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Malaria remains a looming threat for . While Plasmodium falciparum (one of the five Plasmodium parasites that cause malaria in humans) dominates in sub-Saharan Africa, its lesser-known cousin P. vivax has a hold on the rest of the world. 

P. vivax is much less lethal than P. falciparum, and in part for that reason it hasn’t garnered as much research attention. Consequently, we know relatively little about vivax’s history with its human and mosquito hosts, or how it made its way around the globe.

That black box is starting to crack open a little. An international team led by Dan Neafsey, associate director of ӳ����ý’s Genomic Center for Infectious Diseases, and New York University’s hopes to clear up some of the mystery around P. vivax with a study of 195 parasite genomes gathered from 11 countries across four continents — the largest such collection studied to date. The work, , gives tantalizing hints as to how humans and P. vivax migrated together, and how we might be driving its evolution.

P. vivax on the move

The genomes came from 182 patient samples collected by the National Institute of Allergy and Infectious Diseases-funded (ICEMR, a consortium of 10 research networks in malaria-endemic regions), plus 13 additional patient samples and monkey-adapted laboratory strains. Scouring the sequences for informative single nucleotide polymorphisms (SNPs; common single letter changes in a DNA sequence), the team found evidence that bolsters some existing theories about P. vivax’s global diversity and evolution, and provides fodder for new ones. 

P. vivax strains fall into four geographic clusters.

When mapped geographically, the team’s samples’ SNP profiles fell into four distinct clusters: 

• New World
• Africa/Indian Ocean
• Southeast Asia
• Papua New Guinea

The data not only confirmed the suspicion that P. vivax is genetically more diverse than P. falciparum, but revealed that even the least diverse subpopulation of vivax is more diverse than all falciparum populations globally.

Deep analysis of the clusters provided intriguing hints about P. vivax’s global travels. South American samples’ SNPs suggested that vivax malaria came to the Americas with European colonists (P. vivax was endemic in Europe until being exterminated about 50 years ago). Once here, it adapted to New World mosquitoes, Native American populations, and Africans brought to the Americas via the trans-Atlantic slave trade. In essence, Old World European vivax became New World vivax.

“New World P. vivax is very distinct genetically from Old World populations,” Neafsey said. “Given that vivax likely was not present in the Americas before European contact, the parasite diversity we saw suggests a large importation of an ancient lineage.”

In addition, African and Indian samples harbored SNPs associated with both Old and New World parasites. This suggests, Neafsey and Carlton think, that now-extinct European parasites may have mingled with strains from the Indian Ocean basin in colonial times. Alternatively, P. vivax may have followed human migrations and trade routes linking Africa, the Middle East, and India. 

“There’s a complicated history of human movements across South Asia,” Neafsey said. “We think the parasite results mirror some aspect of that.”

P. vivax's global spread seems to track human migrations and trade. (Dark blue: Route firmly supported by data. Light blue: Possible route suggested by data.)

I evolve you

Humans and P. vivax have clearly pushed each other to evolve over their long history together. Case-in-point: human Duffy antigen mutations, which altered a human cell surface marker P. vivax uses to worm its way into red blood cells. Duffy mutations nearly eliminated vivax malaria across much of sub-Saharan Africa over the last 50,000 years.

“It’s evidence that while P. vivax doesn’t cause much mortality today,” Neafsey explained, “it likely exerted a strong evolutionary pressure on humans in the past.”

Neafsey and Carlton’s team combed their parasite genomes for signs of pressures we, in turn, have put on P. vivax. As they reported in their paper, three things stood out:

• Divergence between New and Old World strains in Pvs47 (a gene for a parasite surface marker), which may have helped P. vivax adapt to life in New World mosquitoes.
• Mutations in DHPS and DHRF-TS, two genes that in P. falciparum are associated with antimalarial drug resistance.
• Significant diversity in antigen genes like the MSP3, MSP7, and SERA families, which code for surface or immune evasion proteins.

“The high divergence at known drug resistance genes suggest that parasites from different parts of the world are independently but convergently refining their resistance,” Neafsey explained. “We also see the antigenic diversity as evidence of the pressures our immune system has put on vivax over time.”

Forward movement for vivax research

While it may not be the killer falciparum is, vivax causes its victims a great deal of suffering, sapping their ability to go to school or work and impacting the economies of endemic countries. Despite this, Neafsey worries that his team’s work suffers a plight similar to that of other neglected diseases. 

“There isn’t a large infrastructure around vivax that we can plug this information into,” Neafsey said. “Vivax work is less well funded, and it can’t be cultured in vitro, which makes it hard to study in the laboratory.”

“What this work does, however,” he continued, “is bring vivax closer to falciparum’s state of genomic knowledge. There are thousands of falciparum sequences from sites around the world. Having a couple of hundred vivax genomes is certainly better than a handful, which is where we stood before.”

He fears the parasite’s genetic diversity could complicate efforts to develop a P. vivax vaccine. “Vivax is more diverse than falciparum, and we don’t have an approved falciparum vaccine despite 30 years of work,” he said. “These data form a resource that could help point out potential vivax vaccine targets that are less variable.”

The team’s discoveries could also be useful for drug development. “If you have a target, you could check whether it’s variable across populations,” he said. “That could tell you whether a drug’s efficacy might vary in different parts of the world.”

Paper cited:

Hupalo DN, Luo Z, et al. . Nature Genetics. June 27, 2016. DOI: 10.1038/ng.3588