November 2, 2005

Researchers Develop New Method To
Find Deadly Malaria Parasite’s Achilles Heel

By Rex Graham

Researchers at UCSD have discovered that the single-celled parasite responsible for an estimated 1 million deaths per year worldwide from malaria has protein “wiring” that differs markedly from the cellular circuitry of other higher organisms, a finding which could lead to the development of antimalarial drugs that exploit that difference.

The scientists will report in the Nov. 3 issue of Nature a comparison of newly discovered protein-interactions in Plasmodium falciparum with protein interactions reported earlier in four other well studied model organisms -- yeast, a nematode worm, the fruit fly, and a bacterium that causes digestive-tract ulcers in humans. The authors of the study, Trey Ideker, a professor of bioengineering at UCSD’s Jacobs School of Engineering, UCSD Ph.D. candidate Silpa Suthram, and Howard Hughes Medical Institute (HHMI) medical student research fellow Taylor Sittler, said the malaria parasite’s protein interactions “set it apart from other species.”

Bioengineering professor Trey Ideker, left, and Ph.D. candidate Silpa Suthram say that the malaria parasite Plasmodium falciparum's protein interactions set it apart from other organisms.

“We’ve known since the Plasmodium genome was sequenced three years ago that 40 percent of its 5,300 proteins are significantly similar, or homologous, to proteins in other eukaryotes, but until now we didn’t know that the malaria parasite assembles those proteins so uniquely,” said Ideker. “Since our earlier research showed that yeast, worm, and fly have hundreds of both conserved proteins and protein interactions, we didn’t initially believe our own analysis, which showed that there are only three Plasmodium protein interactions in common with yeast and none in common with the other species studied.”

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Malaria is a protozoan disease caused by four species of the genus Plasmodium, with P. falciparum by far the most deadly. The World Health Organization warns that malaria is a growing health threat, particularly in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. No malaria vaccine has been developed, and once powerful antimalarial drugs are less and less effective because Plasmodium falciparum has developed resistance to those drugs. Even mosquitoes that transmit malaria are developing resistance to the most commonly used insecticides.

“The demonstration that the Plasmodium protein network differs significantly from those of several model organisms is an intriguing result that could lead to the identification of novel drug targets for fighting malaria,” said John Whitmarsh, acting director of the Center for Bioinformatics and Computational Biology at the National Institute of General Medical Sciences, which partially funded the work. “Ideker and his team have demonstrated the effectiveness of a computational approach based on mathematics for understanding complex biological interactions.”

Researchers studying protein expression under controlled laboratory conditions have been slowed because techniques designed for other organisms work poorly with Plasmodium because 80 percent of its genome is comprised of only two of the four building blocks of DNA.

Stanly Fields, an HHMI investigator and professor of genomic sciences at the University of Washington, invented an ingenious way to identify pairs of proteins that physically interact with one another. Fields modified his technique and added special culture conditions to enable his group to study Plasmodium. Fields’s team and collaborators at Prolexys Pharmaceuticals of Salt Lake City, UT, discovered 2,846 interactions involving 1,312 Plasmodium falciparum proteins. The team provided data on those interactions to Ideker’s group earlier and also reported the results in the Nov. 3 issue of Nature.

Ideker’s team applied a rigorous statistical analysis approach to the Fields group’s data, focusing on interacting Plasmodium proteins that have homologs in other species. While the genomes of hundreds of species are filled with homologous proteins, Ideker and his colleagues are eager to understand how they interact with one another as part of a new approach to help in the design of drugs that disrupt proteins in pathogens while sparing patients from side effects.

Malaria is transmitted to humans by the bite of an infected female mosquito of the genus Anopheles. The protozoan parasite has a four-stage life cycle, however the Fields group analyzed only the proteins expressed in the phase that infects human red blood cells, an infection that leads to extreme exhaustion associated with fever, shaking chills, headache, muscle aches, and other symptoms. Ideker said critics may fault his study because only a subset of the Plasmodium’s proteins is expressed in the erythrocytic stage. However, he noted that the parasite’s asexual-phase is actually enriched in proteins for which homologs have been found in other species. Ideker also noted that the known protein interactions in yeast, worm, and fly represent only 20 percent of the total interactions and some of the reported interactions may be erroneous.

“All the protein networks described so far are incomplete and statistically noisy,” said Ideker. “But whether they are incomplete and noisy in the same way or not, we can say with confidence that this particular stage of Plasmodium is different from the other organisms we’ve examined so far. It’s this lack of overlap with other species that’s surprising.”

Ideker said the Plasmodium’s membrane-protein complexes may be of particular interest. “Plasmodium presents many of these proteins to the red blood cell during infection and prior to replication,” he said. “What really jumps out of our paper is the large number of membrane protein interactions in Plasmodium that are absent in other organisms. While this is potentially good news for fighting malaria, we need to know much more before we start talking about which membrane-protein interactions to target with a new drug.”

We acknowledge the following funding support: the National Science Foundation (S.S.); the National Institute of General Medical Sciences (T.I.); a David and Lucille Packard Fellowship award (T.I.); the Howard Hughes Medical Institute (T.S.); and Unilever (T.S.).

Media Contact: Rex Graham, (858) 822-3075