Parasite's genetic variability hinders control of malaria, study shows

ICEMR network sequenced complete genomes of 182 samples of Plasmodium vivax, the predominant malaria parasite in the Americas. The results have just been published in Nature Genetics.

By Karina Toledo  |  Agência FAPESP – The complete genomes of 182 samples of the parasite Plasmodium vivax, the leading cause of malaria in the Americas, have been sequenced by researchers in the International Centers of Excellence for Malaria Research (ICEMR), a global network sponsored by the US National Institutes of Health (NIH).

Among the participants in the initiative is Brazilian Marcelo Urbano Ferreira, a professor at the University of São Paulo’s Biomedical Science Institute (ICB-USP).

The findings were published on June 27 in an article in the journal Nature Genetics. According to Ferreira, they confirm previous research showing far higher genomic variability in P. vivax than in P. falciparum, the predominant African malaria parasite, which causes a more aggressive form of the disease.

In Ferreira’s opinion, this broader repertoire of genetic variants makes the species P. vivax more capable of adapting to the environment it inhabits. Its adaptability includes “learning” to circumvent the host organism’s defenses more effectively and developing resistance to the drugs used to treat the disease.

“It’s important to bear the parasite’s genomic plasticity in mind,” he said. “A species with a large repertoire of genetic variants and the ability to modify this repertoire swiftly is hard to control. That seems to be the case with P. vivax.”

Until the article was published only five complete genomes of P. vivax had been described – all in a previous paper also published in Nature Genetics in 2012. In the case of P. falciparum, more than 1,000 complete genomes are described in the scientific literature, according to Ferreira.

The 182 samples analyzed in this new study were collected from patients in 11 countries: Brazil, Cambodia, Colombia, India, Madagascar, Mexico, Myanmar, North Korea, Papua-New Guinea, Peru and Thailand. According to Ferreira, this covers all the geographies in which P. vivax is present.

The task force was coordinated by Jane M. Carlton, a professor at New York University in the US and head of a research center in India affiliated with the ICEMR program. ICEMR is funded by NIH through the National Institute of Allergy & Infectious Diseases (NIAID).

Ferreira belongs to a research center in the ICEMR network that studies malaria in the Amazon region of both Brazil and Peru. This center is headed by Joseph M. Vinetz, a professor at the University of California San Diego.

Ferreira contributed 20 samples collected in Acrelândia, a municipality in Acre State on Brazil’s border with Bolivia, during a research project supported by FAPESP.

Adaptation to vector

One of the conclusions presented in the article is that there is much more genetic diversity in a geographically restricted population of P. vivax, such as that found in the Amazon, for example, than in the global population of P. falciparum. This variability is measured by the quantity of polymorphisms, alternative versions of the same gene.

For Ferreira, there are two possible explanations for this phenomenon: either P. vivax’s mutation rate is higher than that of P. falciparum or the species has been adapting to human beings for a longer period and has accumulated a larger number of polymorphisms over many more years of evolution.

The bad news is that the more polymorphic genes (the ones with a larger number of alternative versions) are those that code for antigens, meaning they are responsible for expressing the proteins recognized by the immune system of the vector mosquito or human being that serves as the parasite’s host. According to Ferreira, this hinders the development of protective immunity.

Another conclusion of the study is that in the species P. vivax there is a clear divergence between parasites of the Old World (Africa, Asia and Oceania) and those of the New World (Latin America).

“When we look at the phylogenetic tree, we see a very clear split between the New World and Old World branches,” Ferreira said.

The researchers performed a series of analyses to discover where this distinction between the Old and New World was most evident. Their attention was drawn to Pvs47, a gene located in chromosome 12.

“The protein it codes for is associated with the parasite’s ability to escape the vector mosquito’s immune response,” Ferreira said. “So it’s expressed only in the sexual form of the parasite that infects the mosquito.”

The results of the sequencing, he went on, show that while there is a large variety of polymorphisms for the gene Pvs47 in Old World parasites, there is practically no variation in this gene in New World specimens.

“This finding points to the occurrence of a phenomenon we call selective sweep. When it arrived in the Americas, the species had to adapt to the vectors that lived in the region, and only parasites with a given polymorphism that enabled them to escape the new mosquito’s immune response survived,” he said.

Although malaria is transmitted by mosquitoes of the genus Anopheles in both the Old and New Worlds, the genus comprises many species. In Africa the most common are A. gambiae, A. funestus and A. arabiensis. A. sinensis stands out in Asia. In Brazil and its neighbors the most widespread species is A. darlingi.

“The selective sweep hypothesis relating to the gene Pvs47 was originally put forward for P. falciparum, but many scientists don’t believe a single gene is responsible for as complex a biological process as adaptation to a completely different vector. It’s likely that Pvs47 isn’t the only actor in this play and that other genes are involved,” Ferreira said.

Brazilian data

Besides the 20 Brazilian samples analyzed for the study described in Nature Genetics, the group led by Ferreira has sequenced the genomes of nine other samples collected in Acrelândia. The research is being conducted during Thaís Crippa de Oliveira’s master’s research, co-supervised by Ferreira and João Marcelo Alves Pereira, also affiliated with ICB-USP and a specialist in bioinformatics.

“Our goal is to explore in greater depth the position occupied by Brazil with respect to the other Latin American countries,” Ferreira said. “We’re comparing the Brazilian data with data for Colombia, Peru and Mexico that’s part of the work done by ICEMR. We plan to publish shortly.”

About 85% of malaria cases in Brazil are caused by P. vivax and the rest by P. falciparum, he added. Until the 1980s they each accounted for the same percentage but the control measures implemented since then have considerably reduced the number of cases caused by P. falciparum.

“P. vivax is harder to control, for reasons linked to its biology. The human host remains infectious to mosquitoes for longer and even if cured may have several relapses. Every time the parasite re-enters circulation, the individual becomes infectious again,” Ferreira said.

The article “Population genomics studies identify signatures of global dispersal and drug resistance in Plasmodium vivax” (doi: 10.1038/ng.3588) can be read at nature.com/ng/journal/vaop/ncurrent/full/ng.3588.html.