Discovery Provides New Target for Malaria Treatments
NIH researchers have found pore-like holes in the membranes of red blood cells infected by the deadliest form of the malaria parasite. That parasite, Plasmodium falciparum, apparently uses these holes to supply itself with the nutrients it needs to grow and reproduce. The discovery may lead to the development of new treatments for malaria, a widespread and devastating disease.
The finding, which appears in the August 31 issue of Nature, resulted from a collaboration headed by the corresponding author, Sanjay A. Desai, M.D., Ph.D., an expert in malaria biology with the Laboratory of Parasitic Diseases of the National Institute of Allergy and Infectious Diseases (NIAID), and last author Joshua Zimmerberg, M.D., Ph.D., chief of the Laboratory of Cellular and Molecular Biophysics of the National Institute of Child Health and Human Development (NICHD), where the research took place.
"Malaria kills more than one million people each year, most of them under age 5, and the disease is becoming resistant to many of the drugs used to treat it," said NICHD Director Duane Alexander, M.D. "This important finding provides a new target for potential new malaria treatments."
"In addition to causing enormous human suffering," added NIAID Director Anthony S. Fauci, M.D., "malaria impedes the economic development and stability of many developing countries. This discovery is an important step forward in our understanding of malaria and the search for new interventions to reduce the burden of this devastating disease."
P. falciparum is transmitted through the bite of mosquitoes infected with the parasite, explained Dr. Zimmerberg. More than 40 percent of the world's population lives in countries where malaria is endemic. Each year, 300 to 500 million people become ill with malaria, and the vast majority of deaths from the disease occur among young children in Africa. Moreover, the death toll is rising, because P. falciparum is becoming resistant to current treatments.
After the malaria parasite infects a human red blood cell, it must get many nutrients-proteins, sugars and precursors for DNA-to survive and grow. While it obtains some of these by digesting the red blood cell's hemoglobin, it must get the rest from outside the cell. Dr. Desai used microscopic electrodes and powerful amplifiers to show that the parasite creates tiny channels in the red blood cell membrane, through which it can absorb nutrients. This required developing special methods, he noted, to measure electrical uptake in infected red blood cells, a feat never previously accomplished. In fact, each infected red blood cell had a thousand or more such channels, which were not present on normal, uninfected red blood cells.
"Many infectious agents need to create holes in membranes to cause disease," Dr. Zimmerberg said, "and the electrophysiology I have pioneered in my laboratory is the best way to study such pores. Previously, we delineated the pathway by which the influenza virus enters cells through a fusion pore, and with NIAID, discovered an infection pore made by the parasite that causes toxoplasmosis. For malaria, it is not clear whether the parasite creates the channels by changing a protein in the cell membrane or by trafficking a new protein made in the malaria parasite to the cell membrane for subsequent incorporation."
Dr. Desai is currently trying to identify the molecules that make up the channel. "With this information, researchers may be better able to develop drugs to cut off the parasite's nutrient supply," Dr. Desai said. In addition, any new protein that the parasite adds to the red blood cell surface might be an attractive candidate for vaccine development.
NICHD and NIAID are components of the NIH. NICHD conducts and supports laboratory, clinical and epidemiological research on the reproductive, neurobiologic, developmental and behavioral processes that determine and maintain the health of children, adults, families and populations. NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
Reference: Desai SA et al. A voltage-dependent channel involved in nutrient uptake by red blood cells infected with the malaria parasite. Nature 406:1001-05 (2000).