Resurrection of over 50,000-year-old gene reveals how malaria parasite jumped from gorillas to humans
Discovery of molecular pathway is valuable example of how a pathogen can switch from one host species to another
For the first time, scientists have uncovered the likely series of events that led to the world’s deadliest malaria parasite being able to jump from gorillas to humans. Researchers at the Wellcome Sanger Institute and the University of Montpellier reconstructed an approximately 50,000-year-old gene sequence that was acquired by the ancestor of Plasmodium falciparum, giving it the ability to infect human red blood cells.
They found that this rh5 gene enabled the parasite to infect both gorillas and humans for a limited time, explaining how the jump was made at a molecular level. The team also identified the specific DNA mutation that subsequently restricted P. falciparum to humans.
The study, published today (15 October 2019) in PLOS Biology, provides a plausible molecular explanation for how one of the world’s most deadly infectious diseases came to infect humans, and will be important more generally for understanding how pathogens are able to jump from one species to another.
Malaria remains a major global health problem causing an estimated 435,000 deaths per year, with 61 per cent occurring in children under five years of age. P. falciparum is the species of parasite that is responsible for the most deadly form of malaria and is particularly prevalent in Africa, where it accounted for 99.7 per cent of malaria cases in 2017*.
P. falciparum is one of seven species of parasite that can cause malaria in a family known as the Laverania. These parasites originated in African great apes and today are restricted to their own specific host species, with three parasite species confined to chimpanzees and three to gorillas. The seventh, P. falciparum, only infects humans, after switching host from gorillas through a process known as zoonosis around 50,000 years ago.
Genome sequencing of all seven Laverania parasite species revealed a section of DNA that had transferred from a gorilla parasite, Plasmodium adleri, to the ancestor of P. falciparum. This DNA sequence included a gene called rh5. This gene produces the protein RH5, which binds to a protein receptor in human red blood cells called basigin.
This RH5-basigin interaction is critical for the P. falciparum parasite to infect humans. As such, RH5 is a promising malaria vaccine target – if this interaction can be disrupted, the parasite would no longer be able to invade human red blood cells and cause malaria.
To further investigate the origin of P. falciparum, researchers at the University of Montpellier used ancestral sequence reconstruction** to ‘resurrect’ the RH5 DNA sequence that was transferred to the ancestor of P. falciparum around 50,000 years ago. Synthetic copies of the ancestral rh5 gene were created in the laboratory by scientists at the Wellcome Sanger Institute, where the molecular interactions of the RH5 protein could be observed.
Researchers had expected that the transferred RH5 protein would bind only gorilla basigin, but remarkably this protein had the dual property of being able to bind both gorilla and human basigin. This immediately suggested how the parasite could switch host.
