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Researchers zero in on malaria’s lethal skill

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Outside the window of his lab, Manuel Llinás and Sharon Weeks, a senior molecular biology major, talk surrounded by images representing each stage of the Plasmodium's life cycle.

PRINCETON (US)—The parasite that causes malaria has a very deadly talent. By switching off an important amino acid in its quest to invade the human body, the parasite may trigger a more critical and lethal phase of the disease. The findings could pave the way to more effective Malaria treatments.

The researchers from Princeton University and the Drexel University College of Medicine who made the discovery believe that shedding light on this poorly understood aspect of malaria metabolism has given them new insights on the interactions between the parasite and its human hosts.

“The more we know about the parasite’s metabolic network, the more intelligent we can be about targeting therapies that will cure malaria,” says Kellen Olszewski, a graduate student at Princeton University and first author of the paper describing the work. The project was led by Manuel Llinás, an assistant professor of molecular biology at Princeton.

As a central part of the research, the scientists created a “metabolomic” profile of the parasite, Plasmodium falciparum to simultaneously measure the levels of the more than 500 core elements, or metabolites, that make up an organism’s “metabolic network.” The researchers were interested in seeing how the concentrations of metabolites in parasite-infected human red blood cells change over a single 48-hour “generation” of parasite growth. Scanning the data, the scientists noted that arginine levels dramatically dipped by the end of one 48-hour cycle.

“The parasite destroys this amino acid specifically and preferentially over all other amino acids,” Olszewski says.

Follow-up experiments showed that the parasite doesn’t break down arginine in order to grow, suggesting that this process serves some secondary function that helps P. falciparum proliferate within the human body. Arginine is an essential fuel for the human body’s immune system, which uses it to produce a molecule called nitric oxide that is highly toxic to foreign organisms. The parasite-led attack on arginine may be an attempt by the parasite to “switch off” a human immune function that might threaten its survival, the researchers said.

Scientists are interested in studying the metabolism of P. falciparum to understand how organisms adapt to a parasitic lifestyle. Understanding this is important because many of the drugs used to treat malaria successfully in the past have targeted some aspect of the parasite’s metabolism.

“Designing the next generation of anti-malarial drugs will likely require a detailed knowledge of the ‘weak points’ in the parasite’s metabolic network,” Llinás says.

According to the World Health Organization, some 350 to 500 million people are infected with malaria every year by mosquitoes carrying one of the four human malaria parasites. The P. falciparum infections are by far the most deadly, killing more than 1 million people each year, mainly young children and pregnant women. The disease, which can incapacitate a victim for several weeks, also imposes a massive social and economic burden. People living in endemic areas can be infected up to several times a year. About 60 percent of the cases of malaria worldwide and more than 80 percent of malaria deaths occur in sub-Saharan Africa.

Stanford University news: www.princeton.edu/main/news

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