Yoshihiro Kawaoka/University of Wisconsin, Madison

Pandemic.
The 1918 flu virus multiplied faster (red) and created more lesions (blue) than a common virus does.

Portrait of a Killer

The extreme virulence of the "Spanish flu" virus, which killed nearly 50 million people worldwide in 1918 and 1919, has puzzled scientists for decades. Now, a study of the virus's effects on monkeys has unraveled a little more about its mysterious powers, boosting the idea that the microbe killed by meddling with its victims' immune systems.

The molecular basis of the virus's lethality began to unfold in 2005, when pathologist Jeffrey Taubenberger, then at the Armed Forces Institute of Pathology in Washington, D.C., resurrected the flu virus from historic samples and demonstrated its lethality in mice (ScienceNOW, 5 October 2005). A year later, Taubenberger's team, along with John Kash and Michael Katze of the University of Washington School of Medicine in Seattle, reported evidence that the virus killed its victims by making their immune systems run amok (ScienceNOW, 29 September 2006). But researchers wanted to confirm the notion in animals more closely related to humans.

To do that, a team including Kash and Katze infected seven macaques with the reconstructed virus. The symptoms in these monkeys were very similar to those described in its 1918 human victims. The virus had invaded and ravaged the lungs. By the eighth day, a time when the three control monkeys infected with a common human flu virus were recovering, the experimental animals were so sick that they had to be euthanized. The researchers determined that the virus did indeed activate many genes involved in the immune response. They remained activated long after the gene expression had turned off or gone down in the control animals, thus confirming the earlier observation that the virus causes the immune system to overreact. The virus also switched off or lowered the expression of genes that code for a group of proteins called interferons, which help the body ultimately defeat the viral intruders. The team reports its findings in this week's issue of Nature.

The study shows that the severity of the 1918 pandemic was caused by the virus itself, not the lack of good medical care or secondary bacterial infections, says epidemiologist Arnold Monto of the University of Michigan, Ann Arbor. But the study was unrealistic in that the monkeys were infected through the mouth, nose, eyes, and trachea. Victims in 1918, in contrast, were only infected through their noses.

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