New discoveries in the battle against a world-renowned microscopic killer
The malaria parasite is rendered barren when the transport of heavy metals such as copper and iron is blocked. This is the conclusion reached by malaria researcher Taco Kooij, Dept. of Medical Microbiology, theme Infectious diseases and global health and international colleagues in a study published in Nature Communications. In addition, the researchers identified six proteins that are essential to the life stages of the parasite in which it sickens its host. They also discovered a gene that is essential for the parasite to settle in its host. This study provides clues for new malaria drugs and vaccines.
Every year, nearly half a million people die from the effects of malaria, mostly children up to the age of five. Worldwide, more than 200 million people become sick. Resistance against existing resources is a major problem and there is still no effective vaccine on the market. Finding new targets for malaria medication is therefore crucial. Taco Kooij and his colleagues describe three of them.
Complex life cycle
One of the reasons why malaria is such a big problem is the complex life cycle of this parasite. The parasite waits in the salivary glands of a female mosquito until the mosquito bites a human. That’s when it enters the human bloodstream and ends up in the liver. This is where it divides and matures. Daughter parasites enter the bloodstream and invade red blood cells, where the division and maturation continues. When the red blood cells burst open, the released parasites penetrate new red blood cells. At this point the patient becomes sick, often developing a fever and headaches. Male and female reproductive cells of the parasite are also being created during the maturation. When a new mosquito bites the patient, it extracts these reproductive cells and fertilization takes place in the mosquito’s stomach. The young offspring crawl to the salivary glands of the mosquito and the cycle begins again.
Transport proteins ensure the transport of nutrients and waste and are therefore crucial for the survival of cells. Because of their function, they form one of the primary targets for drugs against various diseases. In the case of malaria, few of the major transport proteins are known. One of the best known medications for malaria is chloroquine, which inhibits the breakdown of nutrients for the parasite. However, parasites are becoming increasingly resistant to this drug. Kooij and his colleagues investigated the role of 35 transport proteins on the cell membrane of the parasite. “To determine their function, we created several genetically crippled parasites, each time switching off a different gene,” says Kooij. They followed these parasites through their entire life cycle, beginning in mice and then via mosquitoes back to uninfected mice. “This is how we discovered, among other things, a mutation that prevents the parasite from going beyond the liver. A vaccine containing these crippled parasites provides a safe method for immunizing an individual against malaria. The vaccine that is currently in development is based on the same principle. A combination of this new mutation and the old one may be safer because it reduces the chance of a parasite escaping and completing its life cycle.”
The researchers also discovered six transport proteins that are essential at the stage where the parasites make people sick. These proteins provide a breakdown of nutrients. Kooij: “If we could develop a drug that blocks these proteins, the parasite would not get enough nutrients and the infected person would not become ill.” A final important finding is that the malaria parasite becomes infertile when the transport of heavy metals such as copper and iron is blocked. “With mutations in the genes involved, we saw that the parasite was unable to produce reproductive cells, or only produced infertile cells. This blocks the movement of parasites from the mouse to the mosquito. This also provides potential targets for medication, because it will prevent further spread of the disease.”
Sanketha Kenthirapalan, Andrew P. Waters, Kai Matuschewski& Taco W.A. Kooij, Functional profiles of orphan membrane transporters in the life cycle of the malaria parasite, Nature Communications; ncomms10519
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