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

• Published in: Nature (London) Vol. 585; no. 7826; pp. 579 - 583
• Main Authors: Kariuki, Silvia N., Marin-Menendez, Alejandro, Introini, Viola, Ravenhill, Benjamin J., Lin, Yen-Chun, Macharia, Alex, Makale, Johnstone, Tendwa, Metrine, Nyamu, Wilfred, Kotar, Jurij, Carrasquilla, Manuela, Rowe, J. Alexandra, Rockett, Kirk, Kwiatkowski, Dominic, Weekes, Michael P., Cicuta, Pietro, Williams, Thomas N., Rayner, Julian C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.09.2020; Nature Publishing Group
• Subjects: 13; 14; 14/1; 14/34; 14/63; 38/77; 631/1647/1407/1492; 631/1647/296; 631/208/726/649/2157; 631/208/727/2000; 631/57/2272/2274; 82/58; Analysis; Antigens; Blood Group Antigens - classification; Blood Group Antigens - genetics; Blood Group Antigens - metabolism; Blood groups; Child; Erythrocytes; Erythrocytes - cytology; Erythrocytes - metabolism; Erythrocytes - parasitology; Erythrocytes - pathology; Female; Flow cytometry; Genomes; Genotype; Health aspects; Humanities and Social Sciences; Humans; Influence; Kenya; Life Sciences; Ligands; Malaria; Malaria, Falciparum - pathology; Malaria, Falciparum - prevention & control; Male; Mass spectrometry; Merozoites - metabolism; Merozoites - pathogenicity; Microscopy; Microscopy, Video; multidisciplinary; Parasites; Plasmodium falciparum; Plasmodium falciparum - growth & development; Plasmodium falciparum - metabolism; Plasmodium falciparum - pathogenicity; Polymorphism, Genetic; Prevention; Proteins; Science; Science (multidisciplinary); Scientific imaging; Surface tension; Tension; Vector-borne diseases; Viscosity; Kenya; United Kingdom
• ISSN: 0028-0836; 1476-4687
• DOI: 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 regions 1 , 2 . The blood group variant Dantu provides 74% protection against all forms of severe malaria in homozygous individuals 3 – 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. The rare blood group Dantu is known to protect against severe malaria, and a mechanism is proposed here: Dantu red blood cells have a high membrane tension that prevents invasion by malaria parasites.