Protection. A mutation that’s common among the Papua’s of New Guinea prevents the malaria parasite from infecting red blood cells (inset).

Malaria’s Plan B for Infection

Researchers have discovered that a gene variant in humans, common in Papua New Guinea, confers protection against malaria. At the same time, others have shown that the malaria parasite has multiple ways to elude this type of defense, casting doubt on efforts to find a simple vaccine against the disease.

Plasmodium falciparum causes malaria by invading red blood cells, reproducing inside, and then breaking the cells open to release a new brood of parasites. To gain entrance, the parasite fits a protein on its outer membrane into a receptor protein on the blood cell's surface, like a key in a lock. Researchers knew about one such key-lock combination, and last year, several groups identified a second possible "key" protein, called BAEBL or EBA140. Studies suggested its corresponding "lock" might be a blood cell receptor called glycophorin C.

In the January issue of Nature Medicine, parasitologist Alan Cowman at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, and his colleagues show that EBA140 does indeed bind to glycophorin C. What's more, when they added antibodies to EBA140 to a mixture of parasites and red blood cells, the antibodies clung to the protein, preventing the parasites from making their sneaky entrance.

Cowman points out that epidemiological work also seems to support a role for EBA140. In Papua New Guinea, an area rife with malaria, nearly half the population have a mutated version of glycophorin C, which makes them resistant to the disease. The researchers showed that antibodies against EBA140 did not inhibit the parasite's entry into cells with the mutated glycophorin C, suggesting the parasite cannot use EBA140 to latch onto the altered receptor.

Meanwhile, malaria researcher Louis Miller of the National Institute for Allergy and Infectious Diseases in Bethesda, Maryland, and his colleagues studied variation in the part of EBA140 that binds to the red blood cell. In parasite samples taken from around the world, they found four slightly different versions of the protein, only one of which binds to glycophorin C; the other three had as-yet-unknown targets, the team reports in the 2 December issue of the Journal of Experimental Medicine. Apparently, small changes in the protein can lead to whole new ways of entering cells, the researchers say--which would help the parasite elude mutations like the one that's frequent in Papua New Guinea.

"The two papers complement each other very well," says malaria researcher Peter Preiser of the National Institute for Medical Research in London. And together, he says, they dash any hopes of developing a simple vaccine that blocks the parasites' entry. "There's not going to be one magic protein you vaccinate with that's going to solve all malaria problems." Instead, he says, researchers will have to uncover all of Plasmodium's routes into the cell and develop combination vaccines.

Related sites
Cowman's research
Miller's paper in the Journal of Experimental Medicine
More information on Plasmodium

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