Platelets — those tiny, unassuming cells that
cause blood to clot and scabs to form when you cut
yourself — play an important early role in promoting
cerebral malaria, an often-lethal complication that
occurs mostly in children.
Affecting as many as half a billion people in tropical
and subtropical regions, malaria is one of
the oldest recorded diseases and the parasite responsible
for it, Plasmodium, among the most studied
pathogens of all time. Still, cerebral malaria, which
results from a combination of blood vessel and
immune system dysfunction, is not well understood.
In a study described in the Aug. 14 issue of Cell Host
and Microbe, Johns Hopkins researchers
reveal that when red blood cells are infected with the
malaria parasite, they activate platelets to
secrete the PF4 protein, which triggers the immune system
to inflame blood vessels and obstruct
capillaries in the brain; both are hallmarks of cerebral
malaria.
In its experiments, the Johns Hopkins team first
infected human red blood cells in culture with
the malaria parasite and found that this did, indeed,
induce platelet activation.
The researchers then infected separate sets of live
mice with the malaria parasite: one set
treated so that it lacked platelets altogether and two
others treated with aspirin or Plavix, platelet
inhibitors that prevent the release of PF4.
The survival rate of mice without platelets as well as
those treated with inhibitors was
improved over that of the mice left alone, but only when
the treatment began very soon after
infection. When researchers started treating mice with
platelet inhibitors one day after infecting
them, those mice survived more often than control mice.
However, when researchers waited until
after three days to treat infected mice with platelet
inhibitors, that group did no better in terms of
survival.
"Cerebral malaria is lethal 20 percent of the time in
the best of hands, and here we've shown
that something as simple as aspirin, because of its effect
on platelets, might be able to improve the
outcomes of those who contract this deadly form of the
disease," said David Sullivan, an associate
professor of molecular
microbiology and immunology in the Johns Hopkins
Bloomberg School of Public
Health.
To make the specific connection between PF4 and
malaria, the scientists compared the
responses to malaria infection by so-called "wild type"
normal mice and mice genetically engineered to
lack pF4. They found that the amount of parasite in the
blood was the same in both sets of mice. The
notable difference was in the animals' immune responses to
that same parasite burden. More than 60
percent of the mice lacking PF4 were still alive after day
10, while only 30 percent of the mice with
PF4 survived that long.
Craig Morrell, an assistant professor of molecular and
comparative pathobiology at the Johns
Hopkins School of Medicine, said, "The take-home lesson is
that platelets, by releasing PF4, are
playing an early role in the wind-up phase of cerebral
malaria. Our mouse studies show that timing is
critical; with the mice, we know when we infected them and
controlled when we treated them. A big
challenge in translating this to humans is that people
don't know when they get infected," he said.
"Platelets don't get any respect, but they're the
second most abundant cell in the blood after
red blood cells and packed full of factors that rally the
immune system to action," Morrell said. "By
taking what we know about platelets and their activation
and applying it to malaria, we have found a
driver of cerebral malaria."
The research was funded by the National Institutes of
Health and supported by the Johns Hopkins Malaria
Research Institute.
In addition to Sullivan and Morrell, authors on the
paper are Kalyan Srivastava, Ian A. Cockburn,
Anne Marie Swaim, Laura E. Thompson, Abhai Tripathi, Craig
A. Fletcher, Erin M. Shirk, Henry Sun,
Karen Fox-Talbot and Fidel Zavala, all of Johns Hopkins;
and M. Anna Kowalska, of the Children's
Hospital of Philadelphia.