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People who carry one copy of a mutation that leads to sickle-cell disease are protected from the worst effects of malaria, research shows. A sickled red blood cell is shown (top) alongside normal red blood cells.Wellcome Trust, UK

Sickle-cell hemoglobin may gas malaria into submission, a new study proposes.

People who carry a mutation that deforms the oxygen-carrying protein in red blood cells are well-known to be protected against malaria. Scientists used to think the mutation prevented the malaria parasite from getting into blood cells. But researchers led by Miguel Soares at the Instituto Gulbenkian de Ciência in Oeiras, Portugal, now suggest another mechanism.

The sickle-cell mutation leads to higher production of a protein called heme oxygenase-1, which makes carbon monoxide gas. The gas helps reduce inflammation and protects against death in mice with malaria infection in their brains, the team reports in the April 29 Cell.

Using mice genetically engineered to make human hemoglobin with the sickle-cell mutation, Soares and his colleagues discovered that the mutation primes the body to deal with the red blood cell–shredding activities of the malaria parasite.

Hemoglobin breaks down more easily in people with the sickle mutation, Soares says, releasing a toxic compound called heme. To compensate, the body makes more of the heme oxygenase-1 enzyme, leading to more carbon monoxide production. The carbon monoxide then latches on to hemoglobin and prevents heme from popping off and causing more trouble.

“Before you get infected, sickle hemoglobin is releasing tiny amounts of heme. Your body looks at it and says, ‘This could be very dangerous, so I’m going to shut it down,’” Soares says.

Priming the body to deal with the extra heme also means that cells are prepared for the effects of the malaria parasite. The parasite can still infect cells, but the host doesn’t get as sick, allowing more time for the immune system to deal with the infection. “It’s a politician’s approach; you open a dialog with it while you’re still fighting it.”

Mice infected with malaria fared well when kept in a chamber with a little bit of carbon monoxide, while infected mice kept in a chamber with regular air died, the team found. That finding may suggest that very low doses of carbon monoxide could help treat malaria, Soares says.

Although the study carefully teases apart the mechanism, researchers don’t know how well heme oxygenase-1 works against malaria in people.

“Humans may not react as uniformly as mice do,” says Michael Walther, formerly a senior immunologist at the United Kingdom’s Medical Research Council laboratories in Gambia. People have genetic variants that control production of the heme oxygenase-1 enzyme, so some people with the sickle-cell mutation may not make as much of the enzyme as others do. And too much of the enzyme can be harmful, previous research has shown. “The window where heme oxygenase-1 induction may be beneficial may be quite narrow,” Walther says.

This new mechanism may be one of several ways sickle cell protects against malaria, says Rick Fairhurst, an immunologist at the National Institutes of Health in Rockville, Md. But he thinks other immune system factors may be more important for keeping malaria in check in people.

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