BioWorld International Correspondent

LONDON - People who have a particular mutant version of the protein known as CD36, which plays an important role in the body's response to infection with malaria parasites, are less likely to develop some types of severe malaria if they become infected, a new study has shown.

David Roberts, of the Blood Research Laboratory within the National Blood Service at Oxford University in Oxford, UK, and his colleagues report their findings in a letter to The Lancet titled "A non-sense mutation in Cd36 gene is associated with protection from severe malaria."

Arnab Pain, of the Institute of Molecular Medicine at Oxford University, together with Roberts, identified a mutation present in some people of African origin, which has the effect of truncating the CD36 protein.

Roberts told BioWorld International: "We found that people heterozygous for this mutation are protected from particular syndromes of severe malaria, although not from cerebral malaria. This supports our hypothesis that some interactions with CD36 harm the host and some benefit the host. In the future, we want to understand how malaria parasites interact with the immune system and with platelets. Because of the genetic association, we are sure that these interactions are important in the outcome of severe disease."

Roberts, with Britta Urban, also of the Institute of Molecular Medicine, has a patent pending on immunoregulation of dendritic cells (cells of the immune system) via CD36. They hope to identify molecules that are potential targets for drugs to treat a range of autoimmune diseases, and are looking for partners to help them develop their findings.

CD36 is expressed on the endothelial cells lining blood vessels, as well as on white blood cells and platelets. Red blood cells infected with the malarial parasite Plasmodium falciparum express proteins of parasite origin on their surfaces, which bind with CD36, thus allowing the infected cells to adhere to endothelium and cells of the immune system. Parasites that have adhered to the endothelium also avoid being circulated in the blood through the spleen, which would eliminate them.

Roberts and his colleagues have been studying the role of CD36 in malaria for some years. In 1999, they showed that malaria parasites bind to and modulate the function of dendritic cells. The group also reported that malaria-infected red blood cells bind to platelets via CD36, and that this interaction can lead to the formation of large clumps of infected cells and platelets which probably contribute to the development of severe disease.

For the study reported in The Lancet, they first sequenced DNA from two Afro-Americans who did not express CD36 on their platelets. They found a mutation that had the effect of introducing a stop codon, leading to the manufacture of a truncated protein. Working in Kenya, they then looked for the mutation in 693 children with severe malaria and in the same number of controls from the same community, who were matched by ethnic group.

They found that 121 of the 693 children (17 percent) were heterozygous for the mutation, compared with 95 out of 693 controls (14 percent). The odds ratio was 0.74. In other words, those children with the mutation had only three-quarters of the chance of getting severe malaria of those who did not have the mutation.

The clinical symptoms of malaria can vary widely, so the group also asked whether the mutation was associated with particular malarial syndromes. They found that the mutation was protective for respiratory distress, severe anemia and hypoglycemia, but not for cerebral malaria. They speculate that this may be because the infected red blood cells stick less well to endothelial cells in people with the mutation.

In their letter to The Lancet, Roberts and his colleagues wrote that the absence of protection from cerebral malaria is "at first sight puzzling." They point out, however, that infected red blood cells may interact not only with endothelial cells expressing CD36 but also with monocytes, macrophages and dendritic cells. Perhaps, they suggest, the immune response to malaria in those people carrying this CD36 mutation is altered in some deleterious way, and this outweighs the benefit of reducing the parasite's ability to stick to the blood vessels.

Roberts said, "What we are seeing here is the outcome of the balance between a good effect and a bad effect of this mutation."

Last year, a group led by Timothy Aitman, clinical reader and consultant physician at Hammersmith Hospital in London, reported that mutations in the gene encoding CD36 were, to their surprise, associated with susceptibility to malaria. People with cerebral malaria were significantly more likely to have a mutation than controls without cerebral malaria. (See BioWorld International, July 5, 2000.)

Roberts and his colleagues said in The Lancet that these earlier findings, together with their own results, suggest that the mutation they identified "has a complex effect in malaria infection - by decreasing parasite sequestration on the one hand, and by depressing host immune response on the other."