MAPPING PROTECTION The gene frequencies of hemoglobin C in West Africa (shown in shades of red), based on a simple diffusion model, overlap with areas where malaria is endemic or that are prone to malaria epidemics.
	COURTESY OF THOMAS WELLEMS

Scientists have known for five years that West Africans with the variant hemoglobin C are protected against severe malaria. Previous studies have shown that hemoglobin C reduces the prevalence of severe malaria by as much as 80%, but the mechanism of that protection has been a mystery.

Now, Thomas E. Wellems, chief of the Laboratory of Malaria & Vector Research at NIH in Bethesda, Md., and his international team of researchers think they have the answer.

They find that hemoglobin C reduces the expression of a cytoadherence protein called PfEMP-1. The parasite displays this protein on the surface of host red blood cells in knoblike protrusions. The protein enables infected cells to adhere to endothelial cells that line the tiny blood vessels of the host circulatory system, where the parasites can sequester themselves.

In addition, PfEMP-1 allows infected host cells to stick to uninfected red blood cells in a process called rosetting, producing clumps that can impair blood flow in critical tissues such as the brain. The researchers find that infected red blood cells containing hemoglobin C are less able to adhere to endothelial cells and other red blood cells in malaria (Nature 2005, 435, 1117).

Hemoglobin C is less stable than normal hemoglobin A, which may explain its effects. Oxidation of hemoglobin C appears to affect the red blood cell's cytoskeleton in a way that hinders the parasite from placing PfEMP-1 normally on its host red cell. "If we can find ways to interfere with the normal function of this major surface cytoadherence protein, we may have ways to reduce the impact of malaria," Wellems says.

PfEMP-1 will be a tough target for drugs or vaccines, however. "Attacking this target with a vaccine is going to be very difficult because it's an antigenically variable molecule" that can be encoded by any of 50 to 100 genes in the parasite, Wellems says.

"It sounds as if at long last we have a plausible explanation for how this hemoglobinopathy might protect against malaria," says Geoffrey Pasvol, a malaria expert at Imperial College London in Middlesex, England. "While this has been shown for hemoglobin C, it might well apply to the [other hemoglobin variants], such as S and E and thalassemia."

TAKAYUKI ARIE AND JAMES A. DVORAK

SURFACE STORY Malaria-parasite-infected red blood cells containing hemoglobin C (right) have fewer knoblike protrusions with PfEMP-1 than infected cells containing normal hemoglobin A (center). An uninfected red blood cell with hemoglobin A (left) is shown for comparison. The insets are confocal microscope images of the cells prior to being imaged with atomic force microscopy.