Red blood cell tension protects against severe malaria in the Dantu blood group.
Ravenhill, Benjamin J
Springer Science and Business Media LLC
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Kariuki, S. N., Marin-Menendez, A., Introini, V., Ravenhill, B. J., Lin, Y., Macharia, A., Makale, J., et al. (2020). Red blood cell tension protects against severe malaria in the Dantu blood group.. Nature, 585 (7826), 579-583. https://doi.org/10.1038/s41586-020-2726-6
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.
Blood Group Antigens, Child, Erythrocytes, Female, Genotype, Humans, Kenya, Ligands, Malaria, Falciparum, Male, Merozoites, Microscopy, Video, Plasmodium falciparum, Polymorphism, Genetic
JCR, AM and DK were supported by the Wellcome Trust (206194/Z/17/Z). MPW is funded by a Wellcome Senior Fellowship (108070). TNW is funded through Fellowships awarded by the Wellcome Trust (091758 and 202800). SNK is supported by the Wellcome Trust-funded Initiative to Develop African Research Leaders (IDeAL) early-career postdoctoral fellowship (107769/Z/10/Z), supported through the DELTAS Africa Initiative (DEL-15-003). The Wellcome Trust provides core support to The KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya (084535), Wellcome Sanger Institute, Cambridge, UK (206194/Z/17/Z) and the Wellcome Centre for Human Genetics, Oxford, UK (090532/Z/09/Z, 203141). PC is supported by the Engineering and Physical Sciences Research Council (EPSRC) (EP/R011443/1), and VI is supported by the EPSRC and the Sackler fellowship.
Wellcome Trust (108070/Z/15/Z)
Engineering and Physical Sciences Research Council (EP/R011443/1)
External DOI: https://doi.org/10.1038/s41586-020-2726-6
This record's URL: https://www.repository.cam.ac.uk/handle/1810/310315
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