Just as a car can approach a city using different roads, Plasmodium falciparum can invade a red blood cell through several portals, says Alan F. Cowman, an HHMI international research scholar at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia.

Cowman thinks he's found a new route of the malaria parasite. Cued by an unusually high frequency of malaria resistance and very mild cases among the Melanesian people of Papua New Guinea, Cowman and his colleagues have identified an important point of entry on red blood cells that could ultimately serve as a vaccine target. Defects in this portal may explain the relatively healthy Melanesians who live in an area where malaria is otherwise quite common.

That entry point is glycophorin C, which accounts for a mere 4 percent of the glycoproteins that dot the red blood cell's surface. About half of the Papuan Melanesians are missing part of glycophorin C, and evidence suggests that they do not suffer severe malaria. In 1984, Michael J. Tanner, at the University of Bristol, showed that cells lacking glycophorin C admit fewer parasites, but he didn't zero in on the significance of his findings. "Our results are now explained," Tanner says, "by the presence of a distinct invasion pathway elucidated in the paper by the Cowman group" (published in the January 2003 issue of Nature Medicine).

With fewer parasites entering red blood cells, the critical mass necessary to trigger a full-fledged siege of chills and fever isn't reached. "The parasites still invade, but the person is unlikely to get as sick," says Cowman. The mutation in the glycophorin C gene may also deform the red blood cell membrane, which may contribute to dampening parasite invasion.

Cowman and his colleagues identified a molecule that participates in the bonding between the malaria parasite and its host. First, the researchers identified a protein they named EBA140 (for erythrocyte-binding antigen) from P. falciparum. Then, using normal parasites as well as mutants they constructed that lack EBA140, and red blood cells that have or lack glycophorin C, they mixed combinations of surface proteins from the parasite and host cells to reveal the important relationships. Results were clear: Parasites lacking EBA140 could not latch onto glycophorin C, and parasites with EBA140 could not attach to proteins from red blood cells that lack glycophorin C. That is, the pathogen's EBA140 must bind with the red blood cell's glycophorin C to gain entry to the cell.

Blocking glycophorin C, then, might prevent or slow infection, at little or no physical cost. Though glycophorin C normally helps hold the cell's outer membrane to its inner skeleton, other glycoproteins do the same, so its loss is not harmful.

The discovery of the role of glycophorin C in malaria explains why Papuan Melanesians have an easy time with the disease. "Their mutation is an advantage," says Cowman. Over time, the mutation accumulated in the population as malaria weeded out those who lacked it. Now, the discovery may benefit countless others elsewhere. "The work done by Dr. Cowman and his colleagues could help develop a vaccine that would stop the parasite from spreading from one red cell to another," says Brian Greenwood, director of the Malaria Centre at the London School of Hygiene and Tropical Medicine.

—Ricki Lewis

Photos: The Walter and Eliza Hall Institute of Medical Research

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Reprinted from the HHMI Bulletin,
March 2003, pages 14-19.
©2003 Howard Hughes Medical Institute