Researchers Find Therapeutic Targets To Fight Dengue Fever

Duke University Medical Center researchers have identified potential therapeutic targets to fight dengue fever.

By painstakingly silencing genes one at a time, they have identified dozens of proteins the dengue fever virus depends upon to grow and spread among mosquitoes and humans.

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"Dengue is a nasty disease, and right now, there is no treatment for it and no way to prevent it. But if we can find a weakness in the virus, we can design a strategy to fight it. This study has helped us identify some gaps in dengue's armour," said Mariano Garcia-Blanco, M.D., Ph.D., professor of molecular genetics and microbiology at Duke University Medical Center and senior author of the study.

Garcia-Blanco used RNA interference (RNAi) to unlock dengue's secrets. RNA interference is a normal biological process cells use to turn gene expression on or off depending upon which gene products, or proteins, are needed at any given moment.

"That very same system proved to be the perfect investigative tool for our study," said Garcia-Blanco.

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Garcia-Blanco and colleagues in Duke's RNAi facility were able to knock down gene function in fruit fly cells infected with a strain of the dengue virus known as DENV-2.

Silencing one gene at a time (there were about 14,000 of them) allowed researchers to pinpoint which genes, or host factors, were essential to viral growth and which ones were not.

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They used fruit flies as a model because the genetic tools needed for the same work in mosquitoes have not been developed yet.

The process yielded 116 host factors that appeared to be important to successful dengue infection in fruit flies.

In testing several of these host factors in mosquitoes at Johns Hopkins University, researchers subsequently discovered that at least one, and possibly a second, was necessary for dengue infection to occur in the insects.

Researchers also infected human cells with the DENV-2 virus and found 82 of the mosquito genes had analogous genes in humans. About half that number turned out to be dengue-specific host factors important in human infection.

"Each one of these newly identified host factors is a potential therapeutic target that could be used to block or slow dengue infection," said Garcia-Blanco.

Currently, there are no vaccines to prevent the disease, "so new ways to fight the disease are important," he added.

The study appears in the April 23 issue of the journal Nature. br>
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