An investigation into the mysterious inner workings of the malaria parasite revealed that it survives and proliferates in the human bloodstream thanks in part to a single, crucial chemical that the parasite produces internally.

According to scientists at the University of California, San Francisco (UCSF) and Stanford Medical School, this insight provides a tool for discovering and designing drugs to treat malaria. The work also gives researchers a hypothetical new vaccine to test: a weakened version of the parasite, which the scientists grew in the test tube by supplying it with the chemical it needed to live while at the same time treating it with drugs to eliminate its ability to produce that chemical on its own.

“It’s as if we designed a ticking time bomb inside the parasite that’s ready to go off, and when it does, the parasite dies,” explains Joseph DeRisi, PhD, a Howard Hughes Medical Institute investigator at UCSF and vice chair of the department of biochemistry and biophysics.

In theory, health officials could inoculate people living in areas where malaria is common with a similar “attenuated” form of the parasite. If it works, the modified parasite would not make those people sick but would give them resistance to the pathogen if they were later exposed to it – although that approach would need to be tested in clinical trials to determine whether it would work. “It is an intriguing possibility that must be explored,” says Ellen Yeh, MD, PhD, a postdoctoral researcher at UCSF.

For years scientists knew that the most fruitful way to fight the parasite would be to target the form in which it exists in the bloodstream, since that is where the majority of clinical symptoms occur.

About 15 years ago, scientists discovered a potential new source of drug targets in a tiny, factory-like enveloped organelle called an apicoplast that exists within the parasite. It was unlike anything found normally in the human body, which suggested that drugs designed to interfere with it might kill the parasite while essentially leaving people unharmed.

“It was a very exciting discovery,” DeRisi says, “but in the years since, the prospect of finding drugs to target it has been frustrating and disappointing in many respects.” In the last decade, the evolutionary history of this strange organelle has unfolded. The apicoplast is the strange remnant of collisions between competing cells far back in evolutionary history. Scientists reason that through the course of evolution, the apicoplast arose from its origin as a standalone bacterium into its current form through a series of at least two endosymbiotic events, in which one cell engulfs and permanently acquires genetic material and cellular machinery of another for its own benefit.

The discovery of this strange organelle in modern Plasmodium immediately suggested that there might be ways to target it with new drugs. However, even after extensive research revealed the genes of this apicoplast, efforts to raise new drugs against it were mostly fruitless – largely because nobody knew what the organelle actually did while the parasite was inside the human bloodstream. Now DeRisi and Yeh have shown that the sole essential function of the apicoplast while the parasite is in the blood is to produce a single chemical known as isopentenyl pyrophosphate (IPP), a necessary building block the parasite uses to construct a variety of other molecules.

They discovered this by growing samples of Plasmodium falciparum within red blood cells in the test tube. If they treated the parasite with antibiotic drugs that kill the apicoplast, the parasites would all die. If they fed the parasites IPP at the same time, they lived—even though the parasites lost the organelle completely over time.

The work provides a new tool for probing the basic biology of the Plasmodium parasite, and it also suggests a new way of discovering promising new drugs to fight malaria. While many previous drug-screening efforts have identified multitudes of compounds that appear to inhibit growth of the parasites, most are without a known target within the parasites. Knowing the target of a drug greatly enables the necessary process of medicinal chemistry, in which the compound is optimized with respect to the target. Now, DeRisi and Yeh’s discovery has provided a simple tool to determine whether any particular drug candidate targets the apicoplast.

The attenuated form of the parasite also provides an intriguing hypothetical vaccine candidate —and one that would be relatively cheap to produce, DeRisi says. However, he cautioned, the history of malaria control is filled with failed efforts, and several past vaccines have fallen short. Only time and clinical trials will tell if this is a viable solution to the problem.

The research was published in PLoS Biology.

Release Date: August 30, 2011
Source: University of California, San Francisco