Dec. 14, 2000 St. Louis, Dec. 11, 2000 -- Researchers have identified a previously unknown step that enables the malaria parasite to spread in the bloodstream. And they have found a way to block this key event. The findings, reported in the Dec. 12 online edition of Proceedings of the National Academy of Sciences, may lead to promising targets for drug development.
Malaria afflicts 300 to 500 million people worldwide and kills nearly 2 million children each year. The parasites that cause the disease multiply inside red blood cells, bursting from them to invade new cells.
"But little was known about how the parasites break out of cells," said Daniel E. Goldberg, M.D., Ph.D., senior author of the paper and a professor of medicine and of molecular microbiology in the Howard Hughes Medical Institute at Washington University School of Medicine in St. Louis. "Now that we have identified the major stages, we will be able to study the process better."
As if they were instantly replaying a football scrimmage, the researchers slowed the action with inhibitors. They discovered that the parasites emerge from red blood cells in two steps. "First, they exit enclosed in a sac they have made. Then the sac quickly bursts, releasing the parasites," Goldberg said.
Enzymes that break down proteins—proteases—were thought to help the parasite emerge from red blood cells. And inhibitors of these enzymes are effective against other infectious agents, notably the virus that causes AIDS. Therefore, Goldberg's group studied the effect of a protease inhibitor called E64 on the malaria parasite.
E64 did not stop the parasites from escaping out of red blood cells. But it prevented them from rupturing the sac that enclosed them. When E64 was removed, the parasites spilled from the sac to infect other red blood cells. Similar sacs had been seen in infected blood samples, but only fleetingly, and their significance had not been grasped. "By better understanding the role of proteases in the parasite's escape from the host cell, we may be able to develop clinically useful inhibitors that will keep it from getting out to infect new cells," Goldberg said.
Salmon BL, Oksman A, Goldberg DE. Malaria parasite exit from the host erythrocyte: a two step process requiring extraerythrocytic proteolysis. Proceedings of the National Academy of Sciences, online edition, Dec. 12, 2000.
The work was supported by the Burroughs Wellcome Fund
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