title: Targets of antibodies against Plasmodium falciparum-infected erythrocytes in malaria immunity.
abstract: Plasmodium falciparum is the major cause of malaria globally and is transmitted by mosquitoes. During parasitic development, P. falciparum-infected erythrocytes (P. falciparum-IEs) express multiple polymorphic proteins known as variant surface antigens (VSAs), including the P. falciparum erythrocyte membrane protein 1 (PfEMP1). VSA-specific antibodies are associated with protection from symptomatic and severe malaria. However, the importance of the different VSA targets of immunity to malaria remains unclear, which has impeded an understanding of malaria immunity and vaccine development. In this study, we developed assays using transgenic P. falciparum with modified PfEMP1 expression to quantify serum antibodies to VSAs among individuals exposed to malaria. We found that the majority of the human antibody response to the IE targets PfEMP1. Furthermore, our longitudinal studies showed that individuals with PfEMP1-specific antibodies had a significantly reduced risk of developing symptomatic malaria, whereas antibodies to other surface antigens were not associated with protective immunity. Using assays that measure antibody-mediated phagocytosis of IEs, an important mechanism in parasite clearance, we identified PfEMP1 as the major target of these functional antibodies. Taken together, these data demonstrate that PfEMP1 is a key target of humoral immunity. These findings advance our understanding of the targets and mediators of human immunity to malaria and have major implications for malaria vaccine development.
authors.affiliation: Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, Australia.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Chan
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Howell
authors.forename: Linda
authors.initials: L
authors.lastname: Reiling
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ataide
authors.forename: Claire L
authors.initials: CL
authors.lastname: Mackintosh
authors.forename: Freya J I
authors.initials: FJ
authors.lastname: Fowkes
authors.forename: Michaela
authors.initials: M
authors.lastname: Petter
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Chesson
authors.forename: Christine
authors.initials: C
authors.lastname: Langer
authors.forename: George M
authors.initials: GM
authors.lastname: Warimwe
authors.forename: Michael F
authors.initials: MF
authors.lastname: Duffy
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Rogerson
authors.forename: Peter C
authors.initials: PC
authors.lastname: Bull
authors.forename: Alan F
authors.initials: AF
authors.lastname: Cowman
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
mesh_terms: D000293:Adolescent; D000328:Adult; D000913:Antibodies, Protozoan / Q000097:blood*; D000953:Antigens, Protozoan / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D060467:Disease Resistance; D018572:Disease-Free Survival; D019353:Endemic Diseases; D004912:Erythrocytes / Q000469:parasitology*; D005818:Genetic Engineering; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D007630:Kenya / Q000453:epidemiology; D016778:Malaria, Falciparum / Q000097:blood / Q000453:epidemiology / Q000276:immunology*; D008875:Middle Aged; D030781:Organisms, Genetically Modified; D010587:Phagocytosis; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum