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Biology Articles » Parasitology » Scientists Make Malaria Parasite Work To Reveal Its Own Vulnerabilities
February 2, 2009 — Researchers seeking ways to defeat malaria have found a way to get help from the parasite that causes the disease.
Scientists at Washington University School of Medicine in St. Louis
stepped aside and let Plasmodium falciparum, one of the deadliest
strains of malaria, do a significant portion of the genetic engineering
work in their new study. With that help, they could unambiguously show
that the parasite relies heavily on a one-of-a-kind protein that it
only makes in small quantities, two qualities that make the protein an
attractive drug development target.
"The protein in question, which we're calling Pcalp, belongs to a
class of cutting proteins known as proteases, which also are good drug
targets generally," says senior author Daniel E. Goldberg, M.D., Ph.D.
"There's already quite a bit of knowledge available about how we can
inhibit such proteins, spurred in part by the effort to develop drugs
to combat HIV."
Pcalp caught researchers' attention because it's the parasite's only
calpain, a specialized form of protease. Humans, in contrast, have more
than a dozen calpains. Because the parasite makes so little Pcalp
during the stage of its lifecycle that takes place in human blood, lead
author Ilaria Russo, Ph.D., a postdoctoral fellow, had to develop
special techniques just to detect it.
"When we first talked about Pcalp, the low levels we reported had
people skeptical that it could do much at all during human infection,"
Goldberg says. "They suggested that Pcalp had to be more important to
malaria during other stages in its lifecycle, such as the one that
takes place in mosquitoes."
Normally microbiologists test a protein's importance by simply
removing the gene for the protein and checking if the organism
survives. However, a few recent reports suggested that the way
scientists were removing genetic material from the parasite could
adversely impact its chances for survival, producing false
positives—genes that seemed to be essential but were not.
To solve this problem, Russo took advantage of microorganisms'
natural ability to genetically re-engineer themselves using mobile bits
of DNA called plasmids. She created multiple copies of two plasmids:
one with a slightly altered but still functional version of Pcalp, and
another with a copy of Pcalp mutated so that it could not work
The parasite could incorporate the first version of Pcalp, but the
researchers found evidence that it avoided stitching the second,
defective version into its DNA. This showed that Pcalp is essential to
the malaria parasite, according to Goldberg.
When Russo adapted a system previously only used in higher organisms
to let her increase or decrease levels of Pcalp available to the
parasite, she found evidence that it needs the Pcalp protein to
progress through its normal cell cycle.
"There are a number of other labs already interested in developing a
drug to block Pcalp, and in the meantime we're going to try to further
clarify exactly how Pcalp helps regulate the parasite's cell cycle,"
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