Most of the time, being ill with the flu is little more than a nuisance. Other times, it can spark an exaggerated immune response and turn deadly. Researchers reporting in the September 16th issue of the journal Cell, a Cell Press publication, have now traced the origins of this severe immune response -- called a cytokine storm -- to its source.
Cytokines are the chemical signals that drive inflammation, and cytokine storms are thought to be the cause of many of the deaths attributed to the 1918 worldwide influenza pandemic and to the more recent outbreaks of swine and bird flu infection. The new study provides encouraging news by offering the foundations for a completely new kind of flu therapy.
"We are showing for the first time that you can actually separate the deleterious events from those needed to control the virus," said Hugh Rosen, senior author of this study, from The Scripps Research Institute.
"It had been thought for a long time that all injury from influenza was due to the virus itself, consequently, and rationally, the focus was on developing antiviral drugs," said study co-author Michael Oldstone, also of Scripps.
The new results suggest that drugs aimed at the dangerous immune response may offer a life-saving new line of defense, by protecting infected hosts from themselves. Another bonus is that such an approach doesn't put the same pressure on viruses to adapt and develop drug resistance.
The cytokines associated with flu infection were thought to come from virus-infected cells found primarily in the lungs and nasal passages. The authors find that the cytokines are instead released from the endothelial cells that line blood vessels. A protein found on the surface of endothelial cells, called Sphingosine-1-phosphate receptor (S1P1), is essential for flu-associated cytokine storms.
In mice treated with a molecule that targets S1P1, cytokine production and the early signs of inflammation are suppressed. As a result, the animals are much more likely to survive infection with H1N1 swine flu virus. Notably, several companies are already testing S1P1-targeted drugs in clinical trials, the researchers say.
"Now that we know where cytokines come from and have isolated the specific receptor-based mechanism, it is likely that a single oral dose of a compound can be developed that will provide protection from cytokine storm early in infection," Rosen says.
That's not to say that antiviral drugs will be a thing of the past. Rosen and Oldstone suggest that the most promising therapies of the future would include a combination of drugs designed to protect against cytokine storms and tackle viruses head-on.
- John R. Teijaro, Kevin B. Walsh, Stuart Cahalan, Daniel M. Fremgen, Edward Roberts, Fiona Scott, Esther Martinborough, Robert Peach, Michael B.A. Oldstone, Hugh Rosen. Endothelial Cells Are Central Orchestrators of Cytokine Amplification during Influenza Virus Infection. Cell, 2011; 146 (6): 980-991 DOI: 10.1016/j.cell.2011.08.015
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