Targets of antibodies against Plasmodium falciparum–infected erythrocytes in malaria immunity
Jo-Anne Chan, … , Kevin Marsh, James G. Beeson
Jo-Anne Chan, … , Kevin Marsh, James G. Beeson
Published August 1, 2012
Citation Information: J Clin Invest. 2012;122(9):3227-3238. https://doi.org/10.1172/JCI62182.
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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

Jo-Anne Chan, Katherine B. Howell, Linda Reiling, Ricardo Ataide, Claire L. Mackintosh, Freya J.I. Fowkes, Michaela Petter, Joanne M. Chesson, Christine Langer, George M. Warimwe, Michael F. Duffy, Stephen J. Rogerson, Peter C. Bull, Alan F. Cowman, Kevin Marsh, James G. Beeson

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Figure 4

Antibodies among sera from Kenyan children and adults to surface antigens expressed by P. falciparum–IEs.

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Antibodies among sera from Kenyan children and adults to surface antigen...
(A) IgG binding to the surface of erythrocytes infected with 3D7vpkd parasites was markedly reduced compared with that of 3D7 parental parasites. Assays were performed twice independently; bars represent median and interquartile ranges of samples tested in duplicate (n = 296). The P value was calculated using a paired Wilcoxon signed-rank test. (B) A representative selection of samples tested for antibodies to 3D7 parental and 3D7vpkd parasites. Samples tested were from residents (C1–C7) exposed to malaria in the Chonyi cohort, Kenya, and nonexposed United Kingdom residents (Cont). IgG binding to 3D7vpkd parasites was substantially reduced in most individuals. There was minimal reactivity observed among sera from nonexposed United Kingdom residents. Assays were performed twice independently; bars represent mean and range of samples tested in duplicate. (C) Antibody responses among children of different age groups from the Chonyi cohort. Antibody acquisition was age-dependent as older children had higher levels of IgG binding to 3D7 parental parasites. Children from all age groups had very low IgG binding levels to 3D7vpkd parasites. Bars represent median and interquartile ranges. (A–C) IgG binding levels are expressed as geometric MFI for all graphs. (D) Antibodies to IE surface proteins measured by agglutination assays among a selection of sera from children (n = 20). A representative selection is shown (C8–C14); most individuals have antibodies that agglutinated 3D7 parental parasites to a much greater extent than 3D7vpkd parasites. Bars represent mean and range of samples tested in duplicate.