title: Complement receptor 1 is a sialic acid-independent erythrocyte receptor of Plasmodium falciparum.
abstract: Plasmodium falciparum is a highly lethal malaria parasite of humans. A major portion of its life cycle is dedicated to invading and multiplying inside erythrocytes. The molecular mechanisms of erythrocyte invasion are incompletely understood. P. falciparum depends heavily on sialic acid present on glycophorins to invade erythrocytes. However, a significant proportion of laboratory and field isolates are also able to invade erythrocytes in a sialic acid-independent manner. The identity of the erythrocyte sialic acid-independent receptor has been a mystery for decades. We report here that the complement receptor 1 (CR1) is a sialic acid-independent receptor for the invasion of erythrocytes by P. falciparum. We show that soluble CR1 (sCR1) as well as polyclonal and monoclonal antibodies against CR1 inhibit sialic acid-independent invasion in a variety of laboratory strains and wild isolates, and that merozoites interact directly with CR1 on the erythrocyte surface and with sCR1-coated microspheres. Also, the invasion of neuraminidase-treated erythrocytes correlates with the level of CR1 expression. Finally, both sialic acid-independent and dependent strains invade CR1 transgenic mouse erythrocytes preferentially over wild-type erythrocytes but invasion by the latter is more sensitive to neuraminidase. These results suggest that both sialic acid-dependent and independent strains interact with CR1 in the normal red cell during the invasion process. However, only sialic acid-independent strains can do so without the presence of glycophorin sialic acid. Our results close a longstanding and important gap in the understanding of the mechanism of erythrocyte invasion by P. falciparum that will eventually make possible the development of an effective blood stage vaccine.
authors.affiliation: Department of Medicine, the Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Carmenza
authors.initials: C
authors.lastname: Spadafora
authors.forename: Gordon A
authors.initials: GA
authors.lastname: Awandare
authors.forename: Karen M
authors.initials: KM
authors.lastname: Kopydlowski
authors.forename: Jozsef
authors.initials: J
authors.lastname: Czege
authors.forename: J Kathleen
authors.initials: JK
authors.lastname: Moch
authors.forename: Robert W
authors.initials: RW
authors.lastname: Finberg
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
authors.forename: José A
authors.initials: JA
authors.lastname: Stoute
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004912:Erythrocytes / Q000378:metabolism* / Q000469:parasitology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D016778:Malaria, Falciparum / Q000378:metabolism* / Q000821:virology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D052940:Merozoites / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000502:physiology*; D011951:Receptors, Complement / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*; D063267:Sialic Acid Binding Ig-like Lectin 1
chemical_list: D008562:Membrane Glycoproteins; D011951:Receptors, Complement; D011971:Receptors, Immunologic; C571166:SIGLEC1 protein, human; D063267:Sialic Acid Binding Ig-like Lectin 1; C571167:Siglec1 protein, mouse; D019158:N-Acetylneuraminic Acid