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Researchers discover how malaria parasite disperses from red blood cells
September 20, 2005Researchers at the National Institute of Child Health and Human Development have determined the sequence in which the malaria parasite disperses from the red blood cells it infects. The National Institute of Child Health and Human Development is one of the Institutes comprising the National Institutes of Health.
The study appears in the September 20 Current Biology.
"This discovery provides the groundwork for possible new approaches to treating malaria, " said Duane Alexander, M.D., Director of the NICHD. "The malaria parasite is growing resistant to the drugs used to treat it, and new knowledge is essential for developing strategies to protect against the disease."
The study supplants earlier theories on how the malaria parasite spreads from the red blood cells it infects.
According to the World Health Organization, malaria kills more than 1 million people a year. (The WHO fact sheet, "What is Malaria?" is available on the organization's Web site at http://mosquito.who.int/cmc_upload/0/000/015/372/RBMInfosheet_1.htm )
Malaria is caused by four species of the parasite Plasmodium, the most common and deadly of which is Plasmodium falciparum. P. falciparum spends part of its life cycle in the salivary glands of mosquitoes and is transmitted to human beings through the bite of infected mosquitoes. The parasite infects red blood cells. Called a merozoite at the stage of its life when it infects red blood cells, the parasite multiplies inside the cell, until the cell ruptures and releases them. The newly released merozoites infect still other cells, and the process begins again.
To conduct the study, the researchers stained red blood cells infected with P. falciparum with two kinds of dye, explained the study's senior author, Joshua Zimmerberg, M.D., Ph.D., Chief of NICHD's Laboratory of Cellular and Molecular Biophysics. One dye stained the blood cells green, the other stained the parasites red.
In the first stage of the merozoites' release, which the researchers dubbed the "irregular schizont" stage, the red blood cell resembles a lop-sided fried egg, with the parasites visible as a sphere near the center of the cell. (A diagram of the entire sequence appears at http://www.nichd.nih.gov/new/releases/malaria_graphic.cfm ) The cell's lop-sided appearance probably results from destruction of the cytoskeleton, the molecular scaffolding that helps the cell to maintain its rounded shape.
In the next stage, called the "flower" stage, the red blood cell assumes a roughly spherical shape, covered with rounded structures that resemble the petals of a flower. Shortly thereafter, the blood cell's membrane appears to break apart. At roughly the same time, cellular compartments, called vacuoles, which encase the newly formed merozoites, also break apart. The entire process has an explosive appearance, dispersing the merozoites some distance from the cell.
During the release, Dr. Zimmerberg explained, the cell membrane appears to collapse inward upon itself and fragment into pieces.
One previous theory held that the red blood cells and the merozoite-containing vacuoles inside them swelled and then burst like a balloon containing too much air.
"The swelling was an artifact of too much light from the microscope," Dr. Zimmerberg said. "The cell membrane was light sensitive. When we turned the light down, we didn't see the swelling." Rather, he said, upon release of the merozoites, the cell membrane appeared to contract in upon itself.
Another theory held that the merozoite-containing vacuoles would fuse with the cell membrane, and then release their contents.
"But we didn't see any fusion," Dr. Zimmerberg said.
The third theory held that the cell membrane ruptured, expelling merozoite-containing vacuoles. Again, however, the researchers observed that this theory also offered an inaccurate picture, as the vacuoles ruptured at roughly the same time as the cell membrane.
Each step in the release process is a potential avenue for new therapies to treat the disease, Dr. Zimmerberg said. By first understanding how the parasite brings about these steps, it may be possible to find ways to prevent them from occurring.
NIH/National Institute of Child Health and Human D
The study supplants earlier theories on how the malaria parasite spreads from the red blood cells it infects.
According to the World Health Organization, malaria kills more than 1 million people a year. (The WHO fact sheet, "What is Malaria?" is available on the organization's Web site at http://mosquito.who.int/cmc_upload/0/000/015/372/RBMInfosheet_1.htm )
Malaria is caused by four species of the parasite Plasmodium, the most common and deadly of which is Plasmodium falciparum. P. falciparum spends part of its life cycle in the salivary glands of mosquitoes and is transmitted to human beings through the bite of infected mosquitoes. The parasite infects red blood cells. Called a merozoite at the stage of its life when it infects red blood cells, the parasite multiplies inside the cell, until the cell ruptures and releases them. The newly released merozoites infect still other cells, and the process begins again.
To conduct the study, the researchers stained red blood cells infected with P. falciparum with two kinds of dye, explained the study's senior author, Joshua Zimmerberg, M.D., Ph.D., Chief of NICHD's Laboratory of Cellular and Molecular Biophysics. One dye stained the blood cells green, the other stained the parasites red.
In the first stage of the merozoites' release, which the researchers dubbed the "irregular schizont" stage, the red blood cell resembles a lop-sided fried egg, with the parasites visible as a sphere near the center of the cell. (A diagram of the entire sequence appears at http://www.nichd.nih.gov/new/releases/malaria_graphic.cfm ) The cell's lop-sided appearance probably results from destruction of the cytoskeleton, the molecular scaffolding that helps the cell to maintain its rounded shape.
In the next stage, called the "flower" stage, the red blood cell assumes a roughly spherical shape, covered with rounded structures that resemble the petals of a flower. Shortly thereafter, the blood cell's membrane appears to break apart. At roughly the same time, cellular compartments, called vacuoles, which encase the newly formed merozoites, also break apart. The entire process has an explosive appearance, dispersing the merozoites some distance from the cell.
During the release, Dr. Zimmerberg explained, the cell membrane appears to collapse inward upon itself and fragment into pieces.
One previous theory held that the red blood cells and the merozoite-containing vacuoles inside them swelled and then burst like a balloon containing too much air.
"The swelling was an artifact of too much light from the microscope," Dr. Zimmerberg said. "The cell membrane was light sensitive. When we turned the light down, we didn't see the swelling." Rather, he said, upon release of the merozoites, the cell membrane appeared to contract in upon itself.
Another theory held that the merozoite-containing vacuoles would fuse with the cell membrane, and then release their contents.
"But we didn't see any fusion," Dr. Zimmerberg said.
The third theory held that the cell membrane ruptured, expelling merozoite-containing vacuoles. Again, however, the researchers observed that this theory also offered an inaccurate picture, as the vacuoles ruptured at roughly the same time as the cell membrane.
Each step in the release process is a potential avenue for new therapies to treat the disease, Dr. Zimmerberg said. By first understanding how the parasite brings about these steps, it may be possible to find ways to prevent them from occurring.
NIH/National Institute of Child Health and Human D
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