Image by Peter H. Seeberger
Malaria-infected cell bursting
Researchers believe they may have discovered why iron can sometimes worsen malaria infection.
By studying mice and samples from malaria patients, the researchers found that extra iron interferes with ferroportin, a protein that prevents a toxic buildup of iron in red blood cells and helps protect these cells against malaria infection.
The team also found a mutant form of ferroportin that occurs in African populations appears to protect against malaria.
These findings, published in Science, may help researchers and healthcare officials develop strategies to prevent and treat malaria.
“Our study helps solve a long-standing mystery,” said study author Tracey Rouault, MD, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Maryland.
“Iron supplements can sometimes worsen malaria infection and, conversely, iron deficiency can be protective in some cases. Our findings reveal that ferroportin—its function, as well as its regulation by iron levels—helps to explain these observations.”
The team found that red blood cells use ferroportin to remove excess iron, which malaria parasites consume as a food source.
In studies of mice, the researchers found the absence of ferroportin in erythroid cells caused iron to accumulate to toxic levels inside red blood cells. This, in turn, stressed the cells and shortened their life span.
In addition, the team found that mice lacking ferroportin had more parasites and worse outcomes when infected with malaria, compared to malaria-infected mice with intact ferroportin.
When they fed mice a high-iron diet, the researchers found that hepcidin regulated ferroportin in erythroid cells. The hormone, which is more abundant in high-iron environments, lowered ferroportin levels on erythroblasts and, subsequently, in red blood cells.
Additionally, hepcidin physically bound to ferroportin, preventing iron removal from the cells.
Next, the researchers sought to determine whether the ferroportin mutation Q248H, which is found in African populations, protects against malaria. This mutation shields ferroportin from hepcidin’s effects.
The team analyzed patient samples from 2 existing malaria studies. In one study, which enrolled children hospitalized for malaria in Zambia, 19.7% of the 66 patients had the Q248H mutation.
Children with the mutation tended to have fewer malarial parasites in their blood and tolerated their fevers for a longer period before coming to the hospital. While the trends were not statistically significant, they raise the possibility that Q248H reduces the iron available in the blood, therefore reducing the malaria parasite’s food source.
In the other study, which enrolled 290 pregnant women in Ghana, 8.6% had the Q248H mutation. Women with the mutation were significantly less likely to have pregnancy-associated malaria, in which parasites accumulate in the placenta and can cause adverse pregnancy and birth outcomes.
“Our findings suggest that Q248H does protect against malaria, possibly explaining why it occurs in people who live in malaria-endemic regions,” said study author De-Liang Zhang, PhD, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
“Given the importance of iron metabolism overall, we will continue studying the ferroportin mutation and explore its other potential health effects.”