title: Allelic polymorphisms in apical membrane antigen-1 are responsible for evasion of antibody-mediated inhibition in Plasmodium falciparum.
abstract: Apical membrane antigen-1 (AMA-1) is a target of antibodies that inhibit invasion of Plasmodium falciparum into human erythrocytes and is a candidate for inclusion in a malaria vaccine. We have identified a line of P. falciparum (W2mef) less susceptible to anti-AMA1 antibodies raised to the protein from a heterologous parasite line (3D7). We have constructed transgenic P. falciparum expressing heterologous AMA-1 alleles. In vitro invasion assays show that these transgenic parasites differ from parental lines in susceptibility to inhibitory antibodies, providing direct evidence that sequence polymorphisms within AMA-1 are responsible for evasion of immune responses that inhibit parasite invasion. We also generated a parasite line that would express a chimeric AMA-1 protein, in which highly polymorphic residues within domain 1 were exchanged. Inhibition assays suggest that these residues are not sufficient for inhibition by invasion-blocking antibodies. This study is the first to use P. falciparum allelic exchange to examine the relationship between genetic diversity and susceptibility to protective antibodies. The findings have important implications for the development of an AMA-1-based malaria vaccine.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Melbourne, 3050, Australia.
authors.forename: Julie
authors.initials: J
authors.lastname: Healer
authors.forename: Vince
authors.initials: V
authors.lastname: Murphy
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Hodder
authors.forename: Rosella
authors.initials: R
authors.lastname: Masciantonio
authors.forename: Alan W
authors.initials: AW
authors.lastname: Gemmill
authors.forename: Robin F
authors.initials: RF
authors.lastname: Anders
authors.forename: Alan F
authors.initials: AF
authors.lastname: Cowman
authors.forename: Adrian
authors.initials: A
authors.lastname: Batchelor
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology*; D000953:Antigens, Protozoan / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D016054:DNA, Protozoan / Q000235:genetics; D014644:Genetic Variation; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D030781:Organisms, Genetically Modified; D010963:Plasmodium falciparum / Q000235:genetics* / Q000254:growth & development / Q000276:immunology*; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D016054:DNA, Protozoan; D008565:Membrane Proteins; D015800:Protozoan Proteins; C090077:apical membrane antigen I, Plasmodium