Study Points to Genes Responsible for Malaria Parasite’s Survival in Face of Attempts to Eradicate It

By Mika Ono

A team of scientists at The Scripps Research Institute, Harvard University, the University of Chicago, the Genomics Institute of the Novartis Research Foundation, and Cheik Anta Diop University (Senegal) has discovered hundreds of novel genes that may help the malaria parasite evade destruction by the human immune system and anti-malarial drugs. The findings could lead to the development of new therapies or vaccines for the deadly disease.

The study is being published online June 16 in PloS Pathogens, a peer-reviewed, open access journal of the Public Library of Science.

"While millions of dollars have been spent to develop a malaria vaccine, we still don’t have a licensed product," says Associate Professor Elizabeth Winzeler of Scripps Research, who led the study. “Our findings may help in the vaccine-development effort, because they point to novel immunogens that could be targeted.”

Winzeler adds the study also identified novel genes involved in the parasite’s development of drug resistance—another critical issue in the fight against malaria.

Malaria is a nasty and often fatal disease, which may lead to kidney failure, seizures, permanent neurological damage, coma, and death. There are four types of Plasmodium parasites that cause the disease, of which falciparum, the subject of the recent study, is the most deadly.

Despite a century of effort to globally control malaria, the disease remains endemic in many parts of the world. With some 40 percent of the world's population living in these areas, the need for more effective vaccines and treatments is profound. The spread of drug-resistance adds to the urgency.

In the study, the scientists used gene-chip technology to compare the genomes of 14 different field and laboratory strains of Plasmodium falciparum collected from four continents. Of the parasite’s roughly 5,000 genes, about 500 were found to be highly variable across the different strains, indicating that these genes are evolving at a faster-than-neutral rate.

“These genes exhibit variability far above and beyond basic housekeeping genes,” notes Winzeler. “Most genes in the malaria parasite are highly conserved, but these appear to be evolving rapidly.”

Why? According to the study, “guilt by association” would indicate that the genes that are rapidly evolving are the very genes responding to our best attempts to eradicate the parasite. “The two largest forces exerting selection pressures on the parasite are our immune system and anti-malarial drugs, particularly chloroquine,” says Winzeler.

Previous to this study, no systematic overview of these potential targets in the parasite’s genome existed. The study’s results include known drug and vaccine targets, and—intriguingly—areas of the genome not currently under investigation.

One example of a promising potential new target highlighted by the research is the P. falciparum GTP cyclohydrolase gene, the first enzyme in the folate biosynthesis pathway. Downstream members of this pathway are targeted by several widely used antimalarials, and authors speculate that an amplification of the GTP cyclohydrolase enzyme facilitates parasite resistance to antifolate drugs.

“I’m super excited about the paper,” says Winzeler. “It’s going to have an impact on the research community.”

The article, "A Systematic Map of Genetic Variation in Plasmodium falciparum," was authored by Claire Kidgell, Sarah K. Volkman, Johanna Daily, Justin O. Borevitz, David Plouffe, Yingyao Zhou, Jeffrey R. Johnson, Karine G. Le Roch, Ousmane Sarr, Omar Ndir, Soulyemane Mboup, Serge Batalov, Dyann F. Wirth, and Elizabeth A. Winzeler. It can be viewed at: http://dx.doi.org/10.1371/journal.ppat.0020057.

This work was supported by the National Institutes of Health; the Ellison Medical Foundation; and the W. M. Keck Foundation.

Send comments to: mikaono[at]scripps.edu

The new study suggests reasons why our immune systems and anti-malarial drugs have not eliminated the parasite that causes malaria. Here, red blood cells are shown infected by the malaria-causing parasite Plasmodium falciparum.