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In a study published today in PLOS Biology, researchers from the Wellcome Sanger Institute and the University of Montpellier have reconstructed a ~50,000-year-old gene sequence acquired by the ancestor of Plasmodium falciparum. The acquisition of the gene sequence enabled the parasite to infect human red blood cells.



The gene, known as Rh5, enabled the parasite to infect both gorillas and humans for a limited period of time. The study provides insight in the molecular mechanisms behind this jump.



Malaria – A major global health problem



Malaria causes 435,000 deaths per year on average, with ~61% occurring in children <5 years of age. P. falciparum is the of seven species of parasite that can cause malaria in a family known as the Laverania and causes the deadliest form of the infectious disease; in 2017, this parasite accounted for 99.7% of cases in Africa.



The Laverania parasites originated in African great apes; however, they are now restricted to their own specific host species. Three parasite species are confined to chimpanzees, and three are combined to gorillas. What about the seventh, you ask? P. falciparum only infects humans now, as it switched host from gorillas. This process whereby a disease is transmitted to humans from an animal is known as zoonosis. But how exactly did the switching of the parasite from gorillas to humans occur at the molecular level?



Gavin Wright, lead author of the study and Senior Group Leader at the Wellcome Sanger Institute, said: "In the history of mankind, Plasmodium falciparum malaria has arguably been responsible for more human deaths than any other disease. So, it is both important and fascinating to understand the molecular pathways that enabled this deadly parasite to infect humans."



The evolution of P. falciparum and malaria



The scientists conducted genome sequencing of all seven Laverania parasite species, and uncovered a section of DNA that had been transferred from a gorilla parasite, Plasmodium adleri, to the ancestor of P. falciparum. The gene sequence included Rh5, a gene that produces the protein reticulocyte binding-like protein 5, which binds to a protein receptor in human red blood cells known as basigin. The interaction of this protein and its receptor is critical for the P. falciparum parasite to infect humans, and thus Rh5 is showing promise as a potential malaria vaccine target. If scientists can disrupt the interaction, the parasite cannot enter the red blood cell and cause disease.



The research team at the University of Montpellier wanted to understand further the ancestral origins of P. falciparum. They therefore adopted ancestral sequence reconstruction to effectively "reconstruct" the Rh5 DNA sequence that had been transferred to the ancestor of P. falciparum all those 50,000 years ago. The scientists at the Wellcome Sanger Institute then created synthetic copies of the Rh5 gene in the laboratory, enabling the molecular interactions of the encoded Rh5 protein to be explored.



Interestingly, the study findings demonstrate that the transferred Rh5 protein possessed dual binding ability for the red blood cell receptor in both humans and gorillas – thus demonstrating how P. falciparum was able to switch hosts.



Francis Galaway, first author of the study and Staff Scientist at the Wellcome Sanger Institute, said: "The fact that this ancestral RH5 protein was able to bind to the red blood cell receptor basigin from both humans and gorillas, immediately provided a molecular explanation for how P. falciparum evolved to infect humans."



But how did P. falciparum become restricted to humans?



The researchers identified six differences between the ancestral Rh5 gene sequence, and the current sequence observed in P. falciparum. Surprisingly, one specific mutation resulted in the complete loss of ability to bind the gorilla form of basigin, depicting how the parasite became restricted to humans.



Franck Prugnolle, from the University of Montpellier, said: "It's fascinating to be able to 'resurrect' ancestral genes such as the one which allowed Plasmodium falciparum to jump from gorillas to humans. We've discovered not only how a species host switch has occurred, but the individual mutation which has then restricted P. falciparum to a single host species."



The scientists hypothesize that the genetic transfer of the Rh5 gene occurred when a gorilla cell was infected with two species of the Plasmodium parasite in parallel – known as introgression.



This form of introgression is extremely rare. Of the seven Laverania species, genomic analyses have revealed only a few instances of this occurring over a span of approximately one million years.



Reference: Galaway et al. 2019. Resurrection of the ancestral RH5 invasion ligand provides a molecular explanation for the origin of P. falciparum malaria in humans. PLOS Biology. https://doi.org/10.1371/journal.pbio.3000490.