction with ICAM-1 that is not disrupted by individual amino acid substitutions at putative key residues. This information might be important for the future design of anti-malarial vaccines based on PfEMP1 antigens.
Insights
Antibodies targeting the full DBL2βPF11_0521 domain of Plasmodium falciparum block its binding to ICAM-1, suggesting its potential for malaria vaccine development.
Area of Science:
- Immunology
- Parasitology
- Structural Biology
Background:
- Plasmodium falciparum causes severe malaria by sequestering infected red blood cells in deep vascular beds.
- This sequestration is mediated by PfEMP1 proteins binding to endothelial receptors like ICAM-1.
- Naturally acquired antibodies blocking PfEMP1-ICAM-1 interaction reduce malaria hospitalization risk.
Purpose of the Study:
- To characterize the structural basis of DBL2βPF11_0521 binding to ICAM-1.
- To investigate the functional and immunogenic properties of the DBL2βPF11_0521 domain.
- To inform the design of PfEMP1-based malaria vaccines.
Main Methods:
- Binding assays to quantify DBL2βPF11_0521 and ICAM-1 interaction.
- Site-directed mutagenesis to assess the role of specific substructures in binding.
- Antibody generation against full-length and truncated DBL2βPF11_0521 domains.
Main Results:
- DBL2βPF11_0521 binds ICAM-1 with high affinity (low nM range).
- ICAM-1 binding is not impaired by mutations in the N-terminal subdomain or Loop 4.
- Antibodies against full-length DBL2βPF11_0521 effectively block ICAM-1 interaction, unlike those against truncated forms.
Conclusions:
- The full-length DBL2βPF11_0521 domain is optimal for displaying functional epitopes that block ICAM-1 binding.
- The interaction surface with ICAM-1 is broad and resilient to individual amino acid substitutions.
- These findings are crucial for designing effective malaria vaccines targeting PfEMP1.
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