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Binding of infected erythrocytes to brain venules is a central pathogenic event in the lethal malaria disease complication, cerebral malaria. The only parasite adhesion trait linked to cerebral sequestration is binding to intercellular adhesion molecule-1 (ICAM-1). In this report, we show that Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) binds ICAM-1. We have cloned and expressed PfEMP1 recombinant proteins from the A4tres parasite. Using heterologous expression in mammalian cells, the minimal ICAM-1 binding domain was a complex domain consisting of the second Duffy binding-like (DBL) domain and the C2 domain. Constructs that contained either domain alone did not bind ICAM-1. Based on phylogenetic criteria, there are five distinct PfEMP1 DBL types designated alpha, beta, gamma, delta, and epsilon. The DBL domain from the A4tres that binds ICAM-1 is DBLbeta type. A PfEMP1 cloned from a distinct ICAM-1 binding variant, the A4 parasite, contains a DBLbeta domain and a C2 domain in tandem arrangement similar to the A4tres PfEMP1. Anti-PfEMP1 antisera implicate the DBLbeta domain from A4var PfEMP1 in ICAM-1 adhesion. The identification of a P. falciparum ICAM-1 binding domain may clarify mechanisms responsible for the pathogenesis of cerebral malaria and lead to interventions or vaccines that reduce malarial disease.

Original publication

DOI

10.1073/pnas.040545897

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

15/02/2000

Volume

97

Pages

1766 - 1771

Keywords

Amino Acid Sequence, Animals, Antibodies, Antigens, CD36, COS Cells, Cell Adhesion, Cell Adhesion Molecules, Cloning, Molecular, Erythrocytes, Intercellular Adhesion Molecule-1, Malaria, Cerebral, Molecular Sequence Data, Peptide Fragments, Plasmodium falciparum, Protein Binding, Protozoan Proteins, Recombinant Proteins, Sequence Alignment, Transfection