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Research advances in the search for new malaria treatments

Maíra Menezes (IOC/Fiocruz)

The search for malaria elimination is based on a combination of measures to treat patients and prevent the transmission of the disease. New research points out that a molecule investigated for cancer treatment may contribute to achieve this goal. In mice, considered a model for the study of cerebral malaria, the most serious complication of infection, the administration of the compound known as DON (6-diazo-5-oxo-L-norleucine) significantly reduced the presence of Plasmodium parasites in the blood, preventing animals’ deaths and blocking transmission to mosquitoes.

“The research shows that the compound interrupts the life cycle of the parasite. With treatment, the development of Plasmodium within the red blood cells [blood cells] is blocked. Therefore, the symptoms do not settle and the mosquito does not become infected by sucking the blood of the animals. These results point to the potential of DON as another force in combined therapies in search of an efficient intervention against malaria,” says Alexandre Morrot, researcher at the Oswaldo Cruz Institute's Immunoparasitology Laboratory (IOC / Fiocruz) and coordinator of the study.

Published on the scientific magazine Frontiers in Microbiology, the work was led by IOC in partnership with the Federal University of Rio de Janeiro (UFRJ). At IOC, in addition to the Immunoparasitology Laboratory, the Malaria Research, Molecular Biology and Endemic Diseases Laboratories also took part. The University of New York, in the United States, also collaborated with the study. The research was funded by the Oswaldo Cruz Foundation (Fiocruz), the National Council for Scientific and Technological Development (CNPq), the Carlos Chagas Filho Foundation for Research in the State of Rio de Janeiro (Faperj) and the Coordination for the Improvement of Higher Education Personnel (Capes).

Paralyzing process

Malaria-causing, the Plasmodium parasite goes through different stages in mosquitoes and vertebrate hosts - among them humans. The work shows that the compound DON paralyzes the development of the microorganism in the trophozoite form found in blood cells. In contact with the compound, most trophozoites do not reach the mature stage and those that reach this stage present severe morphological alterations. Since mature trophozoites are responsible for both asexual reproduction - capable of multiplying the number of parasites in the blood - and for the formation of gametocytes - sexual forms responsible for mosquito infection - the Plasmodium cycle is broken.

"The compound does not directly cause the death of parasites, but by limiting its reproduction, it prevents the onset of disease symptoms and allows the body to naturally eliminate the infection," Morrot explains.

The action of the compound on the parasite was observed in both cell culture experiments and mice tests. In animals, the reduction in the presence of Plasmodium in the blood was accompanied by the recovery of cerebral malaria, completely preventing mortality. By investigating the presence of parasites in the intestines of mosquitoes that bite mice, the researchers noted that the treatment reduced the vector infection rate to near zero.

Virulence factors

For the first time, the research pointed to the biochemical mechanism behind the effect of the compound on the infection. Experiments indicated that the substance DON inhibits a Plasmodium enzyme known as GFTP. According to Morrot, the activity of this enzyme is fundamental for the synthesis of a type of sugar that integrates the composition of molecules considered as virulence factors of the parasite, ie, that act in the process of cell infection and to circumvent the body's defenses.

“For example, the Plasmodium has a mechanism known as the immune system evasion. The defense cells identify certain proteins on the surface of the parasite and produce antibodies to act against them. Because Plasmodium has these targets anchored in molecules called glycolipids, which allow them to detach after being identified, antibodies cannot recognize the parasite,” says the researcher. "The sugar produced by the enzyme GFTP is essential for the composition of glycolipids as well as glycoproteins that are involved in the process of red blood cell invasion," he lists.

Expanded potential

In the focus of the work, DON is a chemical compound studied since the 1950s for its antitumor action and that, in recent years, has also been targeted by malaria research. Previous studies have indicated that the substance is capable of promoting the recovery of mice in the late phase of infection, when cerebral malaria is advanced. In this situation, the effect of the compound results mainly from the action on the immune system of animals. The therapy inhibits the excess of inflammation that aggravates brain damage, promoting symptoms improvement even before the presence of parasites in the blood is reduced.

By demonstrating the action of the compound in the early stage of infection, current work extends the potential of the substance against malaria. “The findings indicate that DON is able to act directly on the growth and differentiation of Plasmodium blood forms, in addition to attenuating the damage caused by the inflammatory response of the host. These characteristics suggest that the compound can contribute to the treatment of cerebral malaria cases and act as a transmission blocker, emphasizing its importance in the design of new therapies”, points out Morrot.

Cerebral malaria

Associated with changes in brain blood circulation, cerebral malaria is a complication with high lethality. The condition occurs only in infections caused by Plasmodium falciparum, one of the five parasite species that cause the disease. In addition to fever, the patients may present headache, neck stiffness, sensory disturbances, disorientation, drowsiness or arousal, convulsions, vomiting and even coma.

According to the last World Health Organization (WHO) report, in 2017, 219 million cases of malaria were accounted, with 435 thousand deaths. More than 90% of infections and deaths occurred on the African continent, where P. falciparum accounts for 99.7% of occurrences. In Brazil, the Ministry of Health informed that were reported 32 thousand cases of malaria between January and March of 2019, which represents a drop of 38% over the same period last year. Throughout 2018, the country accounted for 194 thousand cases of the disease. About 90% of infections in Brazil are caused by Plasmodium vivax, which is not associated with brain condition. The P. falciparum accounts for approximately 10% of records.

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