September 18, 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, PhD, Charles E. and Emma H. Morrison Professor of Pathology and professor of microbiology—immunology; Jon W. Lomasney, MD, associate professor of pathology; Travis Harrison; and colleagues at the Feinberg School of Medicine were reported in an article in the September 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, Dr. Haldar and co-researchers focused instead on identifying and blocking the process by which red blood cells allow parasite entry.
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 more than 1 million children each year and is responsible for 25 percent of the infant mortality in Africa, according to the 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.
A resurgence of malaria has occurred worldwide 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.
Harrison, who is first author on the article and a research assistant in Dr. 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, Dr. Haldar said.
Research by Dr. 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 showed 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 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,” Drs. 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.
Dr. Haldar’s co-authors on this study were Harrison; Benjamin U. Samuel, MD, research assistant professor of pathology; Dr. Lomasney; and Thomas Akompong, all of the medical school; Heidi Hamm, PhD, Vanderbilt University, Nashville; and Narla Mohandas, New York Blood Center.
Grants from the National Institutes of Health supported this study.
A patent has been filed.