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U.W.ís new fly in the ointment
MADISON, Wis.óAs documented in the July 9 issue of Nature, researchers at the University of WisconsinĖMadison infected fly model Drosophila melanogaster with influenza and identified, as the university notes in its news release about the research, "scores of host genes the pathogen requires for successful infection, revealing a raft of potential new pressure points to thwart the virus."
Led by Yoshihiro Kawaoka and Paul Ahlquist, the U.W.-Madison team tested the ability of a modified flu virus to infect cells whose genes were systematically disabled to see which were co-opted by the virus. The importance of the research lies in the fact that this may demonstrate a "rapid-fire" technique for identifying host factors, such as proteins and carbohydrates, that a virus commandeers to successfully infect a cell. By exposing the virus's dependencies, the researchers are confident they have uncovered a target-rich environment for influenza drug developers.
Although the work was done in cells of a fruit fly, most of the genes have mammalian analogs and initial tests in human cells of three of the 100 genes identified confirmed all three are necessary for the virus to successfully make copies of itself to promote infection.
"The genes we identified in mammalian cells are very specific for influenza," says Kawaoka, a flu expert and a professor of pathobiological sciences at the U.W.-Madison's School of Veterinary Medicine. "Now we know influenza viruses are using specific host proteins so those become targets for drug development."
"Viruses are typically very 'gene-poor' and even though some of them have hundreds of genes, something on the order of five or 10 genes is more common, with flu at the larger end of that range," explains Ahlquist, a Howard Hughes Medical Institute investigator at the university. "Compared to that, a host cell has tens of thousands of genes, and one of the great mysteries of viruses is how they do everything they need to do with so few genes. Obviously, they leverage the considerably greater resources of the host cell, but this research gives us more insight into how they do it exactly so that we know what critical host functions the virus is using."
The problem with antiviral medications used right now, whether for the flu or for other infections like HIV, is the drugs attack functions in the viruses' own genes. But because viruses mutate so fast, they quickly become resistant to those drugs.
"What previous research has show with down-regulating cell functions, is that we can theoretically down-regulate a cell to a level where it is still healthy and happy, but create a situation in which the virus is in trouble," Ahlquist says. "Viruses are all about pushing cells to extremes to create as many progeny as possible. But now we may be on the path to creating drugs that can deny them that ability and create medications that are much harder for a virus to overcome."
Both Ahlquist and Kawaoka say the new system has potential application beyond studies of influenza and could help speed the development of antiviral drugs for many diseases, including AIDS. DDN