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Malaria Cure Step Closer With Discovery Of Parasite's Cloaking Device

A team in Israel believes the hope of a cure for malaria is a step closer after discovering a genetic cloaking device that the parasite uses to evade the immune system and establish infection. They suggest a treatment that interferes with the DNA of the cloaking device could give the immune system a chance to clear the infection.

Ron Dzikowski and colleagues from The Hebrew University-Hadassah Medical School in Jerusalem write about their findings in a paper that was published online ahead of print in the Proceedings of the National Academy of Sciences, PNAS on 29 November.

''These results are a major breakthrough in understanding the parasite's ability to cause damage," Dzikowski says in a press statement.

"This clever parasite knows how to switch masks to evade an immune attack, but our discovery could lead to new ways to prevent it from continuing this dangerous game," he adds.

Malaria Parasite Plasmodium Every year, more than a million people die from malaria, an infection caused by five different strains of Plasmodium, a parasite that lives in the gut of the female Anopheles mosquito and passes to humans through her bite. The disease mostly affects pregnant women and children under 5 and there is currently no effective vaccine.

Once it enters the bloodstream, the parasite survives thanks to its ability to modifiy red blood cells. It reproduces in the cells and sends proteins to their surfaces, causing them to become sticky and cling to the walls of blood vessels. Eventually the blood vessels clog up and damage the body.

In the meantime, cells of the immune system have spotted the foreign proteins and sent signals to make antibodies and mount an attack. But while this is happening, the parasite is busy organizing its cloaking device that will help it evade the immune system and re-establish infection. Sophisticated Genetic Cloaking Device For this study, the researchers looked at Plasmodium falciparum, the parasite strain that causes more than 90% of deaths linked to malaria.

P. falciparum's cloaking device is very sophisticated: although it has several proteins capable of causing havoc in the red blood cells, it only reveals one of them to the host immune system.

Except, while the immune cells are busy fighting the revealed protein, the parasite switches to another one that the immune system has not yet recognized.

The parasite has 60 different proteins to play with, and so presumably can continue this game of of cloak and dagger for quite a while, at least long enough to establish infection.

Dzikowski and colleagues were able for the first time to locate the genetic mechanism that the parasite uses to selectively express one protein while hiding the others. Unique DNA Sequence Using a combination of bioinformatic and genetic techniques, they identified a unique DNA sequence in the gene family that codes for these surface proteins. The DNA sequence is located in the regulatory regions of the genes.

"Antigenic variation is achieved through tight regulation of antigenic switches between variable surface antigens named 'P. falciparum erythrocyte membrane protein-1' encoded by the var multicopy gene family," they write.

They showed that individual parasites rely on this DNA sequence to express only one of the 60 genes at its disposal at a time, while hiding the rest (or keeping them in a "transcriptionally silent state").

"This understanding could lead to strategies for disrupting this ability and giving the immune system an opportunity to clear the infection and overcome the disease," suggests Dzikowski.

Funds from the Israel Academy of Sciences and Humanities and the Einstein Kaye Fellowships, which supports outstanding research students, helped finance the study.

In a July 2012 issue of PNAS, researchers led by the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland in the US, also suggested a genetic solution to foil the malaria parasite: they modified the mosquitoes "friendly" gut bacteria so they produced toxins that are deadly to the parasite but harmless to humans and mosquitoes.

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