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A parasite with multiple identities

A variety of Plasmodium vivax found in the Americas has accumulated genetic alterations that distinguish it from African and Asian strains

Slides of blood from patients infected with malaria caused by Plasmodium vivax

Eduardo Cesar Slides of blood from patients infected with malaria caused by Plasmodium vivaxEduardo Cesar

The varieties of Plasmodium vivax that circulate in the Americas today are quite different from those found in Africa and Asia, according to an international team of researchers, one of whose members is parasitologist Marcelo Urbano Ferreira of the Institute of Biomedical Sciences at the University of São Paulo (ICB/USP). In a study published in the journal Nature Genetics in June 2016, the team suggests that this parasite, which causes the most common form of malaria outside of Africa, has accumulated genetic mutations since its arrival in the Americas that may have helped it adapt to the new environment and bypass the defense mechanisms of its hosts and main vectors, mosquitoes of the genus Anopheles.

Led by biologist Jane Carlton of New York University, the team analyzed genetic material from 182 samples of the parasite obtained in 11 countries of Africa, Asia, and Latin America. Brazil contributed 20 samples, which were collected in the town of Acrelândia, Acre State, near the Bolivian border. Relying on a technique called hybrid selection, the researchers isolated the protozoan’s genetic material from the blood of infected individuals. The samples were sequenced and then compared to each other. The researchers found that the strains of P. vivax originating in African and Asian countries differed sharply from those originating in Latin American countries, from a genetic perspective.

P. vivax is the culprit behind some 16 million of the 214 million cases of malaria that occur worldwide each year. In Brazil, it is estimated that the species accounts for 85% of the 300,000 cases of the disease reported annually in the Amazon. ​Although malaria is considered a serious public health problem in many countries, few studies have been conducted to date on this particular causal agent. This is partly because it is nearly impossible to grow this species of Plasmodium in the laboratory to investigate its biology. P. vivax is not fatal and supposedly is not drug resistant. In recent years, however, cases have surfaced of people who were diagnosed with malaria caused by P. vivax and who presented complications and, in some cases, died. Since the 1990s, reports on the parasite’s resistance to the drug chloroquine – the world’s most commonly used antimalarial medicine – have also been on the rise in various regions of Latin America.

In Acrelândia, Acre, researchers draw blood to diagnose residents presenting symptoms of malaria

Alessandra FratusIn Acrelândia, Acre, researchers draw blood to diagnose residents presenting symptoms of malariaAlessandra Fratus

According to Ferreira, who has spent a number of years researching possible mechanisms of resistance to antimalarial drugs in the Amazon, the findings released in Nature Genetics help explain these phenomena. “This broader repertoire of genetic variants enhances the ability of P. vivax to adapt to the environment in which it lives, and this includes learning how to bypass the defenses of the host organism and develop resistance to the drugs used to treat the disease,” he explains. This means that no vaccine or antimalarial drug would be completely effective in controlling the parasite at present.

Process of adaptation
The study’s researchers also found that the genes that displayed more alternative versions – that is, polymorphisms – were the ones responsible for producing the proteins that are recognized by the immune system of the host, whether the latter is a mosquito or a human. It is therefore likely that the only parasites that survived the move to the Americas were those that had a broad enough variety of genes that they could evade the immune response of the region’s mosquitoes, which differ sharply from the ones circulating in countries of Africa and Asia.

Another valuable finding was that the genomic variability of P. vivax is much greater than that of P. falciparum, the prevalent species in Africa and the one responsible for the most aggressive, fatal form of malaria. “There are many more polymorphisms in a population of P. vivax in the Amazon than in the entire population of P. falciparum worldwide,” says the parasitologist. Researchers have yet to discover why this is, but they have a few hypotheses. One is that the P. vivax genome has less efficacious mechanisms of mutation repair. Another possibility is that P. vivax and P. falciparum accumulate mutations in similar fashion and that the former has acquired more alterations over time because it is an older species.

Malaria_03_290Alessandra FratusIt is also impossible to say exactly when P. vivax reached the Americas. According to Ferreira, the protozoan probably came over with European colonizers and their slaves. In this case, he explains, the parasite’s life cycle may have played a crucial role in its survival during the crossing. In the human body, the protozoan first settles in the liver cells, where it matures and multiplies before moving into the bloodstream. While still in the liver, some specimens of P. vivax enter a state of dormancy, characterized by reduced metabolic activity. “The parasite can remain in this stage for months, until it awakens, multiplies, and spreads through the blood.” This would give it enough time to cross the Atlantic and reach the new continent fully active.

Another hypothesis raised by researchers is that a portion of the parasites circulating in the Americas descend from specimens that came over from eastern Asia more than 10,000 years ago, accompanying the first wave of human migration.

Ferreira is now working with Thaís Crippa de Oliveira, his master’s advisee, to sequence nine other samples of P. vivax obtained in Acre. The researcher wants to use them to examine differences and similarities between P. vivax and strains from other regions of the Americas, like Columbia, Peru, and Mexico. “We intend to develop genetic markers of resistance to chloroquine and compare our laboratory data with information gathered in other regions about reports of the parasite’s resistance to the drug,” he says in conclusion.

Chloroquine resistance in Plasmodium vivax: phenotypic and molecular evaluation in Brazilian Western Amazon (nº 2010/51835-7); Grant Mechanism: Regular research grant; Principal Investigator: Marcelo Urbano Ferreira (ICB-USP); Investment: R$103,417.00.

Scientific article
HUPALO, D. N. et al. Population genomics studies identify signatures of global dispersal and drug resistance in Plasmodium vivax. Nature Genetics. June 27, 2016.