|NIAID Scientists Unveil Mechanism
Behind Resistance to Severe Malaria
Scientists have discovered why people with a specific
type of hemoglobin — the oxygen-carrying molecule that
gives red blood cells their color — are less prone to
severe malaria. In a series of experiments, the researchers
determined how hemoglobin type C impairs the ability
of malaria parasites to cause disease symptoms.
“This research gives us a new insight into malaria,
a major global killer that preys especially on young
children and claims a life every 30 seconds,” notes
Anthony S. Fauci, M.D., director of the National Institute
of Allergy and Infectious Diseases (NIAID), part of
the National Institutes of Health, where the research
“If we better understand the natural protective mechanisms
against malaria, we might be able to mimic that protective
effect through vaccines or drugs,” says NIAID researcher
Thomas E. Wellems, M.D., Ph.D., whose team’s findings
appear this week in the journal Nature.
Hemoglobin exists in several varieties. Hemoglobin
A is the most common, but in parts of West Africa, where
malaria is rife, one-fourth of the population has at
least one gene for hemoglobin C. Children with at least
one hemoglobin C gene are less prone to deadly cerebral
malaria, in which parasite-infected red blood cells
accumulate in the brain. But how hemoglobin C confers
this protection has puzzled scientists until now.
To solve the mystery, Dr. Wellems and his colleagues
studied laboratory-infected red blood cells and blood
drawn from children with malaria from the African nation
of Mali. Genetically, the samples fell into three groups:
those with two genes for hemoglobin A (AA); those with
two genes for hemoglobin C (CC); or those with one gene
for each type of hemoglobin (AC).
The scientists then measured three phenomena that affect
how well parasitized red blood cells can be made to
stick to one another, to uninfected red blood cells
and to blood vessel walls. These phenomena — known respectively
as agglutination, rosetting and cytoadherence — all depend
on a parasite protein called PfEMP-1.
To evade the immune system, malaria parasites produce
proteins, including PfEMP-1, that remodel the red blood
cell’s surface to their advantage. For example, when
spikes of PfEMP-1 are distributed evenly over the surface
of an infected AA red blood cell, they act like grappling
hooks, allowing the parasitized cells to stick in tiny
capillaries and avoid being cleared from the bloodstream.
When parasite-infected red blood cells stick to blood
vessel walls, the resulting inflammation may increase
the severity of malarial symptoms, explains Dr. Wellems.
Dr. Wellems and his colleagues found uneven and reduced
distribution of PfEMP-1 on the surface of parasite-infected
red blood cells from children with at least one hemoglobin
C gene. This abnormal distribution of PfEMP-1 significantly
impairs the infected cells’ “stickiness.” For instance,
laboratory-grown, parasitized AC blood cells agglutinated
at a 75 percent lower rate than did AA red blood cells,
while parasitized CC blood cells did not stick to each
other at all. Rosette formation, in which parasitized
cells attach to non-parasitized cells, also occurred
significantly less often with AC and CC blood cells
than with AA blood cells. Rosettes can impede blood
flow in small vessels of the brain, contributing to
cerebral malaria and death, notes Dr. Wellems. The scientists
showed that AA cells often stick to blood vessel walls,
whereas this occurs much less often with both AC and
CC blood cells.
Together, the data from Dr. Wellems’ team may explain
why red blood cells containing hemoglobin C are less
hospitable to malaria parasites than normal AA red blood
cells. For people with at least one gene for hemoglobin
C, the result is less severe malaria.
From back to front: normal, uninfected human red
blood cell; malaria parasite-infected red
blood cell containing hemoglobin A and showing
even distribution of small, knob protrusions;
malaria parasite-infected red blood cell containing
hemoglobin C and displaying abnormally large
knob protrusions. (credit: NIAID)
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to prevent, diagnose and treat infectious diseases such
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