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Mutation is genetic armor against malaria
By Kate Dalke

A single genetic mutation protects some African children from the deadly symptoms of malaria, a new study has found. Children in Tanzania and Kenya who have the mutation are much less likely to develop the disease than children who do not.

There is no effective vaccine against malaria, and the parasite's resistance to commonly used drugs is widespread. But knowing why some individuals are naturally immune to the disease could help researchers develop novel strategies for preventing malaria.

The mutation occurs in the gene NOS2 that encodes an enzyme to produce the gas nitric oxide—which is present throughout the human body. The mutation is a polymorphism, a single letter change in DNA. It causes cells to ramp up production of the gas, which is thought to protect people against malaria.

Children in Tanzania with the mutation were almost 90 percent less likely to develop severe malaria than individuals without the mutation, the researchers found. They analyzed DNA from 185 Tanzanian children with and without clinical malaria, and more than 1,100 children in Kenya.

The scientists hypothesize that the gene mutation may have evolved from repeated exposure to the malaria parasite as a way to protect individuals in endemic areas. The new trait has not been found in Caucasian populations.

Natural immunity to malaria has been seen in other groups of people. Individuals who carry one of the genes for sickle-cell anemia are less susceptible to malaria, for instance. But the two genetic 'armors' do not travel together. Healthy persons with the sickle-cell trait do not carry the newly described trait, the researchers report in The Lancet.

Prior work had indicated that nitric oxide can be toxic to malaria parasites in the lab and it protects against malaria in humans. Using these clues and information in the human genome, the researchers searched for variations in the sequences of the gene NOS2, which could be increasing nitric oxide in the bloodstream.

Still, no one knows for sure why nitric oxide protects humans from malaria disease. It may lower the level of certain key proteins in cells that line blood vessels. In cerebral malaria, it may prevent parasitic red blood cells from adhering to blood vessels, thus keeping a clear flow of blood to the brain.

Surprisingly, children with the NOS2 polymorphism have the same concentrations of parasites in their blood as those without the mutation—but they don't get sick. Therefore, the mutation does not directly reduce the number of parasites in the host's bloodstream.

"Nitric oxide has anti-disease effects, but not necessarily anti-parasitic effects," says J. Brice Weinberg of the VA and Duke University Medical Centers in Durham, North Carolina, who led the study.

Weinberg says they were pleased to see the same protective mutation in two different ethnic groups and in two forms of the disease—cerebral malaria and severe malarial anaemia.

Mimicking the protective effects of nitric oxide in individuals without the mutation is difficult, says Weinberg. Nitric oxide can have damaging effects on the body. In other conditions, it is associated with inflammation (arthritis) and in septic shock, with a sometimes-fatal drop in blood pressure.

"Nitric oxide would have to be made in the right place, in the right amount, and at the right time," says Weinberg. He and others are looking at novel ways to deliver nitric oxide to the body.

In addition to the human genome, the malaria parasite and mosquito genomes published earlier this year have also improved basic understanding of the role of nitric oxide in the lifecycle of disease.

Humans are not the only ones that produce nitric oxide. The mosquito vector also uses the gas to regulate parasites in its body and this phenomenon could be exploited to control the spread of disease.

See related GNN article
»The Parasite and the Mosquito: Malaria's deadly partners are sequenced

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Hobbs, M.R. et al. A new NOS2 promoter polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children. Lancet 360, 1468-1475 (November 9, 2002).

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