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Cerebral Plasmodium falciparum malaria is characterized by adhesion of infected erythrocytes (IEs) to the cerebral microvasculature. This has been linked to parasites expressing the structurally related group A subset of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of IE adhesion ligands and to IEs with affinity for ICAM-1. However, recent evidence has cast doubt on both these associations, tempering hopes of the feasibility of developing a vaccine based on ICAM-1-binding PfEMP1. In this study, we report the identification of a domain cassette (DC) present in group A var genes from six genetically distinct P. falciparum parasites. The three domains in the cassette, which we call DC4, had a high level of sequence identity and cluster together phylogenetically. Erythrocytes infected by these parasites and selected in vitro for expression of DC4 adhered specifically to ICAM-1. The ICAM-1-binding capacity of DC4 was mapped to the C-terminal third of its Duffy-binding-like β3 domain. DC4 was the target of broadly cross-reactive and adhesion-inhibitory IgG Abs, and levels of DC4-specific and adhesion-inhibitory IgG increased with age among P. falciparum-exposed children. Our study challenges earlier conclusions that group A PfEMP1 proteins are not central to ICAM-1-specific IE adhesion and support the feasibility of developing a vaccine preventing cerebral malaria by inhibiting cerebral IE sequestration.

Original publication

DOI

10.4049/jimmunol.1202578

Type

Journal article

Journal

J Immunol

Publication Date

01/01/2013

Volume

190

Pages

240 - 249

Keywords

Animals, Antibodies, Blocking, Antigens, Protozoan, Binding Sites, Antibody, Cell Adhesion, Conserved Sequence, Cross Reactions, Erythrocyte Membrane, Genomics, HEK293 Cells, Humans, Intercellular Adhesion Molecule-1, Mutagenesis, Insertional, Plasmodium falciparum, Protein Binding, Protein Structure, Tertiary, Protozoan Proteins, Rats