Scientists have uncovered the reason why the rare Dantu blood group helps to protect against malaria.
A team from the Wellcome Sanger Institute, the University of Cambridge and the KEMRI-Wellcome Trust Research Programme, Kenya, discovered that red blood cells in the Dantu blood variant have a high surface tension that prevents them from being invaded by Plasmodium falciparum.
The findings, published yesterday (16 September 2020) in Nature, could herald the development of drugs that imitate the natural process that sees surface tension increase as the cell gets older, to help prevent malaria infection or reduce its severity.
The rare Dantu blood variant, which is found regularly only in parts of East Africa, was discovered in 2017, and in this study, red blood cell samples were collected from 42 healthy children in Kilifi, Kenya, who had either one, two or zero copies of the Dantu gene.
The researchers used multiple tools, including time-lapse video microscopy, to track the ability of parasites to invade the cells and to identify the specific step at which invasion was impaired.
Analysis suggested that at a certain tension, malaria parasites were no longer able to enter the Dantu red blood cell, halting their lifecycle and preventing their ability to multiply in the blood. It has a novel chimeric protein that is expressed on the surface of red blood cells, and alters the balance of other surface proteins.
Dr Silvia Kariuki, of the KEMRI-Wellcome Trust Research Programme, Kenya, said: “Malaria parasites utilise a specific ‘lock-and-key’ mechanism to infiltrate human red blood cells. When we set out to explain how the Dantu variant protects against these parasites, we expected to find subtle changes in the way this molecular mechanism works, but the answer turned out to be much more fundamental.
“The Dantu variant actually slightly increases the tension of the red blood cell surface. It’s like the parasite still has the key to the lock, but the door is too heavy for it to open.”
In Kilifi, a town on the Kenyan coast, 10% of the population have one copy of the Dantu gene, which provides up to 40% protection against malaria, while 1% has two copies, which confer up to 70% protection. The best malaria vaccines currently provide 35% protection.
The research team writes that one of the most significant findings is that because surface tension of human red blood cells varies naturally, generally increasing during their approximately 90-day lifespan, it means a proportion of all of our red blood cells are naturally resistant to infection by malaria parasites, and it may be possible to develop drugs that take advantage of this process.
Dr Viola Introini, of the University of Cambridge, said: “The explanation for how Dantu protects against malaria is potentially very important. The red cell membrane only needs to be slightly more tense than usual to block malaria parasites from entering.
“Developing a drug that emulates this increased tension could be a simple but effective way to prevent or treat malaria. This would depend on the increase in cell tension not having unintended consequences, of course, but evidence from the natural protection already seen in Dantu people, who don’t seem to suffer negative side effects, is promising.”
Kariuki SN, Marin-Menendez A, Introini V et al. Red blood cell tension protects against severe malaria in the Dantu blood group. Nature 16 September 2020.
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