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Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations

Abstract

Geographic overlap between malaria and the occurrence of mutant hemoglobin and erythrocyte surface proteins has indicated that polymorphisms in human genes have been selected by severe malaria1,2. Deletion of exon 3 in the glycophorin C gene (called GYPCΔex3 here) has been found in Melanesians; this alteration changes the serologic phenotype of the Gerbich (Ge) blood group system, resulting in Ge negativity3,4. The GYPCΔex3 allele reaches a high frequency (46.5%) in coastal areas of Papua New Guinea where malaria is hyperendemic5. The Plasmodium falciparum erythrocyte-binding antigen 140 (EBA140, also known as BAEBL)6,7,8 binds with high affinity to the surface of human erythrocytes. Here we show that the receptor for EBA140 is glycophorin C (GYPC) and that this interaction mediates a principal P. falciparum invasion pathway into human erythrocytes. EBA140 does not bind to GYPC in Ge-negative erythrocytes, nor can P. falciparum invade such cells using this invasion pathway. This provides compelling evidence that Ge negativity has arisen in Melanesian populations through natural selection by severe malaria.

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Figure 1: Disruption of the gene encoding EBA140 in P. falciparum.
Figure 2: EBA140 binds to GYPC on human erythrocytes.
Figure 3: Antibodies against the EBA140 F2 domain inhibit the EBA140–GYPC invasion pathway of P. falciparum.

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Acknowledgements

We thank study volunteers for their willing participation, and M. Bockarie and G. Casey (Papua New Guinea Institute of Medical Research) for collecting the blood. We thank J. Thompson and T. Triglia for assistance, and A. Batchelor, S. Miller and B. Crabb for gifts of antibodies. We thank R. Thomson for independent statistical assistance. We acknowledge the Red Cross Blood Service (Melbourne, Australia) for supply of human erythrocytes and serum. This work is supported by grants from the National Health and Medical Research Council of Australia and the National Institutes of Health USA (AI36478-07, AI46919-01A2, AI49390-01). A.F.C. is supported by an International Research Scholarship from the Howard Hughes Medical Institute. M.T.D. is supported by a Wellcome Trust Advanced Training Fellowship (Tropical Medicine) and A.G.M. is a recipient of a Deutsche Forschungsgemeinschaft Research-Fellowship.

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Correspondence to Alan F. Cowman.

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Maier, A., Duraisingh, M., Reeder, J. et al. Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations. Nat Med 9, 87–92 (2003). https://doi.org/10.1038/nm807

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