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 beta 3 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. The Journal of Immunology, 2013, 190: 240-249.
Journal of Immunology, 2013, Vol 190, Issue 1, p. 240-249
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; Journal Article; Research Support, Non-U.S. Gov't; cerebral malaria Malaria, Cerebral (MeSH) nervous system disease, parasitic disease; Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae  HEK293F cell line cell_line human embryonic kidney cells; Protozoa Invertebrata Animalia (Animals, Invertebrates, Microorganisms, Protozoans) - Sporozoa  Plasmodium falciparum species parasite strain-3D7, strain-BM057; Plasmodium falciparum var gene [Sporozoa]; ICAM-1; Plasmodium falciparum erythrocyte membrane protein 1 PfEMP1; 02506, Cytology - Animal; 02508, Cytology - Human; 03506, Genetics - Animal; 03508, Genetics - Human; 10064, Biochemistry studies - Proteins, peptides and amino acids; 15002, Blood - Blood and lymph studies; 15004, Blood - Blood cell studies; 20504, Nervous system - Physiology and biochemistry; 20506, Nervous system - Pathology; 60502, Parasitology - General; 60504, Parasitology - Medical; 64002, Invertebrata: comparative, experimental morphology, physiology and pathology - Protozoa; Neural Coordination; erythrocyte blood and lymphatics; Nervous System; Parasitology