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 e vent in the lethal malaria disease complication, cerebral malaria. The only parasite adhesion trait linked to cerebral sequestration is binding to int ercellular adhesion molecule-1 (ICAM-1). In this report, we show that Plasm odium falciparum erythrocyte membrane protein 1 (PfEMP1) binds ICAM-1, We h ave cloned and expressed PfEMP1 recombinant proteins from the A4tres parasi te. Using heterologous expression in mammalian cells, the minimal ICAM-1 bi nding domain was a complex domain consisting of the second Duffy binding-li ke (DBL) domain and the C2 domain. Constructs that contained either domain alone did not bind ICAM-1. Based on phylogenetic criteria, there are five d istinct PfEMP1 DBL types designated alpha, beta, gamma, delta, and epsilon. The DBL domain from the A4tres that binds ICAM-1 is DBL beta type. A PfEMP 1 cloned from a distinct ICAM-1 binding variant, the A4 parasite, contains a DBL beta domain and a C2 domain in tandem arrangement similar to the A4tr es PfEMP1, Anti-PfEMP1 antisera implicate the DBL beta domain from A4var Pf EMP1 in ICAM-1 adhesion. The identification of a P. falciparum ICAM-1 bindi ng domain may clarify mechanisms responsible for the pathogenesis of cerebr al malaria and lead to interventions or vaccines that reduce malarial disea se.