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A principal target of human immunity to malaria identified by molecular population genetic and immunological analyses

Nature Medicine volume 6, pages 689–692 (2000)Cite this article

Abstract

New strategies are required to identify the most important targets of protective immunity in complex eukaryotic pathogens. Natural selection maintains allelic variation in some antigens of the malaria parasite Plasmodium falciparum1,2,3. Analysis of allele frequency distributions could identify the loci under most intense selection4,5,6,7. The merozoite surface protein 1 (Msp1) is the most-abundant surface component on the erythrocyte-invading stage of P. falciparum8,9,10. Immunization with whole Msp1 has protected monkeys completely against homologous11 and partially against non-homologous12 parasite strains. The single-copy msp1 gene, of about 5 kilobases, has highly divergent alleles13 with stable frequencies in endemic populations14,15. To identify the region of msp1 under strongest selection to maintain alleles within populations, we studied multiple intragenic sequence loci in populations in different regions of Africa and Southeast Asia. On both continents, the locus with the lowest inter-population variance in allele frequencies was block 2, indicating selection in this part of the gene. To test the hypothesis of immune selection, we undertook a large prospective longitudinal cohort study. This demonstrated that serum IgG antibodies against each of the two most frequent allelic types of block 2 of the protein were strongly associated with protection from P. falciparum malaria.

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Acknowledgements

We thank O. Ogundahunsi, M. Grobusch, K. Hirayama, K. Na-Bangchang, C. Curtis, J. Trigg, J. Curtis, G. Warnasuriya, and D. Warhurst for support with sample collection and processing; H. Weiss for help with the cohort study database; T. Anderson for advice on microsatellites; and R. Gregory for technical assistance with the ABI 377. This work was supported by The Wellcome Trust (grant references 013163/Z/94/B,C and 0471191/Z/96), the UK Medical Research Council (grant reference G9803180), and The Ministry of Education, Science and Culture, Japan.

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Authors and Affiliations

  1. Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel St, London, WC1E 7HT

    David J. Conway, Cally Roper, Zsuzsanna S. Mikes & Brian M. Greenwood

  2. Institute of Cell, Animal, and Population Biology, University of Edinburgh, EH9 3JT

    David R. Cavanagh, David E. Arnot & Jana S. McBride

  3. Laboratory of Biology, Osaka Institute of Technology, Osaka, 535-8535, Japan

    Kazuyuki Tanabe & Naoko Sakihama

  4. Medical Research Council Laboratories, Fajara, PO Box 273, Banjul, The Gambia

    Kalifa A. Bojang

  5. Postgraduate Institute of Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Nigeria

    Ayoade M. J. Oduola

  6. Department of Parasitology, Institute of Tropical Medicine, University of Tubingen, Germany

    Peter G. Kremsner

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  1. David J. Conway
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Correspondence to David J. Conway.

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Conway, D., Cavanagh, D., Tanabe, K. et al. A principal target of human immunity to malaria identified by molecular population genetic and immunological analyses. Nat Med 6, 689–692 (2000). https://doi.org/10.1038/76272

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