October 10, 2003

Malaria study in ‘Science’ points to new ways to fight infection

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Heidi Hamm, Ph.D.

Malaria study in ‘Science’ points to new ways to fight infection

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 month 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.

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.