September 19, 2003
Beta Blockers Effective Against Malaria Parasites
CHICAGO --- Hormones that regulate cardiovascular function have
been discovered to influence malaria infection. As a consequence,
beta-blockers, which are safe, inexpensive and commonly prescribed
drugs used worldwide to treat high blood pressure, are effective
against the deadliest and most drug-resistant strain of malaria
parasites.
These findings, by Kasturi Haldar, Jon Lomasney, Travis Harrison
and colleagues at the Feinberg School of Medicine at Northwestern
University, were reported in an article in the Sept. 19 issue of
the journal Science.
Rather than targeting the parasite that causes malaria, an approach
that has resulted in mounting resistance to a variety of antimalarial
drugs, Haldar and co-researchers focused instead on identifying
and blocking the process by which red blood cells allow parasite
entry.
Haldar is Charles E. and Emma H. Morrison Professor in Pathology
and professor of microbiology-immunology at the Feinberg School.
Malaria
is a blood-borne illness transmitted by mosquitoes. Forty percent
of the world’s population lives at risk for infection
and between 200 and 300 million people are afflicted each year,
particularly in underdeveloped and impoverished tropical and sub-Saharan
countries.
The most virulent form of the four human malaria parasite species,
Plasmodium falciparum, kills over 1 million children each year
and is responsible for 25 percent of the infant mortality in Africa,
according to latest estimates by the World Health Organization.
Recently, however, P. falciparum also has been confirmed as the
cause of over 50 cases of malaria among the 625 U.S. troops sent
into Liberia. Another strain of malaria, P. vivax, has been confirmed
in seven cases in Florida.
World
wide there has been a resurgence of malaria in recent years,
due mainly
to the parasite’s growing resistance to drugs
and the mosquito’s acquired resistance to insecticides developed
to control the spread of the disease.
Athough
malaria infects both liver and blood cells, it is during the “blood stage” of malaria -- when infected red blood
cells that are “incubating” thousands of parasites
literally explode and release more parasites into the blood stream
-- that the symptoms of malaria occur. These symptoms include fever
and flu-like symptoms such as chills, headache, muscle aches and
fatigue. Immunity is slow to develop, and left untreated, malaria
may be fatal, taking its greatest toll in children.
Blocking blood-stage infection by preventing the entry of the
P. falciparum parasite into red blood cells provides the most direct
way to control infection and quell the symptoms of malaria. But
how red blood cells allow the entry of malaria parasites was unknown.
Travis
Harrison, who is first author on the article and a research assistant
in
Haldar’s laboratory, found that G proteins in
the red blood cell may be used by the parasite.
G
proteins are essentially “go-betweens,” or transducers,
that translate signals from hormones, neurotransmitters and other
substances and in turn activate such cell processes as gene transcription,
motility, secretion and contractility. G proteins have been intensively
studied in a wide range of cells, but their functions in oxygen-carrying
red blood cells are only beginning to be understood, Haldar said.
Research by Haldar and co-investigators showed that a G protein
subunit, called Gs, concentrates around the malaria parasite during
infection of the red blood cell.
Using special peptides, compounds similar to proteins, that inhibited
the interaction of Gs protein, the researchers were able to show
in several laboratory models of malaria that blocking the Gs signal
resulted in decreased malaria infection.
Two major Gs-associated receptors, the beta-adrenergic and the
adenosine receptors, are known to be present in red blood cells.
Stimulating these receptors with a drug called an agonist increased
infection of P. falciparum, while beta-blockers, which are antagonists,
prevented the P. falciparum parasite from entering red blood cells.
“The use of beta-receptor antagonists, such as those already
used to treat high blood pressure, may provide new approaches for
treating malaria. Since beta-blockers are directed against a host
target, there is low chance of rapid emergence of resistance to
these drugs. Moreover, they may be used in combination therapy
with existing drugs against parasite targets,” Lomasney and
Haldar said.
“This finding offers the opportunity to use well-characterized,
inexpensive drugs for a new, much-need application and the impetus
for the development of new beta-blockers and other drugs to be
tested for effectiveness against malaria,” they said.
Haldar’s
co-authors on this study were Travis Harrison, Benjamin U. Samuel,
and Thomas Akompong, departments of pathology
and of microbiology-immunology, Feinberg School of Medicine; Heidi
Hamm, Vanderbilt University, Nashville; Narla Mohandas, New York
Blood Center, New York; and Jon W. Lomasney professor of pathology,
Feinberg School of Medicine.
Grants from the National Institutes of Health supported this
study.
A
patent has been filed. |