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 1

Phenotypic analyses of var promoter knockdown parasites.

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Phenotypic analyses of var promoter knockdown parasites. (A) Northern ...
(A) Northern blot of var gene transcription by hybridization with a specific var exon 2 sequence. Compared with that in 3D7 parental parasites, var transcripts (arrow) are markedly reduced or absent in 3D7vpkd parasites. RNA was extracted from highly synchronous ring-stage IEs at approximately 10 hours after invasion. The position of molecular weight standards (kb) is indicated on the left. Ethidium bromide–stained gel prior to blotting was used as the loading control (Supplemental Figure 1B). (B) Western blot analyses of membrane extracts from mature trophozoite-IEs probed with anti-PfEMP1 and anti-RIF29 antibodies. In E8B parental parasites, full-length PfEMP1, which was absent in E8Bvpkd parasites, was detected at approximately 300 kDa (arrows). The double band represents different PfEMP1 variants expressed by E8B parental parasites. This anti-PfEMP1 antibody cross-reacts with erythrocyte spectrin (asterisk), as shown by comparison with extracts from uninfected erythrocytes (uRBC). The anti-RIF29 antibodies detected a protein at approximately 40 kDa, representing RIFIN in both E8B parental and E8Bvpkd parasites (bottom). ATS, acidic terminal sequence of PfEMP1. Adhesion of IEs to immobilized (C) ICAM-1 and (D) CD36 was significantly reduced in E8Bvpkd parasites compared with that in E8B parental parasites. (E) Adhesion of IEs to immobilized CD36 was significantly reduced in 3D7vpkd parasites compared with that in 3D7 parental parasites. However, adhesion to CD36 was partially retained in E8Bvpkd and 3D7vpkd parasites. Values are expressed as a percentage of parental parasites binding to each receptor. Assays were performed twice independently; bars represent median and interquartile ranges of samples tested in triplicate.