How sickle-cell carriers

fend off malaria

By Catherine de Lange
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 and Ana Ferreira 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.
Soaress 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?

Soaress 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.