Sickle-cell carriers fend off Malaria

The elusive mechanism by which people carrying the gene for sickle-cell disease are protected from malaria has finally been identified. This could point to a treatment for malaria.

People develop sickle-cell disease, a condition in which the red blood cells are abnormally shaped, if they inherit two faulty copies of the gene for the oxygen-carrying protein haemoglobin. The faulty gene persists because even carrying one copy of it confers some resistance to malaria.

Now Miguel Soares of the Gulbenkian Institute of Science in Oeiras, Portugal, and colleagues have discovered how mice that have been genetically modified to carry one version of the faulty gene are protected from malaria.

Their results show that the gene does not protect against infection by the malaria parasite, as was previously thought. Instead, it prevents the disease taking hold after the animal has been infected.

Soares's team found that haem – a component of haemoglobin – is present in a free form in the blood of mice with one faulty haemoglobin gene, but largely absent from normal mice. To find out whether this helped guard against malaria, the team injected haem into the blood of normal mice before infecting them with malaria. The mice did not develop the disease.

Paradoxical effect

Paradoxically, Soares also found that if there are high levels of haem in the blood after infection with the malaria parasite, the disease is more likely to develop. In fact, even the mice carrying one copy of the sickle-cell gene, and therefore less likely to develop malaria, could be made more likely to develop the disease by injecting them with haem after they were infected.

So how can it be that free haem is at once dangerous and protective? Soares's findings suggest that a mechanism similar to vaccination is at work.

The low levels of free haem circulating in the blood of mice carrying the sickle-cell gene stimulate the production of an enzyme that breaks it down, called haem oxygenase-1. This releases small quantities of carbon monoxide – a gas that in large quantities is highly toxic.

In the low concentration found in the blood of the mice, however, carbon monoxide seems to play a role in preventing the accumulation of haem after infection with the malaria parasite. It is this limitation of levels of haem that appears to protect against the disease developing.

Protection confirmed

To confirm this, Soares and colleagues tested whether the gas could protect normal mice from succumbing to malaria. They infected the mice with the malaria parasite and then allowed them to inhale small doses of carbon monoxide – too low to have a toxic effect. The mice did not develop the disease.

Soares suggests the gas – which is already known to have some therapeutic properties in small quantities – could be used to protect against malaria in people infected with the parasite.

But there is likely to be more to the development of malaria than simply controlling haem levels in the blood. It is already known that an inflammatory response also plays a part in the onset of malaria, Soares says, which suggests the disease is triggered by a two-pronged attack.

The overactive immune response leads to the accumulation of toxic T-cells. In another experiment, Soares and his team showed that build-up of these pathogenic cells after infection with malaria is inhibited in mice with one sickle cell gene – although the protective mechanism at work has yet to be established.

Journal reference: Cell, DOI: 10.1016/j.cell.2011.03.049