Blood Cell Receptors Linked to Natural Malaria Resistance
Researchers have linked large structural variations in red blood cell surface receptors to a naturally lowered risk of contracting malaria. The variations, described in a paper in Science, are unusually common in African populations and have been shown to confer a 40% lower risk of the disease. This research could offer new insights into the development of a malarial vaccine.
More than 200 million people contract malaria every year and resulted in half a million deaths in 2015 alone. Of these 200 million cases, the most common parasite responsible is Plasmodium falciparum, which is also the most dangerous of the malaria parasites. Previous research has shown that the parasite infects red blood cells by entering through receptors that are naturally present on the surface of the cell.
To investigate why some people demonstrated greater resistance to P. falciparum, the team used whole genome sequencing data from various African populations to study the glycophorin gene cluster. The cluster has previously been linked to malaria resistance and is known to be located near to genes responsible for a number of cell surface receptors.
Initially the team looked at data from 765 volunteers from the Gambia, Cameroon, Tanzania, and Burkina Faso to learn more about the gene cluster. They then used this expanded knowledge to study data from 5,310 people in the general population and 4,579 people hospitalised from severe malaria, with participants from Kenya, Malawi, and the Gambia.
“In this new study we found strong evidence that variation in the glycophorin gene cluster influences malaria susceptibility,” said Ellen Leffler, Ph.D., first author of the paper from the University of Oxford. “We found some people have a complex rearrangement of GYPA and GYPB genes, forming a hybrid glycophorin, and these people are less likely to develop severe complications of the disease.”
The hybrid GYPB-A gene was only found in a rare blood group subset (using the MNS blood group system), and was known as Dantu. While the gene was observed in members of the East African population (Kenya, Tanzania, and Malawi), no volunteers from the Western regions of the continent carried it.
“Analysing the DNA sequences allowed us to identify the location of the join between glycophorins A and B in the hybrid gene,” said Kirk Rockett, Ph.D., also from the University of Oxford. “It showed us that the sequence is characteristic of the Dantu antigen in the MNS blood group system.”
Understanding how structural variations in this genomic region can impact malaria susceptibility may help researchers to establish a vaccine capable of stopping infections.
“We are starting to find that the glycophorin region of the genome has an important role in protecting people against malaria. Our discovery that a specific variant of glycophorin invasion receptors can give substantial protection against severe malaria will hopefully inspire further research on exactly how Plasmodium falciparum invade red blood cells,” said Dominic Kwiatkowski, Ph.D., lead investigator in the study at the Wellcome Trust Sanger Institute. “This could also help us discover novel parasite weaknesses that could be exploited in future interventions against this deadly disease.”