Discovery.

Malaria's Weakness Uncovered

AUGUST 30, 2011 

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An unusual organelle tucked away in malaria parasites may hold the key to killing the pathogen and preventing disease, HHMI researchers have discovered. The first definitive proof of a weak spot in apicoplasts – organelles with ancient plant origins -- offers hope for drugs and vaccines against malaria and related pathogens.

Pathogens in the genus Plasmodium cause malaria, which infects more than 225 million people per year, mostly in sub-Saharan Africa, and kills hundreds of thousands of young children. There is currently no vaccine against malaria. Artemesinin, the current first-line treatment, is effective, but resistance against it has been growing. Moreover, scientists have yet to discover the molecular target of artemesinin.

“This, in no uncertain terms, confirms that the only truly essential function of the apicoplast during the blood stage is the production of this one chemical.”
Joseph L. DeRisi

Researchers have suspected that the apicoplast might be one of the pathogen’s key vulnerabilities since the organelle was discovered in 1996. The apicoplast contains its own genes, and these have origins in red algae and cyanobacteria, suggesting that the organelle is the result of an endosymbiotic event, in which the ancestral malaria parasite engulfed another cell and began to rely on it for particular functions. Since the apicoplast’s genes are plant-like, drugs that block them are unlikely to interfere with human genes.

Destroying the whole apicoplast with antibiotics is enough to kill malaria cells. But although scientists have identified possible functions of the apicoplast and found ways to block various apicoplast pathways, it has been difficult to specifically find apicoplast-targeting drugs that impair the overall function of the malaria pathogen.

“When folks discovered the apicoplast, it was heralded to be the Achilles’ heel of malaria,” says Howard Hughes Medical Institute investigator Joseph L. DeRisi, who spearheaded the latest study at the University of California San Francisco. “But the initial attempts to target it were disappointing. Now we’ve found out why.”

DeRisi and Ellen Yeh, a postdoctoral fellow in his lab, chose to study an apicoplast pathway that hadn’t been targeted yet: a set of genes that synthesize isoprenoids, chemical building blocks with a number of cellular functions. DeRisi and Yeh used a known chemical inhibitor to block the isoprenoid pathway in Plasmodium’s apicoplasts. The cells died as expected, indicating that the pathway is vital to their survival. The scientists then added the end product of the pathway—a compound called isopentenyl pyrophosphate(IPP)—to Plasmodiumcells at the same time as the pathway-blocking drug. The malaria-causing cells survived this time, demonstrating the importance of IPP to malaria.

DeRisi and Yeh didn’t stop there—they wanted to find out whether producing IPP was the only necessary function of the apicoplast, or just one of many vital functions of the organelle. To test this hypothesis, they treated cells with antibiotics, which destroy the entire apicoplast, and then with IPP. The cells, usually rendered dead after a treatment with antibiotics, stayed alive, DeRisi and Yeh report in the August 30, 2011, issue of PLoS Biology.

“This, in no uncertain terms, confirms that the only truly essential function of the apicoplast during the blood stage is the production of this one chemical,” concludes DeRisi.

The discovery of the apicoplast’s weak spot provides researchers with a target for drugs and vaccines, and suggests ways to study malaria further. To investigate exactly how the malaria pathogen uses the IPP that’s so vital to its survival, researchers can remove the apicoplast with antibiotics so it no longer provides the cell with IPP. Then, the researchers can add tagged IPP to the cell, and follow where it goes—a vein of research that DeRisi’s lab is already pursuing.

Additionally, scientists can now pinpoint drugs that treat malaria specifically by blocking the apicoplast’s production of IPP. They can first screen compounds for their ability to kill the pathogen. For those compounds that pass the test, researchers can then see whether adding IPP along with the drug lets Plasmodium cells survive. If so, they’ll know they’ve discovered a drug that works by targeting the apicoplast and blocking IPP production.

Moreover, DeRisi’s findings pave the way for a unique malaria vaccine. His research makes clear thatPlasmodium cells without an apicoplast survive only one generation—long enough to expose a human immune system to the pathogen, but not long enough to cause disease. A vaccine consisting of Plasmodium cells with the apicoplast removed is a potential game-changer for the field of malaria research.

“This finding could also have far reaching implications for other parasites that carry the apicoplast organelle,” DeRisi adds. Pathogens including toxoplasma, the cause of the fooddborne illness toxoplasmosis, also have apicoplasts. Whether the apicoplast has the same function in all these related parasites is yet to be determined, but DeRisi hypothesizes that his findings in malaria will translate broadly to other similar pathogens

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