LONDON - Mutations in a gene encoding a protein that plays a key role in malaria infection might be expected to confer some protection against this tropical disease, particularly as the mutations are common in people of African and Asian origin. New research shows, however, that people with these mutations are more likely to suffer severe complications if they contract malaria.

The finding suggests that the mutations may provide some protection against another infection common in tropical areas. It also will be of interest to those attempting to develop a vaccine against malaria, as it suggests that some of the strategies currently under investigation could exacerbate malaria rather than prevent it.

The gene concerned is that encoding the CD36 protein, which is expressed on the endothelial cells lining blood vessels. 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 invade body tissues.

Timothy Aitman, clinical reader and consultant physician at the Medical Research Council's Clinical Sciences Centre at Hammersmith Hospital in London, told BioWorld International, "Unexpectedly, we found that these mutations do not protect against malaria. Instead, they do the opposite - they provide susceptibility to malaria, particularly cerebral malaria."

A strategy of blocking CD36 with the aim of preventing malaria infection could therefore be dangerous, Aitman suggested. "Our studies would suggest that a vaccine of this kind could give people cerebral malaria if they subsequently caught the disease."

An account of the study by Aitman, together with colleagues from the Medical College of Wisconsin in Milwaukee; the London School of Hygiene and Tropical Medicine; the Medical Research Council Laboratories in Fajara, The Gambia; the KEMRI Coastal Research Unit in Kilifi, Kenya; and from the University of Oxford in Oxford, UK, appears in the June 29, 2000, Nature in a Brief Communication titled "Malaria susceptibility and CD36 mutation."

Aitman and his colleagues became interested in the gene encoding CD36 because it also plays a role in insulin action and fat metabolism. It also is known as the gene for an enzyme called fatty acid translocase.

They decided to find out if the gene was present in all populations and discovered from the literature that CD36 deficiency was common in certain ethnic groups, including Southeast Asians and Africans. They also knew that one of the functions of CD36 is to act as a receptor for the malarial parasite P. falciparum.

In an attempt to marry up these two observations - knowing malaria is common in the same populations - Aitman and his team first sequenced the CD36 gene from a group of African-Americans with CD36 deficiency. They identified several mutations, and then looked for these in a large group of about 600 people from Kenya and The Gambia who had malaria, matched with more than 700 controls from the same countries.

"We found that one of these mutations was common in all populations we looked at, from The Gambia, from Kenya and from another population of people of Afro-Caribbean origin in the UK," Aitman said. "Between 7 percent and 18 percent of Africans in these populations possessed at least one copy of these mutations."

Such a finding was surprising, he added, because defective genes are normally lost from the gene pool. If they are not, this may be because there is a selective advantage for those who carry such genes - as in the case of the mutations in the gene encoding hemoglobin, which causes sickle cell disease and the thalassemias - which provide a degree of protection from malaria to heterozygotes who carry them.

When the researchers looked for such an effect linked to CD36 deficiency, they were taken aback to find that the reverse was true: People with cerebral malaria were significantly more likely to have mutations in the CD36 gene than controls (p=0.01).

The researchers believe that the mutations probably protect against some other condition, probably another tropical infection, although they do not know what. Aitman said, "We are sure that these mutations are not there by chance. We found seven different mutations. All change the protein in some way and all are in the same part of the protein, so they are not occurring at random."

Why should a deficiency of CD36 lead to cerebral malaria? CD36 on endothelial cells binds to malarial parasites expressed by infected red blood cells. "The part of the body the infected cells stick to will determine whether the malaria parasite can invade the body tissues there," Aitman said. "It may be that CD36 normally allows the malaria parasite to stick to parts of the body where it can be gotten rid of. But if the protein is not there, the infected red blood cells go to the brain, causing cerebral malaria."

Infectious diseases specialists will want to find out exactly what is happening to produce this effect, Aitman predicted. "CD36 does not act as a receptor for other malaria parasites, but even within falciparum malaria there are different strains and they change all the time. It will be very important to find out if this finding holds true over a period of time, and whether people with CD36 deficiency are infected with the same strain of malaria as people without CD36 deficiency."

Aitman's co-authors, Adrian Hill of Oxford University and James Scott, director of the new Institute of Genetics and Genomics at Imperial College of Science, Technology and Medicine in London, will be pursuing these and related topics.

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