Malaria's Master Key

The most dangerous malaria parasite, Plasmodium falciparum, is an unusually versatile bug. The single-celled safecracker carries a wide collection of protein "keys" that it can use to jimmy receptor "locks" on the surface of red blood cells, tricking the cells into letting it in. Block one of these entry points with a drug, and the parasite just uses a different key.

But now, researchers believe they may have found a master key that the parasite uses—a surface protein without which it's unable to invade blood cells. The researchers hope the finding will help them design a new malaria vaccine.

Such a vaccine has been "a difficult nut to crack," Gavin Wright of the Wellcome Trust Sanger Institute in Cambridge, U.K., said at a press briefing about the study in London on Monday. Not only does P. falciparum have numerous keys—scientifically known as ligands—at its disposal, figuring out which ligand key interacts with which of the hundreds of receptors on a cell's surface is a challenge. And it's difficult to study in the lab because ligands bound to receptors quickly rip apart when scientists put them through the chemical washes and treatments needed to identify them.

So, along with malaria researcher Julian Rayner, also of the Sanger Institute, Wright's group developed a chemical treatment that stabilizes the receptors and ligands so that they will remain stuck together longer for researchers to study. When they used this method to look at one of P. falciparum's known "keys," a surface protein called PfRh5, the researchers saw that it interacted with a receptor protein called basigin, sticking off the surface of red blood cells. Using mutated stem cells, the researchers made red blood cells that lacked basigin and discovered that P. falciparum was completely unable to invade. Covering basigin with antibodies also blocked the parasite from getting in.

The researchers tested 15 different strains of P. falciparum, taken straight from malaria patients, and found that none of them were able to invade red blood cells if basigin was unavailable. This makes the interaction between basigin and PfRh5 a promising target for a vaccine, the team reports online today in Nature. Injecting the protein PfRh5 into patients could kick-start the immune system into making antibodies against PfRh5 and prepare for infection by an actual pathogen. The vaccine is still a long way off, the researchers said at the press conference, but they have already found that PfRh5 is easy to produce in large quantities, which is a major hurdle for some vaccines.

"It's a very nice paper," says molecular parasitologist Alan Cowman of the Walter and Eliza Hall Institute of Medical Research in Parkville, Australia. The interaction between basigin and PfRh5 is clearly far more important than other interactions discovered so far, he notes. But as far as a vaccine goes, Cowman says Plasmodium could become resistant against it by finding new entry routes. To prevent that from happening, "my feeling is that [injecting PfRh5] needs to be in combination with other proteins. I'd be wary of using one by itself."

Rayner agrees that a vaccine based on PfRh5 could be used together with others, such as the modestly successful RTS,S vaccine currently being tested by GlaxoSmithKline, which targets the pathogen at a different stage in its life cycle.

Tune in Thursday, 10 November for a live web chat on malaria vaccines.