Working to snip malaria drug resistance

Useful genetic maps showing the inner workings of drug-resistant malaria parasites, and where they live around the world, are being created as part of a major drive against the persistent tropical disease.

According to molecular biologist Dyann Wirth, chair of the Harvard School of Public Health’s Department of Immunology and Infectious Diseases, the large research effort is aimed at identifying the individual mutant proteins that make the malaria parasite resistant to drug treatments. Researchers, she said, are searching for single nucleotide polymorphisms (SNPs) in studying the parasite’s genes. She said the team wants to know “where they occur, and who they are.”

SNPs, or “snips,” can be used as identifying markers for the genes that make drug-resistance proteins.

In a report on the project delivered today at the annual meeting of the American Association for the Advancement of Science in Boston, Wirth told her audience the research team wants to trace the parasite’s various mutant genes back to where they originated. “We want to understand exactly what selected the parasite from the time it separated from its ancestor,” she said.

“It’s important that we understand the spread of drug resistance,” she added, including whether genes for it arise independently in multiple places. It is already clear that the resistance genes are highly variable, that  the parasite uses them for making cell-surface molecules, and that are important for the parasite’s interactions with host cells. The parasite’s surface molecules, or antigens, Wirth said, “have extreme diversity,” which means the parasites have been subjected to strong selection pressures.

Malaria is a widespread infectious disease in tropical regions of Asia, Africa, South America, and elsewhere, and is the fourth-leading cause of death among children under 5 worldwide, claiming 853,000 victims annually according to the Centers for Disease Control and Prevention. It is a mosquito-borne illness that was almost eradicated half a century ago through effective mosquito-control efforts, but rebounded  when the pests began developing resistance to insecticides such as DDT. In time, DDT was banned in most Western nations because of environmental concerns, and it fell into disuse in malaria-prone regions.

Resistance to drug treatments has also facilitated the spread of infections.
“What’s fascinating,” Wirth said, “is that in the mutations that differentiate [one mutant strain from another], there is an enrichment for amino-acid changes. This indicates that diversification is driven by immune systems, and perhaps by factors we can’t measure.”

Such findings allows us to “sort the parasites into continental populations,” she added, identifying them as coming from central America, Africa or Asia. “It’s sort of a bar-code for parasite identification.”

The goal is to develop systems that will allow quick and accurate identification of the types of drug resistance so that health care workers will know what drugs to use, and will not misprescribe and contribute to the resistance problem. But the technologies must be simple and robust enough to be used by medical personnel who don’t have access to well-equipped clinics or hospitals.

Wirth said she and her colleagues are now collaborating with scientists at the Broad Institute of Harvard and MIT and with Genzyme Corp., both in Cambridge, in efforts to develop new drugs against malaria, especially against the drug-resistant forms of the disease.