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Hidden aggressiveness

Team from Unicamp overturns the idea that there is a mild form of malaria

FABIO COSTA / UNICAMPPlasmodium vivax infects blood cells FABIO COSTA / UNICAMP

Long considered an aggressive little parasite, Plasmodium vivax can, in fact, cause serious complications, in addition to the violent bouts of fever that characterize all types of malaria. At the head of an international team, parasitologist Fabio Trindade Maranhão Costa, from the Institute of Biology, of the State University of Campinas (Unicamp), now explains why. Plasmodia vivax have the capacity to adhere to a sick person’s cells, causing damage so far attributed only to its infamous relative, Plasmodium falciparum.

The team identified this characteristic using parasites freshly removed from the blood of patients in the hospital of Tropical Medicine Foundation of Amazonas, in Manaus, and did tests using cells from human lungs and the brain of common squirrel monkeys, both kept in culture, in addition to sections collected from human placenta after delivery. The results of these experiments, published in the Journal of Infectious Diseases, show that P. vivax parasites stick to cells even when subjected to a flow of liquid, simulating the situation they face within a blood vessel. This is probably the explanation for the reports, which have been increasingly common over the past 10 years, of complications, such as lung problems or seizures, in cases of vivax infection.

“There is no such thing as a benign parasite,” Costa pronounces. Although it makes sense to think that an organism that infests another always causes some ill effects, until quite recently, Plasmodium vivax was not taken very seriously. It does not have on its surface the structures, called knobs, features of P. falciparum and considered essential for the microinvader to anchor itself to human cells and leads to an inflammatory process that damages tissue and can lead to death, or an abortion when the infected person is a pregnant woman.

There was also another reason why researchers did not suspect that the Plasmodium vivax adheres to cells; they did not observe the phenomenon called sequestration; the disappearance of adult parasites during the second half of their life cycle. Sequestration is already well known in falciparum: the parasites do not appear in the blood because they are stuck to the inner lining of blood vessels, the endothelium. As the blood of people infected with vivax has adult parasites at any stage in the life cycle, until now it was considered to be less aggressive.

The researchers became accustomed to these indirect indications because of a technical difficulty that is by no means trivial. Since the 1970’s, parasitologists have been able to cultivate colonies of P. falciparum, which reproduce and maintain their capacity to infect, in human erythrocytes in the laboratory. But vivax is more demanding and refuses, even today, to live under artificial conditions.

Costa overcame this adversity by using parasites recently collected from patients and discovered that the plasmodia vivax adhere to endothelial cells, but about 10 times less than falciparum. But, once they adhere, both types of plasmodium have the same ability to remain glued to the cells. “We don’t know exactly how vivax adhere, but seems to be related to genes called vir, a highly variable gene family in plasmodia,” says the parasitologist from Unicamp.

As the parasite does not adapt to laboratory conditions, it is only possible to do this work in endemic regions; in Brazil, the ideal place is Manaus, where many of the patients from the Amazon region are treated. For this work, Costa had the collaboration of two local colleagues: physician Marcos Lacerda from the Tropical Medicine Foundation of Amazonas, and Paulo Nogueira, from the Oswaldo Cruz Foundation. “Without them, the work wouldn’t have been possible,” says the researcher from Unicamp, who intends investing his research funding in improving working conditions in Manaus. The next steps in the research will demand an adequate infrastructure for more sophisticated biological trials. In Manaus Costa also expects to examine tissue samples from patients who died because of malaria and develop methods for studying the inflammatory processes triggered by vivax in vitro.

Understanding the functioning of Plasmodium vivax has a huge potential impact in public health. Around the world 2.85 billion people – most of them in Asia – run the risk of being infected by this parasite species, which is responsible for 85% of malaria cases in Brazil. “And this proportion is increasing,” adds Costa. The worrying thing is that the variety of vivax predominant in the country is already beginning to show signs of resistance to anti-malaria drugs, such as chloroquine. Analyzing the blood of people with malaria in the Amazon, the team of Dr. Marcelo Urbano Ferreira, from the University of São Paulo (USP), found that there is great diversity among the variants of vivax existing in Brazil, which are clearly distinct from those found, for example, in Asia. These findings may help explain the resistance to antimalarial drugs in some of the areas in which this form of malaria occurs.

For the time being, at least, the discovery of the Campinas group does not point directly to new drugs, and there is no efficient medication that acts directly against adhesion in falciparum, although the process is already well known. But the researcher does not discard the possibility that, by studying these mechanisms in vivax, above all when it is possible to study them in vivo, perhaps in monkeys, should lead to knowledge that will help in combating the disease. “It’s breaking a paradigm that’s going to open up huge research possibilities; we’ll begin to see the pathogenesis caused by this parasite in different ways,” predicts Costa.

Until it is discovered how to prevent the adhesion of plasmodia to the cells of the endothelium and placenta, the answer is to seek more efficient strategies for combating the insects that transmit them to humans, like the one recently prepared by Marcelo Ferreira’s group. Over a period of years, Ferreira’s team examined all the houses in the community of Granada, in eastern Acre, and found that just 22% of them accounted for 70% of the cases of the disease. The application of insecticides in 25% of the houses, particularly those that function as a focus of transmission, would already reduce cases of malaria by two thirds, according to a study by Dr. Natal Santos da Silva from Ferreira’s team, which was published in May in the Transactions of the Royal Society of Tropical Medicine and Hygiene. “We hope we have contributed evidence to help plan new interventions for controlling malaria-carrying mosquitoes,” says Ferreira.

The projects
Evaluation of the protective mechanisms of hyperbaric oxygenation (HBO) in experimental cerebral malaria and in parasitic cyto-adherence (nº 2009/08728-8); Modality Regular Research Awards; Coordinator Fabio Trindade Maranhão Costa – IB – Unicamp; Investment R$ 345.124.00 (FAPESP)
2. Population dynamic of polymorphisms of Plasmodium vivax in rural Brazilian Amazon regions(nº 2010/50333-8); Modality Regular Research Awards; Coordinator Marcelo Urbano Ferreira – USP; Investment R$ 347.436.27 (FAPESP)

Scientific articles
CARVALHO, B.O. et al. On the cyto-adhesion of Plasmodium vivax-infected erythrocytes. Journal of Infectious Diseases. no prelo.
DA SILVA, N.S. et al. Epidemiology and control of frontier malaria in Brazil: lessons from community-based studies in rural Amazonia. Transactions of the Royal Society of Tropical Medicine and Hygiene. v. 104 (5), p. 343-350. May 2010.