When it comes to evading the human immune system, the malaria parasite is a master of stealth. But a recent discovery could provide the means to blowing its cover.
A team of researchers—led by Prof. Alan Cowman, head of the infection and immunity division at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia—has found a way to exploit a weakness in the elaborate defense mechanism that the Plasmodium falciparum parasite erects after it has entered a human host.
Initially, the parasites invade the liver, where they multiply 10,000-fold. They’re safely hidden until they burst out and infect red blood cells. At this point they’re vulnerable because infected red blood cells are destroyed when they circulate through the spleen.
To protect themselves from that fate, the parasites deploy grappling hooks called PfEMP1 (plasmodium falciparum erythrocyte membrane protein 1) onto the outside of the red blood cells, latching them to the lining of the blood vessel wall. That sets off one of the most dangerous consequences of infection—the clogging of blood vessels in the brain.
But the PfEMP1 hooks are also malaria’s Achilles’ heel: They can be detected by antibodies. So, like a leopard that’s learned to change its spots, the parasite carries 60 varieties of grappling hook encoded by about 60 so-called var genes. Of the 60 genes, the parasite will employ just one at a time. Once the immune system locks on to the deployed grappling hook, all the parasites using it are destroyed. But 0.1 percent of the parasites have deployed a different var gene, and they survive to reseed the infection. It’s a successful strategy that operates like a genetic jukebox. Out of the entire repertoire only one gene plays at a time while the others stay silent.
Cowman and colleagues, however, have identified the control button that selects which var gene is to be played—an enzyme called PfSET10. Having access to this button gives researchers a chance to strip away the parasite’s stealth cover. For instance, if the 60 var genes were played simultaneously, the parasite would reveal all its disguises, allowing the immune system to destroy all of the infected blood cells.
The research could offer an urgently needed new lead for drug developers. Malaria kills more than one million people a year. Efforts to treat patients are hampered by the parasite’s ability to develop a resistance to drugs. But striking at the ability of the parasite to cloak itself would finally place it in the cross hairs of the immune system. Drugs that interfere with a cell’s ability to silence certain genes are already being developed for other diseases.
“We’ve got such cancer drugs on the shelf,” says Prof. Brendan Crabb, director of Melbourne’s Burnet Institute, which is renowned for its research and public health programs in virology and infectious disease. “This discovery is an important step in trying to develop them to treat malaria.”