Influenza is a wily virus, one that changes its appearance with speed and ease. That's one reason why you have to get a new flu shot each year--antibodies produced in response to last year's vaccine don't recognize newly mutated strains. But at its core, the virus always uses the same tactic: It hijacks the nucleus of an infected cell and changes it into a virus-producing factory. Blocking that process might be an effective way to fight the virus, researchers report in the March issue of Nature Cell Biology.
Trying to zero in on this strategic core, the researchers--virologists Stephan Ludwig of Julius-Maximilians University in Wurzburg, Germany, Stephan Pleschka of Justus-Liebig University in Giessen, Germany, and their colleagues--targeted the cellular machinery the virus uses to replicate itself. They speculated, based on other research, that flu viruses might exploit a well-known molecular pathway that controls cell growth. The team wondered if the influenza virus relied on the Raf/MEK/ERK cascade, a pathway named for three of its main proteins, to replicate itself in a cell.
To find out, the team applied a molecule that blocks the action of the MEK protein to cell cultures infected with the flu virus. After several rounds of viral replication, cell cultures incubated with the MEK-blocking compound contained one-fifth as many viral particles as control cultures. In other experiments, the researchers found that the MEK-blocking compound thwarts the virus by trapping newly formed ribonucleoproteins--complexes of RNA and protein that contain the virus genome--in the cell's nucleus. Because the experimental cells were prevented from packaging viral genes into their proper protein coats, they couldn't make new virus particles.
Virologist Adolfo Garcia-Sastre of the Mt. Sinai School of Medicine in New York City says the research provides an important insight into how influenza commandeers a cell. Although other viral inhibitors are far more effective at blocking viral replication in cell culture, he says, optimized inhibitors of the MEK protein might be promising virus-fighters.
The work is a long way from producing an over-the-counter flu remedy. For example, Raf, MEK, and ERK play key roles in almost all cells, so blocking them might cause side effects. But Ludwig says other MEK blockers in animal trials for cancer treatments have proved safe so far.
Related sites
Stephan
Ludwig's research interests
CDC
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