BioWorld International Correspondent

LONDON - Variations in a gene encoding a protein that is found on the surface of red blood cells can influence a person's risk of developing severe malaria, an international team of researchers has found. The discovery points to new ways of developing therapies and vaccines to protect against the disease, which kills between 1 million and 2 million children worldwide every year.

The protein, called complement receptor 1, or CR1, plays a role in allowing uninfected red blood cells to stick to red blood cells infected with the malaria parasite to form clumps or "rosettes."

Until now, researchers were unsure whether the phenomenon of rosetting seen in blood samples from people with malaria was the cause of severe malaria, or whether it was a product of it.

Alexandra Rowe, Wellcome Senior Research Fellow at the Institute of Cell, Animal and Population Biology at the University of Edinburgh, told BioWorld International, "The findings of our study provide additional evidence that rosetting does actually cause severe disease."

Rowe, together with collaborators at the Weatherall Institute of Molecular Medicine in Oxford, UK, and in the U.S. and Papua New Guinea, reports her findings in the Dec. 12, 2003, issue of the Proceedings of the National Academy of Sciences in a paper titled "A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria."

The team knew that rosetting is associated with severe malaria, because the blood cells of children with severe malaria show lots of rosetting, whereas few rosettes are present in children with uncomplicated malaria. They also knew that red blood cells deficient in CR1 are unable to form rosettes with red blood cells infected with malaria parasites.

One further tantalizing clue came from a 1983 review article that mentioned that 28 out of 67 Melanesian people tested had CR1-deficient red blood cells. Yet CR1 deficiency was thought to be rare in most populations.

Taking all that evidence into account, the researchers formulated a rationale for their study. Rowe said: "We thought that if rosetting is really important in severe malaria, then this polymorphism - which prevents rosetting - should have been selected for in malarious countries, because it should protect people against developing severe disease."

They therefore set out to measure the CR1 levels on red blood cells of healthy adult volunteers from two areas of Papua New Guinea in which malaria is very common, and a Caucasian control group in Edinburgh. They found that 79 percent and 55 percent of people from the two locations in Papua New Guinea had fewer than 200 CR1 molecules per cell, compared with a mean of 786 CR1 molecules per cell for the Edinburgh group. That difference was statistically significant.

For the next part of their study, they examined DNA samples from 180 people with severe malaria and 179 matched community controls in Papua New Guinea. Genotyping showed that people with one copy of the low-expression allele of CR1 were significantly protected from severe malaria (people with two copies of the low-expression allele were less likely to have severe malaria, but the difference did not reach statistical significance).

Rowe said: "These results fulfilled our starting hypothesis. This is a very strong piece of evidence that rosetting is important in causing severe malaria in some cases. It is significant because it means that, if you could block rosetting, you should be able to treat or prevent some cases of severe malaria."

The group has already shown that soluble CR1 can prevent rosetting in vitro. "Although this is theoretically possible, it is not very practical because such a treatment would be very expensive and would require sophisticated hospital facilities, which are not always available in countries where you get severe malaria," Rowe said.

A second option, she added, would be to study the parasite protein that links to CR1 in order to cause rosetting and use it to make a vaccine.

"If you immunized people with part of this protein, which is called PFEMP1, they would make antibodies that would inhibit rosetting and you could prevent some cases of severe disease," Rowe said.

The group is currently studying PFEMP1 to find out how variable it is in different strains of Plasmodium falciparum. "We hope to be able to identify a region of the protein that is common to many different strains of the parasite, to make a vaccine that could protect against all these strains," Rowe said.

She and her colleagues also want to try to identify molecules that might be able to interfere with the interaction between PFEMP1 and CR1.