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 2

Exported proteins remained expressed by 3D7 parental and 3D7vpkd transgenic parasites.

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Exported proteins remained expressed by 3D7 parental and 3D7vpkd transge...
Immunofluorescence assays demonstrate the expression of (A) RIFIN and (B) STEVOR proteins by mature trophozoite-stage parasites (green). Despite the lack of PfEMP1 expression, RIFIN and STEVOR proteins were detectable in the transfected 3D7vpkd parasites similar to 3D7 parental parasites. (C) Mid-trophozoite-stage parasites from 3D7 parental and 3D7vpkd lines were probed with anti-PfEMP3 antibodies as a positive control and anti-AMA1 antibodies as a negative control (green). As expected, the pattern of staining by anti-PfEMP3 antibodies was consistent with labeling of PfEMP3 in the IE membrane, and there was no apparent labeling of AMA1. In all assays, cells were fixed with a mixture of acetone (90%) and methanol (10%), and DAPI was used to stain nuclear DNA (blue). (A–C) All images were taken with equal exposure for both parasite lines (original magnification, ×1000). (D) Electron-dense knobs in the erythrocyte membrane (arrows) were observed for IEs of 3D7 parental and 3D7vpkd parasites by transmission electron microscopy. Scale bar: 1 εm.