21 February 2014

Out of Africa: the evolution of Plasmodium vivax

Research disputes theory of the origin of the deadly human malaria parasite, Plasmodium vivax

Geographic distribution of P. vivax in wild-living apes.

Geographic distribution of P. vivax in wild-living apes. [doi: 10.1038/ncomms4346]


Researchers have shown that Plasmodium vivax, which causes the majority of human malaria infections in Asia and Latin America, actually originated in Africa. The team found that wild-living apes in Central Africa are commonly infected with parasites that, genetically, are nearly identical to human P. vivax.

Until recently, the closest genetic relatives of human P. vivax were thought to be parasites that infect Asian monkeys, leading researchers originally to believe that P. vivax originated in Asia.

However, this was always difficult to reconcile with the fact that P. vivax is virtually non-existent in Central and West Africa because 99 per cent of people in these regions have a protective mutation, Duffy negativity, that prevents P. vivax from invading their red blood cells.

"The absence of the Duffy antigen on the red blood cell surface obviously arose in West Africa, became ubiquitous, and spread to protect people from P. vivax," says Dr Julian Rayner, author from the Wellcome Trust Sanger Institute. "But this has always been difficult to reconcile with the fact that all previous data that suggests that P. vivax arose in South-East Asia"

"This new data solves vexing questions about P. vivax infection: how can a mutation conferring resistance to P. vivax occur at high frequency in the very region where this parasite seems absent and how can travellers returning from regions where almost all humans lack the receptor for P. vivax can be infected with this parasite."

Members of the labs of Beatrice Hahn and George Shaw, University of Pennsylvania, in collaboration with Paul Sharp, an evolutionary biologist from the University of Edinburgh, and primatologists from dozens of field stations and sanctuaries in Africa, tested over 5,000 ape faecal samples for P. vivax DNA.

This work forms part of a larger body of work from the same international group of investigators, which several years ago established that P. falciparum, the most deadly form of human malaria, crossed into humans from lowland gorillas. In that initial work, the team noticed one or two cases of P. vivax in gorillas and chimpanzees in Central Africa.

" It is pivotal that we continue to monitor other species for malaria, and understand the relationships between human and primate malaria "

Dr Julan Rayner

They have now completed a much more comprehensive screen of malaria parasite DNA from wild-living ape faecal samples, establishing P. vivax is more common in apes than previously thought.

To examine the evolutionary relationships between ape and human parasites, the team generated parasite DNA sequences from non-invasive samples from wild and sanctuary apes, as well as from a global sampling of human P. vivax infections. They constructed a family tree from the DNA sequences and found that ape and human parasites were very closely related. Despite the relatedness between ape and human P. vivax, ape parasites were more diverse than the human parasites and did not group according to their host species. In contrast, the human parasites formed a single lineage that fell within the branches of ape parasite sequences.

From these evolutionary relationships, the team concluded that P. vivax is of African -- not Asian -- origin, and that all existing human P. vivax parasites evolved from a single ancestor that spread out of Africa. The high prevalence of P. vivax in wild-living apes, along with the recent finding of ape P. vivax in a European traveller, indicates the existence of a substantial natural reservoir of P. vivax in Africa.

"Our finding that wild-living apes in Central Africa show widespread infection with diverse strains of P. vivax provides new insight into the evolutionary history of human P. vivax and resolves the paradox that a mutation conferring resistance to P. vivax occurs with high frequency in the very region where this parasite is absent from humans," says Professor Beatrice Hahn, author from University of Pennsylvania.

"One interpretation of the phylogenetic relationships that we observed is that a single host switch from apes gave rise to human P. vivax, analogous to the origin of human P. falciparum," says Professor Paul Sharp, senior author from the University of Edinburgh. "However, this seems unlikely in this case since ape P. vivax does not divide into gorilla- and chimpanzee-specific lineages. A more plausible scenario is that an ancestral P. vivax stock was able to infect humans, gorillas and chimpanzees in Africa until the Duffy negative mutation started to spread -- around 30,000 years ago -- and eliminated P. vivax from humans there. Under this scenario, extant human-infecting P. vivax represents a parasite lineage that survived after spreading out of Africa."

As a next step, the team will compare and contrast the molecular and biological properties of human and ape parasites to identify host-specific interactions and transmission requirements, thereby uncovering vulnerabilities that can be exploited to combat human malaria.

"It is pivotal that we continue to monitor other species for malaria, and understand the relationships between human and primate malaria. If we want to eradicate malaria, we need to understand the full extent of the malaria reservoirs that could potentially infect people," adds Dr Rayner.

Notes to Editors

Publication details

  • African origin of the malaria parasite Plasmodium vivax.

    Liu W, Li Y, Shaw KS, Learn GH, Plenderleith LJ, Malenke JA, Sundararaman SA, Ramirez MA, Crystal PA, Smith AG, Bibollet-Ruche F, Ayouba A, Locatelli S, Esteban A, Mouacha F, Guichet E, Butel C, Ahuka-Mundeke S, Inogwabini BI, Ndjango JB, Speede S, Sanz CM, Morgan DB, Gonder MK, Kranzusch PJ, Walsh PD, Georgiev AV, Muller MN, Piel AK, Stewart FA, Wilson ML, Pusey AE, Cui L, Wang Z, Färnert A, Sutherland CJ, Nolder D, Hart JA, Hart TB, Bertolani P, Gillis A, LeBreton M, Tafon B, Kiyang J, Djoko CF, Schneider BS, Wolfe ND, Mpoudi-Ngole E, Delaporte E, Carter R, Culleton RL, Shaw GM, Rayner JC, Peeters M, Hahn BH and Sharp PM

    Nature communications 2014;5;3346


This work was supported by grants from the US National Institutes of Health, the Agence Nationale de Recherche sur le Sida and Agence Nationale de Recherche of France, Harvard University, the Arthur L. Greene Fund, the Jane Goodall Institute, the Wellcome Trust, Google.org, the Skoll Foundation and the United States Agency for International Development (USAID) Emerging Pandemic Threats PREDICT.

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A full list of participating centres appears on the Nature website.

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