Identification of a Plasmodium falciparum intercellular adhesion molecule-1 binding domain: a parasite adhesion trait implicated in cerebral malaria.
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.
Smith
J D
JD
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Craig
A G
AG
Kriek
N
N
Hudson-Taylor
D
D
Kyes
S
S
Fagan
T
T
Fagen
T
T
Pinches
R
R
Baruch
D I
DI
Newbold
C I
CI
Miller
L H
LH
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D018955:CD36 Antigens / Q000378:metabolism; D019556:COS Cells; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics; D003001:Cloning, Molecular; D004912:Erythrocytes / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry*; D016779:Malaria, Cerebral / Q000378:metabolism / Q000469:parasitology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D010963:Plasmodium falciparum / Q000737:chemistry*; D011485:Protein Binding / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins; D016415:Sequence Alignment; D014162:Transfection
D000906:Antibodies; D018955:CD36 Antigens; D015815:Cell Adhesion Molecules; D010446:Peptide Fragments; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D018799:Intercellular Adhesion Molecule-1