title: A single point in protein trafficking by Plasmodium falciparum determines the expression of major antigens on the surface of infected erythrocytes targeted by human antibodies.
abstract: Antibodies to blood-stage antigens of Plasmodium falciparum play a pivotal role in human immunity to malaria. During parasite development, multiple proteins are trafficked from the intracellular parasite to the surface of P. falciparum-infected erythrocytes (IEs). However, the relative importance of different proteins as targets of acquired antibodies, and key pathways involved in trafficking major antigens remain to be clearly defined. We quantified antibodies to surface antigens among children, adults, and pregnant women from different malaria-exposed regions. We quantified the importance of antigens as antibody targets using genetically engineered P. falciparum with modified surface antigen expression. Genetic deletion of the trafficking protein skeleton-binding protein-1 (SBP1), which is involved in trafficking the surface antigen PfEMP1, led to a dramatic reduction in antibody recognition of IEs and the ability of human antibodies to promote opsonic phagocytosis of IEs, a key mechanism of parasite clearance. The great majority of antibody epitopes on the IE surface were SBP1-dependent. This was demonstrated using parasite isolates with different genetic or phenotypic backgrounds, and among antibodies from children, adults, and pregnant women in different populations. Comparisons of antibody reactivity to parasite isolates with SBP1 deletion or inhibited PfEMP1 expression suggest that PfEMP1 is the dominant target of acquired human antibodies, and that other P. falciparum IE surface proteins are minor targets. These results establish SBP1 as part of a critical pathway for the trafficking of major surface antigens targeted by human immunity, and have key implications for vaccine development, and quantifying immunity in populations.
authors.affiliation: Burnet Institute for Medical Research and Public Health, 85 Commercial Road, Melbourne, VIC, 3001, Australia.|Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Chan
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Howell
authors.affiliation: Burnet Institute for Medical Research and Public Health, 85 Commercial Road, Melbourne, VIC, 3001, Australia.
authors.forename: Christine
authors.initials: C
authors.lastname: Langer
authors.affiliation: Research School of Biology, Australian National University, Canberra, ACT, Australia.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Maier
authors.affiliation: Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Wina
authors.initials: W
authors.lastname: Hasang
authors.affiliation: Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Rogerson
authors.affiliation: Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Michaela
authors.initials: M
authors.lastname: Petter
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
authors.forename: Joanne
authors.initials: J
authors.lastname: Chesson
authors.affiliation: Institute for Glycomics, Griffith University, Southport, QLD, Australia.
authors.forename: Danielle I
authors.initials: DI
authors.lastname: Stanisic
authors.affiliation: Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Duffy
authors.affiliation: Programs in Infection and Immunity and Cardiovascular Disease, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.|Department of Microbiology, Monash University, Melbourne, VIC, Australia.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Cooke
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siba
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.affiliation: Centre for Geographic Medicine Research, Coast, Kenya Medical Research Institute, Kilifi, Kenya.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Bull
authors.affiliation: Centre for Geographic Medicine Research, Coast, Kenya Medical Research Institute, Kilifi, Kenya.
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.affiliation: Burnet Institute for Medical Research and Public Health, 85 Commercial Road, Melbourne, VIC, 3001, Australia.|Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Melbourne School of Public Health, University of Melbourne, Parkville, VIC, Australia.|Department of Epidemiology and Preventive Medicine and Department of Infectious Diseases, Monash University, Melbourne, VIC, Australia.
authors.forename: Freya J I
authors.initials: FJ
authors.lastname: Fowkes
authors.affiliation: Burnet Institute for Medical Research and Public Health, 85 Commercial Road, Melbourne, VIC, 3001, Australia. beeson@burnet.edu.au.|Department of Medicine, University of Melbourne, Parkville, VIC, Australia. beeson@burnet.edu.au.|Department of Microbiology, Monash University, Melbourne, VIC, Australia. beeson@burnet.edu.au.
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000953:Antigens, Protozoan / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D004912:Erythrocytes / Q000469:parasitology* / Q000648:ultrastructure; D055786:Gene Knockout Techniques; D006801:Humans; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology*; D008565:Membrane Proteins / Q000378:metabolism; D010271:Parasites / Q000276:immunology / Q000648:ultrastructure; D010641:Phenotype; D010963:Plasmodium falciparum / Q000276:immunology* / Q000648:ultrastructure; D021381:Protein Transport; D015800:Protozoan Proteins / Q000378:metabolism
chemical_list: D000906:Antibodies; D000953:Antigens, Protozoan; D002352:Carrier Proteins; D008565:Membrane Proteins; C417763:Pfsbp1 protein, Plasmodium falciparum; D015800:Protozoan Proteins
keywords: Antibodies; Immunity; Malaria; Plasmodium falciparum; Trafficking; Vaccines