Insight into how malaria parasite invades cells
suggests new therapies
By
Leigh MacMillan
Published: Dec. 9, 2003
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Photo
by Anne Rayner |
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| Heidi
Hamm in her lab |
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Investigators
at Vanderbilt University Medical Center and Northwestern University
have added another piece to the puzzle of how the malaria parasite
enters red blood cells. The team reported
last September in
Science that the red blood cell's own signaling machinery participates
in malaria entry, suggesting a new therapeutic approach to fight
the deadly parasite.
Malaria is
a blood-borne illness transmitted by mosquitoes. Growing resistance
of Plasmodium falciparum — the parasite species that
causes the most virulent form of malaria — to cheap and effective
anti-malarial drugs is contributing to a resurgence of the disease,
especially in sub-Saharan Africa. P. falciparum kills over one
million children each year and is responsible for 25 percent of
the infant mortality in Africa, according to the World Health Organization.
The new studies
demonstrate that drugs developed to block the beta adrenergic
receptor, a receptor important to cardiovascular function and
blood pressure control, may be useful agents in the fight against
malaria. Propranolol, a so-called “beta blocker,” prevented
malaria infection of red blood cells in the laboratory and in mice.
“Our studies open a whole new therapeutic dimension for the future,” said
Heidi E. Hamm, Ph.D., Earl W. Sutherland Jr. Professor and Chair
of Pharmacology. “The idea that it might be possible to prevent
malaria infection by blocking parasite entry into the red blood
cell using well-characterized, safe and relatively inexpensive
drugs like beta blockers is intriguing.
“Of course it's very far from showing something in vitro or even
in mice to actually being able to do this in humans, but the fact
that propranolol is already on the market will speed clinical trials
of it as a way to prevent malaria infection in at-risk individuals,” she
said.
The malaria parasite infects both liver cells and red blood cells,
but it is the blood cell stage of the infection that is responsible
for all of the symptoms and pathologies of the disease.
Kasturi Haldar,
Ph.D., professor of Pathology and Microbiology-Immunology at
Northwestern University, has been investigating how malaria infects
red blood cells. Her group discovered that the parasite uses “lipid rafts” from
the red blood cell membrane to build its own unique membrane-enclosed
compartment inside the cell and that a signaling protein, called
G-alpha-s, was present in the hijacked membranes. Because Hamm,
a recognized expert on G proteins including G-alpha-s, was Haldar's
laboratory neighbor at the time, the two began to collaborate.
G proteins
act as molecular switches to pass signals along from activated
receptors at the cell surface to other proteins inside the cell.
Hamm had pioneered an approach to block the interaction of G
proteins with receptors, using small peptides — bits of proteins.
The peptides designed to block G-alpha-s inhibited P. falciparum
infection of red blood cells in the laboratory by nearly 90 percent,
suggesting that G-alpha-s signaling is playing an important role
in the infective process, Hamm said. Because the complete genome
of P. falciparum has been sequenced, the investigators knew that
the parasite does not have any G proteins of its own, confirming
that it is using the red blood cell's signaling machinery.
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Courtesy
of Science magazine |
Images
of human blood cells newly infected with the malaria parasite P.
falciparum show how different cell proteins respond to the invasion. The
blue area labeled “P” is the parasite's nucleus. The white arrowhead points
to the cell membrane. The red scale bar is three microns long. In the image
on the left, the green stain labels the presence of G s
protein; in the middle image it shows the protein Gq – a
G protein that does not respond to the parasite – and in the right image it
shows distribution of the beta adrenergic receptor. |
It was known
that red blood cells contain at least two types of receptors
that activate G-alpha-s: the beta adrenergic receptor and the
adenosine receptor. The investigators wondered if drugs that
block these receptors —and therefore also prevent activation
of G-alpha-s — would act like the peptides and prevent parasite
infection. Propranolol, a beta adrenergic receptor blocker, had
exactly that effect, in both cells and mice.
The results offer an attractive option for fighting malaria before
it infects red blood cells, Hamm said, and because the treatment
would target the red blood cell's own machinery, it should prevent
the ability of malaria to evolve resistance to the therapy. But
Hamm cautions that the findings are a starting point.
“I think there's a lot more basic science research that has to
be done to fully understand how the P. falciparum is hijacking
red blood cell signaling machinery,” she said. “It's really a problem
of cell fusion and how pathologic organisms change membrane trafficking
mechanisms in order to get into cells. Malaria is actually a very
useful tool for studying how G proteins are involved in the regulation
of membrane trafficking.”
Hamm and Haldar's co-authors of the Science study were Travis
Harrison, Benjamin U. Samuel, Thomas Akompong, and Jon W. Lomasney
of Northwestern University and Narla Mohandas of the New York Blood
Center. The research was supported by the National Institutes of
Health.
"New
Treatment for Malaria Infections" Northwestern News
“Erythrocyte
G Protein-Coupled Receptor Signaling in Malarial Infection,” Science;
19 Sep 2003 (Subscription required)
Hamm Lab's web page
Kasturi Haldar's web page
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