How the rare Dantu blood group protects against severe malaria
We found a strong correlation between red blood cell membrane tension and parasite invasion ability, where increased membrane tension leads to resistance to parasite invasion. We found that Dantu red blood cells had higher average tension, meaning that a greater proportion resisted invasion.
While the incidence of malaria has declined globally, Africa still bears the greatest burden of the disease in the world accounting for more than 90% of all malaria deaths in 2018 , with Plasmodium falciparum being the most prevalent parasite in the region. Over time, malaria has had a significant impact on the human genome. This has resulted in the selection of genetic variants that are protective against malaria, such as sickle cell trait and alpha-thalassaemia. These protective genetic variants are most commonly found in populations living in malaria endemic regions.
Recent studies showed that the rare Dantu blood group variant provides a strongly protective effect against malaria infection, similar in magnitude to the sickle cell trait effect [2-4]. Our study sought to investigate the mechanisms through which Dantu confers its protective effect against malaria. Interestingly, the Dantu variant is found at highest frequency in Kilifi, in the Kenyan coast, which makes this work more impactful for this population, as well as other populations that live in malaria-endemic areas.
We collected red blood cell samples from 42 healthy children in Kilifi across Dantu genotypes, i.e. carried two, one, or zero copies of the Dantu variant. We then carried out a series of experiments using flow cytometry and video microscopy techniques to investigate how the P. falciparum parasite invades red blood cells from the different donors. We observed a significantly reduced ability of the parasite to invade Dantu red blood cells.
Further analysis of the physical characteristics of the red blood cells indicated that this inhibition of invasion was linked to an important property: membrane tension, which varies naturally over the lifespan of the red blood cell. By studying both membrane tension and parasite invasion simultaneously using time-lapse video microscopy, we found a clear correlation between tension and invasion, and identified a tension threshold above which parasites could not invade red blood cells, even in non-Dantu red blood cells. Importantly, more Dantu red blood cells fall above this threshold, which leaves fewer cells available to be invaded by the parasite in individuals with this genotype.
These findings provide critical insights into the interactions between the human host and the malaria parasite, adding a new dimension to our molecular understanding of red blood cell invasion by the P. falciparum malaria parasite. Our study highlights how a host genetic variant found naturally in populations living in malaria-endemic areas in East Africa confers a strongly protective effect against malaria, through increased red blood cell membrane tension. We hope that the findings from this study will inform the development of drugs that could mimic this fundamental change in red blood cell membrane tension to prevent malaria parasite infection.
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- Band, G., et al., A novel locus of resistance to severe malaria in a region of ancient balancing selection. Nature, 2015. 526(7572): p. 253-7.
- Leffler, E.M., et al., Resistance to malaria through structural variation of red blood cell invasion receptors. Science, 2017. 356(6343).
- Ndila, C.M., et al., Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study. Lancet Haematol, 2018.