Malaria has had a major effect on the human genome, many protective polymorphisms
such as sickle cell trait having been selected to high frequencies in malaria endemic
regions1,2. Recently, it was shown that the blood group variant Dantu provides 74%
protection against all forms of severe malaria in homozygous individuals3-5
. This is a similar
degree of protection to sickle cell trait and considerably greater than the best malaria
vaccine, but until now the protective mechanism has been unknown. Here, we demonstrate
a significant impact of Dantu on Plasmodium falciparum-merozoite RBC invasion. Dantu
was associated with extensive changes to the RBC surface protein repertoire, but
unexpectedly, inhibition did not correlate with specific RBC-parasite receptor-ligand
interactions. By following invasion using video microscopy, we found a strong link between
RBC tension and merozoite invasion and identified a tension threshold above which
invasion rarely occurred, even in non-Dantu RBCs. Dantu RBCs had higher average tension,
meaning that a greater proportion resisted invasion. These findings provide both an
explanation for the malaria-protective effect of Dantu, and fresh insights into why the
efficiency of P. falciparum invasion might vary across the heterogenous populations of RBCs
both within and between individuals.