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Malaria's Weakness
by Kendall Powell
With different approaches, two HHMI researchers land on an enzyme critical to the malaria parasite's destructive ways.
In a hallway during an October 2008 science meeting in Bangkok, the chitchat was guarded. The two malaria researchers held their cards close to their chests. Dan Goldberg and Alan Cowman realized, however, that they were working on the same research question, approaching it from opposite directions, and quickly closing in on an answer.
They agreed to share information and keep each other informed of their progress. In the end, their papers were published back-to-back in the February 4, 2010, issue of Nature. Both reveal the central role of one enzyme, plasmepsin V, in the malaria parasite's survival.
“The parasite does lots of things that dramatically affect the physical properties of the red blood cell. It takes over the cell for its own purpose,” says Goldberg, an HHMI investigator and infectious disease physician at Washington University in St. Louis.
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Life Cycle of Malaria
Watch the parasite as it reproduces.
 
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When an infected mosquito injects the malaria parasite, Plasmodium falciparum, into a human's bloodstream, the parasite travels to the liver where it multiplies for 1-2 weeks. Parasites then break out of the liver cells and invade red blood cells. During this stage of its life cycle, the amoeba-like organism cloaks itself within a red blood cell, wrapped in a bit of cell membrane, and converts the cell into a hiding place from the immune system while it reproduces. This coup relies on the parasite shipping 200-300 of its proteins into the cell, which camouflage the cell and turn it into a sticky glob that clings to blood vessel walls. The proteins also help gather nutrients for the hungry parasite so it can continue to multiply.
Cowman, an HHMI international research scholar at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, and his team were searching for the enzyme that chops proteins down for export in a form the parasite can recognize. In 2004, Cowman's lab had identified a specific sequence of amino acids called a PEXEL motif that appeared in all exported proteins. He had a hunch that a protease might recognize the PEXEL sequence and cut at that site. Meanwhile, Goldberg and his group had been characterizing a protease enzyme, called plasmepsin V (PMV), which they had found in the endoplasmic reticulum of the parasite but didn't know what it did.
Illustration: Mark Allen Miller
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