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

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 Carrasquilla, J. Alexandra Rowe, Kirk Rockett, Dominic Kwiatkowski, Michael P. Weekes, Pietro Cicuta (), Thomas N. Williams () and Julian C. Rayner ()
Additional contact information
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
Michael P. Weekes: University of Cambridge
Pietro Cicuta: University of Cambridge
Thomas N. Williams: KEMRI–Wellcome Trust Research Programme
Julian C. Rayner: Wellcome Genome Campus

Nature, 2020, vol. 585, issue 7826, 579-583

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2726-6

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