Overcoming mosquito defense systems
Each year, millions of people fall victim to insect-borne diseases-but Mary Schuler, an affiliate in the IGB's Genomic Ecology of Global Change, hopes her genomics research can help prevent the spread of these illnesses.
Malaria is a nightmare worldwide, affecting over 400 million people each year. Other vector-borne diseases like yellow fever and West Nile are similarly destructive, especially in sub-Saharan Africa, where many strains of mosquitoes have become resistant to the chemicals used to control them-particularly the synthetic pesticide DDT.
Scientists have traditionally dealt with insects' resistance by creating new pesticides, but as insects gradually develop ways to metabolize the new chemicals, the options for that approach are limited.
The only way to break the vicious cycle is to keep the insects from detoxifying pesticides. That's where Schuler and her team come in.
Last summer, Schuler and postdoctoral researchers Ting-Lan Chiu and Sanjeewa Rupasinghe published a paper in Proceedings of the National Academy of Sciences in which they identified the protein that allows resistant mosquitoes to metabolize certain pesticides.
The protein (CYP6Z1) is just one member of a large group of proteins-called cytochrome P450 monooxygenases, or P450s-that are crucial to insects' biochemical defense systems.
Schuler knew that one of these P450s bound to DDT molecules, letting the mosquito safely process the insecticide, so she started by looking at which P450s were found in elevated quantities in the DDT-resistant mosquitoes.
When several proteins met that qualification, Schuler and her colleagues narrowed the field using state-of-the-art molecular modeling software to create three-dimensional models of the proteins. These models predicted (and further biochemical testing confirmed) that CYP6Z1 could bind to and inactivate DDT, while other candidate P450s could not.
After this discovery, Schuler used the modeling software to compare the structure of CYP6Z1 in the pesticide-susceptible and -resistant strains of Anopheles gambiae (one prominent species of malarial mosquito). She found that the two forms of the protein were actually quite similar-which suggests resistance happens when environmental factors cause the CYP6Z1 gene to be overexpressed.
"These proteins are very close," says Schuler, a professor of cell and developmental biology, plant biology, and biochemistry. "They only differ in a few active site residues. That suggests that heavy selective pressures could cause the P450 that can't metabolize DDT to be converted into one that can metabolize it efficiently."
Those "heavy selective pressures" could include plant chemicals and pollutants in the water sources where mosquitoes breed and mature. Eliminating these pollutants could be a way to prevent some mosquitoes from acquiring insecticide resistance.
Schuler's discovery is the first step towards limiting mosquitoes' pesticide resistance and maximizing the impact of current insecticides.
"If we carefully define the proteins that cause high resistance and their allelic differences in natural populations, we'll have all the tools to follow how resistance evolves, even before we see it manifested epidemiologically," Schuler says.
She also hopes to use the modeling technologies to identify the molecules that inhibit the most active P450s. "We may be able to use this information to increase the efficacy of current insecticides," she says, "which means we would need much lower levels of insecticide to control mosquitoes."
In another current research project, Schuler approaches health issues from the pharmaceutical angle. In light of the fact that plant P450s have recently been identified in the pathways for many pharmaceutical compounds, she's working on producing plant-derived compounds in microbial systems. The task combines her knowledge of P450 biochemistry and expression systems, and could be the key to developing new pharmaceutical treatments.
"These projects have the potential not only to generate a number of the alkaloids used in cancer treatments," Schuler says, "but also to produce other classes of alkaloids and terpenes that can serve as carbon skeletons for new pharmaceuticals."
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