1 Department of Systems Biology, Technical University of Denmark2 Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark3 University of Copenhagen4 University of Oxford5 Liverpool School of Tropical Medicine6 University of Cambridge7 University of Oxford8 Liverpool School of Tropical Medicine9 University of Cambridge
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
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; Journal Article; Research Support, Non-U.S. Gov't; 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