Researchers at the Wellcome Sanger Institute, the University of Cambridge and the KEMRI-Wellcome Trust Research Programme, Kenya, have revealed for the first time how the Dantu genetic blood variant helps protect against malaria. Their findings, published in Nature, revealed that in individuals with the rare Dantu blood variant, red blood cells have a higher surface tension that prevent the malaria parasite from invading.
Malaria and the Dantu polymorphism
Malaria is a major global health problem, accounting for 435,000 deaths every year. Estimates indicate that 61% of these deaths occur in children under five. The malaria parasite, Plasmodium falciparum, is responsible for the deadliest form of malaria and is particularly prevalent in Africa. Malaria has had a profound impact on the human genome. Many protective polymorphisms, particularly the sickle-cell trait, have been selected for to high frequencies within malaria-endemic regions.
In 2017, researchers discovered that the rare Dantu blood variant, commonly found in parts of East Africa, could provide some level of protection against severe malaria (74% in homozygous individuals). This polymorphism offers a similar degree of protection to the sickle-cell trait and a greater level of protection than the best malaria vaccine. Researchers previously fine-mapped the Dantu polymorphism to a structural rearrangement in the glycophorin (GYP) gene cluster. The rearrangement generates a hybrid gene that encodes the Dantu blood group antigen. This antigen contains a novel sialoglycoprotein composed of a glycophorin B (GYPB) extracellular domain fused with a glycophorin A (GYPA) intracellular domain. However, until now, the protective mechanism of this polymorphism has been unknown.
Red blood cell tension
The team collected red blood cell samples from 42 healthy children from Kilifi in Kenya. These children harboured either zero, one, or two copies of the Dantu gene. Using a fluorescence-activated cell sorting (FACS)-based preference assay, the team observed and measured red blood cell invasion over one life cycle. In addition, they used time-lapse video microscopy to investigate the specific time points in which invasion was impaired.
They found that Dantu associated with significant changes to the repertoire of proteins on the red blood cell surface. Interestingly, they found that inhibition of invasion did not correlate with specific red blood cell-parasite receptor-ligand interactions. The team identified a strong link between RBC tension and merozoite invasion. They found a tension threshold above which invasion rarely occurred. Researchers discovered that Dantu red blood cells have a higher average tension rate than non-Dantu red blood cells. As a result, a larger proportion of these cells resist invasion.
Dr Silvia Kariuki, KEMRI-Wellcome Trust Research Programme, Kenya, stated:
“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.”
These findings establish a novel mechanism by which the Dantu polymorphism protects against severe malaria. The team highlight that these results suggest the possibility of new malaria interventions that would be based on modifying the biomechanical properties of circulating red blood cells.
Dr Viola Introini, University of Cambridge, stated:
“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.”
Image credit: By nechaev-kon – canva.com