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Red blood cell tension protects against severe malaria in the Dantu blood group

Author

Listed:
  • Silvia N. Kariuki

    (KEMRI–Wellcome Trust Research Programme)

  • Alejandro Marin-Menendez

    (Wellcome Genome Campus)

  • Viola Introini

    (University of Cambridge)

  • Benjamin J. Ravenhill

    (University of Cambridge)

  • Yen-Chun Lin

    (University of Cambridge)

  • Alex Macharia

    (KEMRI–Wellcome Trust Research Programme)

  • Johnstone Makale

    (KEMRI–Wellcome Trust Research Programme)

  • Metrine Tendwa

    (KEMRI–Wellcome Trust Research Programme)

  • Wilfred Nyamu

    (KEMRI–Wellcome Trust Research Programme)

  • Jurij Kotar

    (University of Cambridge)

  • Manuela Carrasquilla

    (Wellcome Genome Campus)

  • J. Alexandra Rowe

    (University of Edinburgh)

  • Kirk Rockett

    (University of Oxford)

  • Dominic Kwiatkowski

    (Wellcome Genome Campus
    University of Oxford
    University of Oxford)

  • Michael P. Weekes

    (University of Cambridge)

  • Pietro Cicuta

    (University of Cambridge)

  • Thomas N. Williams

    (KEMRI–Wellcome Trust Research Programme
    Imperial College London
    Imperial College London)

  • Julian C. Rayner

    (Wellcome Genome Campus
    University of Cambridge)

Abstract

Malaria has had a major effect on the human genome, with many protective polymorphisms—such as the sickle-cell trait—having been selected to high frequencies in malaria-endemic regions1,2. The blood group variant Dantu provides 74% protection against all forms of severe malaria in homozygous individuals3–5, a similar degree of protection to that afforded by the sickle-cell trait and considerably greater than that offered by the best malaria vaccine. Until now, however, the protective mechanism has been unknown. Here we demonstrate the effect of Dantu on the ability of the merozoite form of the malaria parasite Plasmodium falciparum to invade red blood cells (RBCs). We find that Dantu is associated with extensive changes to the repertoire of proteins found on the RBC surface, but, unexpectedly, inhibition of invasion does not correlate with specific RBC–parasite receptor–ligand interactions. By following invasion using video microscopy, we find a strong link between RBC tension and merozoite invasion, and identify a tension threshold above which invasion rarely occurs, even in non-Dantu RBCs. Dantu RBCs have higher average tension than non-Dantu RBCs, meaning that a greater proportion resist invasion. These findings provide both an explanation for the protective effect of Dantu, and fresh insight into why the efficiency of P. falciparum invasion might vary across the heterogenous populations of RBCs found both within and between individuals.

Suggested Citation

  • Silvia N. Kariuki & Alejandro Marin-Menendez & Viola Introini & Benjamin J. Ravenhill & Yen-Chun Lin & Alex Macharia & Johnstone Makale & Metrine Tendwa & Wilfred Nyamu & Jurij Kotar & Manuela Carrasq, 2020. "Red blood cell tension protects against severe malaria in the Dantu blood group," Nature, Nature, vol. 585(7826), pages 579-583, September.
  • Handle: RePEc:nat:nature:v:585:y:2020:i:7826:d:10.1038_s41586-020-2726-6
    DOI: 10.1038/s41586-020-2726-6
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    Cited by:

    1. Prasun Kundu & Deboki Naskar & Shannon J. McKie & Sheena Dass & Usheer Kanjee & Viola Introini & Marcelo U. Ferreira & Pietro Cicuta & Manoj Duraisingh & Janet E. Deane & Julian C. Rayner, 2023. "The structure of a Plasmodium vivax Tryptophan Rich Antigen domain suggests a lipid binding function for a pan-Plasmodium multi-gene family," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. S. Uyoga & J. A. Watson & P. Wanjiku & J. C. Rop & J. Makale & A. W. Macharia & S. N. Kariuki & G. M. Nyutu & M. Shebe & M. Mosobo & N. Mturi & K. A. Rockett & C. J. Woodrow & A. M. Dondorp & K. Maitl, 2022. "The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria," Nature Communications, Nature, vol. 13(1), pages 1-7, December.
    3. Tao Chen & Narain Karedla & Jörg Enderlein, 2024. "Measuring sub-nanometer undulations at microsecond temporal resolution with metal- and graphene-induced energy transfer spectroscopy," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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