Scientists in Australia have discovered that the malaria parasite, Plasmodium falciparum has the ability to switch off certain genes so that the immune system cannot recognise it and initiate action to fight it off.
The findings point to the possibility of developing drugs, which target this mechanism, providing a new method of treating malaria by unmasking its molecular disguise and enabling the body's defences to destroy the parasite.
The study revealed that throughout its lifetime, P. falciparum continually changes the version of a protein known as PfEMP1 that it deposits on the surface of infected cells. By the time the immune system learns to recognise the protein and starts making antibodies against it, the parasite has switched to another form of the protein, and the process starts over.
Previous research done during the mid-1990's discovered the existence of more than 50 "var" genes, which produced different versions of the PfEMP protein. However, only one is active at any one time. Over the course of an infection, expression switches from one var gene to another, a phenomenon that until now, scientists have not understood.
Alan Cowman, one of the lead authors of the study said: "If you could work out a way of causing the parasite to switch all the var genes on, then the body would see all the variations of var genes, and the immune system would be able to control the infection."
In addition, the researchers found that SIR2, another protein, seemed to determine which var gene was active and which were switched off. This protein effectively wraps the DNA of the inactive var genes into tight packages that prevent them from forming proteins and having an effect.
To assess whether a region of DNA containing a particular var gene was active or silent, the scientists measured expression of a gene they artificially inserted adjacent to var in a population of parasites. The introduced gene encoded resistance to a drug.
When the researchers exposed the parasites to that drug, they found that gene silencing was at work. In some parasites, the DNA region was active, and the parasites showed resistance to the drug. In other parasites, the region was not being transcribed, and the drug successfully blocked the biochemical reaction it is meant to block.
After examining the regions around the silent and active var genes, the researchers found differences in the way that the DNA was packaged, some of the DNA was wrapped so tightly with proteins that it ceased to be accessible for transcription. This finding implicated the SIR2 protein, which was previously known to play a role in gene silencing in yeast by modifying gene packaging.
"Silencing occurs by packaging up the DNA into a tight form and preventing it from being expressed. That tight packaging involves SIR2," said Cowman. "The question then was how one of those genes is switched back on."
Cowman said that a better understanding of the process could lead to the design of drugs that give the immune system a good look at all the PfEMP1 proteins it might encounter. This would enable the production of antibodies to fight off malaria at an early enough stage to prevent the worst effects of the disease.
Malaria, which rivals HIV/Aids as the world's most deadly infectious condition, is estimated to kill as many as 3 million people are every year and as many as 300 million cases are reported each year, mostly in tropical areas of South America, Africa and Asia. Victims experience chills, fever and sweating. If left untreated, the parasite can cause kidney and liver failure, coma and death.
The findings are published in the April 8, 2005, issue of the journalCell.