The identification of a new target for fighting Leishmaniasis

An enzyme from a metabolic pathway of the parasite that causes the disease could be a target for new medications that would impede Leishmania growth and infection in humans.

By Elton Alisson

Agência FAPESP – Pentavalent antimonial drugs are considered to be expensive, toxic and ineffective in the current treatment of leishmaniasis, which is a chronic disease caused by protozoan parasites from the genus Leishmania.

Leishmaniasis is considered a “neglected disease” by the World Health Organization (WHO) because it affects poor populations in developing countries and therefore does not receive significant attention from the pharmaceutical industry.

A study performed by researchers at the Universidade de São Paulo Institute of Biological Sciences Physiology Department (IB-USP) and the University of Washington (U.S.) Medical School’s Molecular Microbiology Department could contribute to the development of new medications to prevent the parasite that causes the disease from infecting and proliferating in humans.

The researchers showed for the first time that the localization of the arginase enzyme to the glycosome—organelles exclusive to the trypanosome family, to which Leishmania belongs—is critically important. The arginase enzyme and glycosomes may be potential targets for preventing growth of the protozoa.

The results of the study, which was funded by FAPESP through a Thematic Project, were published in PLoS One.

The results were also presented during the 64th annual Meeting of the Brazilian Society for the Progress of Science (SBPC), which was held from July 22-27 on the campus of the Universidade Federal do Maranhão (UFMA) in São Luís.

In recent years, this group of USP researchers has dedicated itself to understanding how the parasite that causes leishmaniasis interacts with humans and identifying the materials that it uses to ensure its survival when it infects a host.

One of the key proteins identified by these researchers is arginase, a metabolic enzyme in Leishmania that is fundamental for growth of the parasite and is compartmentalized in its glycosomes.

This research, carried out in collaboration with the scientists from the United States, showed that the localization of arginase to the glycosome of Leishmania amazonensis is important for its activity and enables the parasite to infect a host.

“We showed that the location of the arginase is important for the cellular physiology of the parasite,” said Lucile Maria Floeter-Winter, the project coordinator and professor at the IB, in an interview with Agência FAPESP.

According to Floeter-Winter, the findings from this study open the possibility of interfering in the cycle of the disease, for example, by using a new medication that can inhibit the enzyme to interrupt infection.

“The most significant discovery in this study was the importance of the location of arginase, which is an important target for inhibiting parasite growth in mammals,” said Floeter-Winter.

Inhibiting arginase

The leishmaniasis parasite is transmitted to humans by insect vectors known as Phlebotominae, such as the sand fly. Upon biting a mammal to feed on its blood, the sand fly injects protozoa into the host in its promastigote (flagellate) state.

To combat the parasite, humans and other infected mammals recruit blood cells known as macrophages to intercept the protozoa. However, the Leishmania manage to multiply themselves inside the macrophages.

When they burst, the macrophages release these cells in their amastigote state (without a flagellum), and the amastigotes migrate through the body in search of a tissue where they can multiply and establish themselves. When a phlebotomine sand fly bites an infected human or animal, the fly becomes infected by the parasite, continuing the disease cycle.

According to Floeter-Winter, to be more effective than the treatments used today, a new drug to fight leishmaniasis must be able to reach its target during all stages of the parasite’s development.

“This enzyme is compartmentalized inside of the glycosome of the amastigote form of the parasite, inside the phagolysosome (the lysosome that performs phagocytosis) and inside the macrophage, so a new drug or medication for leishmaniasis should be able to inhibit arginase in all these sites: it must be able to cross the membrane of the macrophage, the phagosome, the parasite and the glycosome. This is an arduous path,” she said.

The article “Leishmania amazonensis arginase compartmentalization in the glycosome is important for parasite infectivity” (doi: 10.1371), by Floeter-Winter and colleagues was published in PLoS One and can be read online at: www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0034022.