Abnormal display of PfEMP-1 on erythrocytes carrying haemoglobin C may protect against malaria

Abstract

Haemoglobin C, which carries a glutamate-to-lysine mutation in the β-globin chain, protects West African children against Plasmodium falciparum malaria1,2. Mechanisms of protection are not established for the heterozygous (haemoglobin AC) or homozygous (haemoglobin CC) states. Here we report a marked effect of haemoglobin C on the cell-surface properties of P. falciparum-infected erythrocytes involved in pathogenesis. Relative to parasite-infected normal erythrocytes (haemoglobin AA), parasitized AC and CC erythrocytes show reduced adhesion to endothelial monolayers expressing CD36 and intercellular adhesion molecule-1 (ICAM-1). They also show impaired rosetting interactions with non-parasitized erythrocytes, and reduced agglutination in the presence of pooled sera from malaria-immune adults. Abnormal cell-surface display of the main variable cytoadherence ligand, PfEMP-1 (P. falciparum erythrocyte membrane protein-1), correlates with these findings. The abnormalities in PfEMP-1 display are associated with markers of erythrocyte senescence, and are greater in CC than in AC erythrocytes. Haemoglobin C might protect against malaria by reducing PfEMP-1-mediated adherence of parasitized erythrocytes, thereby mitigating the effects of their sequestration in the microvasculature.

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Figure 1: Cytoadherence, rosetting and agglutination of P. falciparum -infected erythrocytes.
Figure 2: Flow cytometry analysis of PfEMP-1 expression on normal and HbC erythrocytes parasitized with P. falciparum.
Figure 3: PfEMP-1 and knob distributions on normal and HbC erythrocytes parasitized with P. falciparum.
Figure 4: Effects of haemoglobin C on knob formation, hemichrome deposition and senescent antibody binding in vivo.

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Acknowledgements

We thank our blood donors and J. F. Casella, B. Link, G. Rodgers, M. Law, K. D. Luc, N. Murray, J. A. Dvorak, F. Tokumasu, T. Arie, E. Fischer, L. H. Miller, A. Sadou, A. Katilé, B. Dakouo, K. Traoré and S. A. S. Diakité for their efforts in support of this work. H. F. acknowledges support from the United States Agency for International Development and the National Institutes of Health.

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Correspondence to Thomas E. Wellems.

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Supplementary information

Supplementary Table S1

Median fluorescence intensities of parasitized erythrocyte populations probed with rat antisera. (DOC 78 kb)

Supplementary Table S2

Data demonstrating synchrony of the GB4 and 7G8 parasite lines in simultaneously infected AA and CC erythrocytes. (DOC 47 kb)

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Fairhurst, R., Baruch, D., Brittain, N. et al. Abnormal display of PfEMP-1 on erythrocytes carrying haemoglobin C may protect against malaria. Nature 435, 1117–1121 (2005). https://doi.org/10.1038/nature03631

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