title: Reticulocyte and erythrocyte binding-like proteins function cooperatively in invasion of human erythrocytes by malaria parasites.
abstract: Plasmodium falciparum causes the most severe form of malaria in humans and invades erythrocytes using multiple ligand-receptor interactions. Two important protein families involved in erythrocyte binding are the erythrocyte binding-like (EBL) and the reticulocyte binding-like (RBL or P. falciparum Rh [PfRh]) proteins. We constructed P. falciparum lines lacking expression of EBL proteins by creating single and double knockouts of the corresponding genes for eba-175, eba-181, and eba-140 and show that the EBL and PfRh proteins function cooperatively, consistent with them playing a similar role in merozoite invasion. We provide evidence that PfRh and EBL proteins functionally interact, as loss of function of EBA-181 ablates the ability of PfRh2a/b protein antibodies to inhibit merozoite invasion. Additionally, loss of function of some ebl genes results in selection for increased transcription of the PfRh family. This provides a rational basis for considering PfRh and EBL proteins for use as a combination vaccine against P. falciparum. We immunized rabbits with combinations of PfRh and EBL proteins to test the ability of antibodies to block merozoite invasion in growth inhibition assays. A combination of EBA-175, PfRh2a/b, and PfRh4 recombinant proteins induced antibodies that potently blocked merozoite invasion. This validates the use of a combination of these ligands as a potential vaccine that would have broad activity against P. falciparum.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
authors.forename: Sash
authors.initials: S
authors.lastname: Lopaticki
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Maier
authors.forename: Jennifer
authors.initials: J
authors.lastname: Thompson
authors.forename: Danny W
authors.initials: DW
authors.lastname: Wilson
authors.forename: Wai-Hong
authors.initials: WH
authors.lastname: Tham
authors.forename: Tony
authors.initials: T
authors.lastname: Triglia
authors.forename: Alex
authors.initials: A
authors.lastname: Gout
authors.forename: Terence P
authors.initials: TP
authors.lastname: Speed
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
authors.forename: Julie
authors.initials: J
authors.lastname: Healer
authors.forename: Alan F
authors.initials: AF
authors.lastname: Cowman
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D004912:Erythrocytes / Q000276:immunology / Q000378:metabolism / Q000469:parasitology*; D055786:Gene Knockout Techniques; D006801:Humans; D015151:Immunoblotting; D008288:Malaria / Q000276:immunology / Q000378:metabolism*; D017780:Malaria Vaccines / Q000276:immunology; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011817:Rabbits; D012156:Reticulocytes / Q000276:immunology / Q000378:metabolism / Q000469:parasitology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D000913:Antibodies, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins