New Insights into the Evolutionary History of Plasmodium Vivax

Malaria remains one of the world’s most devastating diseases. Campaigns to eradicate transmission have yielded encouraging results in recent years. However, expansion of vector habitats has resulted in substantial increases in disease burden in the Americas, South-East Asia, and Africa, with over 2 million new cases and 445,000 deaths reported in 2016.

While Plasmodium falciparum is responsible for most malaria cases in Africa, Plasmodium vivax is the leading cause of malaria elsewhere in the world, particularly in Southeast Asia and South America. P. vivax is thought to have originated as a human pathogen by zoonoses of ape parasites; the long-standing dogma in the field stated that human P. vivax emerged through a cross-species transmission event from macaque parasites in Asia. However, recent sequencing analysis revealed that wild-living apes throughout Africa harbor numerous strains closely related to human P. vivax. Because of the possibility of cross-species transmission between humans and apes, a complete understanding of the evolutionary history of P. vivax and its related strains is critical, as apes susceptible to infection by similar parasites could serve as reservoirs and hamper eradication efforts. Elizabeth Loy, a 6th year MVP student in Beatrice Hahn’s lab, has been working on further characterizing the relationship between human P. vivax and related non-human primate strains. Her recent findings have helped to articulate a more complete model of the ancestry and dissemination of P. vivax.

Obtaining genome sequences from ape P. vivax strains has historically been challenging. Primate hosts are endangered species, and the infection involves low levels of parasitemia. To circumvent these hurdles, Elizabeth and colleagues adapted a selective-whole genome sequencing amplification (SWGA) method, which amplifies parasite sequences from complex mixtures of host and pathogen DNA. This approach allowed for detection and sequencing of P. vivax in unprocessed blood samples from both chimpanzees and gorillas from multiple regions in Africa, yielding significantly more complete data than previous studies. Comparison of sequences from six different ape P. vivax strains to human strains from both Southeast Asia and Latin America demonstrated that ape and human parasites were highly similar, with 98% sequence identity observed in protein coding regions. However, the diversity among the ape strains was nearly an order of magnitude higher than that of the human strains. Further, the nature of the nucleotide polymorphisms in human and ape parasites was substantially different. Most polymorphisms among ape P. vivax strains were synonymous whereas those among human strains were largely nonsynonymous. This relative excess of nonsynonymous mutations was present broadly across the entire parasite genome, rather than concentrated in any particular subsets of genes, suggesting that these mutations are indicative of population expansion under relatively low selective pressure as opposed to a consequence of directional selection .

Given the relative enrichment of nonsynonymous mutations in human P. vivax genomes, Elizabeth and colleagues hypothesized that some of these mutations may confer increased fitness within the human host. Several red blood cell binding proteins (RBPs) – which are critical for the parasite entry into red blood cells during the intraerythrocytic phase of malaria infection – are pseudogenized in the human parasites, whereas their ape counterparts maintain intact transcripts. Elizabeth reasoned that ape P. vivax strains maintain these proteins in order to more efficiently invade host cells by binding to receptors that are present only on ape erythrocytes, and that the loss of function mutations in human P. vivax represent adaptations to a novel host devoid of these receptors. To test this hypothesis, she constructed recombinant versions of the three RBPs pseudogenized human RBPs and examined their ability to bind erythrocytes from humans, gorillas, and chimpanzees. Surprisingly, the recombinant constructs showed no increased affinity for ape erythrocytes, indicating that there are no ape specific receptors to which these proteins bind in vivo. The fact that human P. vivax has lost function in these genes without incurring a detrimental fitness cost suggests that its population has been expanding under comparatively mild selective pressures.

Taken together, Elizabeth’s findings support a model of P. vivax evolutionary history in which there was a universal ancestor capable of infecting both apes and humans, as evidenced by the near identity of all protein coding regions observed between human and ape parasites. This ancestral parasite is likely to have moved out of Africa during a large-scale migration of its human hosts, and subsequently undergone a severe genetic bottleneck, explaining the substantially reduced diversity among human P. vivax strains compared to their ape counterparts. Finally, in the time following this bottleneck, P. vivax has undergone rapid population expansion under relaxed selective pressure, resulting in an enrichment of nonsynonymous mutations, as well as the non-deleterious pseudogenization of several genes considered to be key virulence factors. Elizabeth’s work illuminates some of the genetic changes that the Plasmodium parasite undergoes as it crosses a species barrier and may possibly be generalized to other instances of pathogens expanding their host range. As such, other members of the Hahn lab are currently investigating whether similar differences in human and ape strains are also observable in P. malariae and P. ovale.

Human P. vivax is hypothesized to have left Africa in a wave of human migration, spreading through Asia and Europe and probably from Europe into the Americas. Strains of P. vivax now present in Madagascar and East Africa likely reflect human re-introductions from Asia.

Loy, D.E., Liu, W., Li, Y., Learn, G.H., Plenderleith, L .J., Sundararaman, S.A., Sharp, P.M ., Hahn, B.H. Out of Africa: origins and evolution of the human malaria parasites falciparum and Plasmodium vivax. Int J Parasitol 2017; 47:87-97.

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