Blood group antigen polymorphism affects susceptibility to malaria, study says

USP scientists participated in a study that was published in the Proceedings of the National Academy of Sciences

By Fábio de Castro

Agência FAPESP – The receptors known as Duffy antigens play an integral role in the process by which Plasmodium vivax – a common malaria parasite – invades red blood cells, where the parasite multiplies during its life cycle.

According to an international study in which Brazilian scientists participated, a polymorphism in the Duffy antigen on the surface of red blood cells affects individuals’ susceptibilities to malaria caused by P. vivax.

The study, published in the Proceedings of the National Academy of Sciences (PNAS), was performed by scientists from Cleveland University, the University of South Florida in Tampa (both in the U.S.), Oxford University in the United Kingdom and the Institute of Biomedical Sciences of Universidade de São Paulo (USP).

Participating in the study were Marcelo Urbano Ferreira, Professor of Parasitology at ICB-USP, and Monica da Silva-Nunes, a professor in the Department of Health Sciences and Physical Education at the Universidade Federal do Acre. Silva-Nunes’s doctorate research was funded by FAPESP and was performed under the guidance of Ferreira.

Today, Ferreira coordinates three FAPESP-funded projects under the Research Support-Regular program. These projects are “Population dynamics of Plasmodium vivax polymorphisms in rural Brazilian Amazonia,” “Chloroquine resistance in Plasmodium vivax: molecular and phenotypic assessment in the western Brazilian Amazon” and “Phenotypic and functional characterizations of CD4+ T lymphocyte populations with possible immunoregulatory function in human malaria.”

Malaria is one of Brazil’s main endemic parasites, with 460,000 clinical cases reported in the Amazon region in 2007. P. vivax is the most common cause of malaria outside Africa, especially in Asia and the Americas. P. falciparum, whose genome was sequenced in 2002, causes the most serious form of the disease.

According to the study, the public health threat posed by P. vivax has increased more than that associated with P. falciparum. Plasmodium vivax is the only malaria parasite whose red cell invasion is almost entirely dependent on the receptors located on the surface of the blood cell known as Duffy antigens (Fy).

According to the study, Fy has two distinct immunological variants, A and B, which are encoded by alleles referred to as Fya and Fyb. These two alleles differ by a single mutation. Although the Duffy antigen is the receptor that allows for the invasion of cells by the parasite, the scientists say that until now it had not been determined whether this polymorphism affects the clinical susceptibility to malaria caused by P. vivax.

In the study, the scientists show that, relative to Fyb, Fya significantly diminishes the connection between the parasite and the surface of the red blood cell and is therefore associated with a reduced risk of malaria caused by Plasmodium vivax.

The red blood cells expressing Fya have binding capacity that is 41% to 50% lower than that of Fyb-expressing cells. According to Ferreira, the relationship between the Duffy antigen and the susceptibility to malaria was discovered in the 1970s during the Vietnam War.

“Both vivax and falciparum were present in the region, but one fact stood out: the Caucasian soldiers contracted infections from both species, and the African-Americans almost never contracted the vivax malaria. As it was known that the Plasmodium invades red blood cells, the hypothesis soon came up that in the African-American population, some of these cells avoided invasion by the parasite,” Ferreira told Agência FAPESP.

He said that, in the 1970s, it was discovered and proven that Duffy antigen-negative individuals are resistant to the infection by P. vivax.

“It was known that in East Africa, most people are Duffy negative and others are generally Fyb. But in Asia, nearly everyone is Fya. There is a more balanced mix of Fya and Fyb in the European populations. Until that time, it was thought that what determined greater susceptibility was to have the Duffy positive phenotype, and that it didn’t matter if it was Fya or Fyb,” he explained.

Puzzle

The new study indicates that there is a difference in the level of susceptibility to malaria between Fya- and Fyb-expressing individuals. This difference is the result of the parasite’s ability to interact with Fyb in a more efficient manner than with Fya.

This discovery impacts widely accepted hypotheses in the field of population genetics. According to Ferreira, it was always believed that Plasmodium vivax was the selective factor that assured fixation of the Duffy-negative phenotype in Africa.

“The hypothesis was that, given the resistance to vivax, the Duffy negative phenotype was advantageous on the African continent. But there are some flaws in this line of reasoning. One is that the malaria transmitted by vivax isn’t such a serious disease,” he said.

Another point contradicting the hypothesis according to Ferreira is that vivax originated from Asian monkey parasites and that human parasites also arose on that continent.

“It would make no sense for a parasite to originate in Asia and much later arrive in other continents and select a resistant phenotype in Africa but not in Asia, where they had lived together with humans for a much longer time,” he declared.

According to Ferreira, the new study points to a solution to the puzzle: the ancestral type would be Fyb. In Africa, a mutation would have been selected but not one in the Fy promoter region.

“So, what we call Duffy negative is an individual that is Fyb in the gene codifying region. Duffy negative, which is found in Africa, would be an Fyb with a mutation in the promoter region. In other words, the individual doesn’t express the Fyb protein on the red blood cell. And the Fya, a mutation in the gene codifying region, would have been selected in Asia,” he explained.

“According to the study, what probably happened is that in Asia selective pressure from vivax selected Fya, while in Africa another mutation would have been selected, this one in the gene’s promoting region, resulting in the Duffy negative phenotype.”

The article Fya/Fyb antigen polymorphism in human erythrocyte Duffy antigen affects susceptibility to Plasmodium vivax malaria by Marcelo Urbano Ferreira, Mônica Nunes and others can be read by PNAS subscribers at www.pnas.org.