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Thursday, January 18, 2007

1918 Flu Provides Clue

1918 killer flu tested on monkeys
By SETH BORENSTEIN, AP Science Writer Wed Jan 17, 11:06 PM ET
WASHINGTON - Scientists who tested monkeys with the resurrected 1918 killer flu virus now have a better idea of how the deadliest epidemic in history attacked and killed so many people — by over-amping the victims' own immune systems.
Those findings in a first-of-its-kind experiment also help explain why so many of the roughly 50 million who died in the Spanish flu pandemic were young and healthy. Based on what was seen in monkeys, the human victims' strong immune systems likely were overstimulated, causing their lungs to rapidly fill with fluid.
"Essentially people are drowned by themselves," said University of Wisconsin virology professor Yoshihiro Kawaoka, lead author of a study being published Thursday in the journal Nature.
Scientists believe the results open a window into what could happen if the current bird flu in Asia morphs into a highly lethal strain that spreads easily among people.
The 1918 virus was reconstructed with reverse genetics, relying on tissue from victims of the early-day flu pandemic. The virus is kept only in two labs where scientists are studying it: the U.S. Centers for Disease Control and Prevention in Atlanta and the Public Health Agency of Canada's lab in Winnipeg where the monkey experiment was done.
When seven macaques were given the virus at the high-level biosafety lab there, scientists were struck by how suddenly and overwhelmingly the flu struck. The virus spread faster than a normal flu bug and triggered a "storm" response in the animal's immune systems.
Their bodies' defenses went haywire, not knowing when to stop, researchers said. The lungs became inflamed and filled with blood and other fluids.
The scientists believe the virus had the same effect on humans in 1918.
The macaque experiment was supposed to last 21 days, but after eight days the monkeys were so sick — feverish, in pain, and struggling to breathe — that ethical guidelines forced the researchers to euthanize them.
"There was some surprise that it was that nasty," University of Washington virologist and study co-author Michael Katze said. "It was the robustness of the immune system that helped victimize them."
The virus is very good at replicating itself, said Peter Palese, chairman of the microbiology department at Mount Sinai School of Medicine in New York. Its effect on the immune system "triggers what one refers to as a cytokine storm," he said. Cytokines transmit messages among cells in the immune system. Palese wasn't part of the study but has worked on the resurrected virus before.
No other flu virus is deadly to monkeys, and the speed in its spread and the overwhelming immune system response is similar to those in the H5N1 bird flu, Kawaoka said.
If bird flu spreads person-to-person, scientists believe understanding the 1918 virus may give them clues about how to protect people from the new one.
The new work "gives us another tool," said Anthony Fauci, director of the National Institute of Allergy and Infectious Disease, who was not part of the research. Fauci praised the study and said what it found in the effects on the body are stunning: "There aren't a lot of things that can induce that robust of an inflammatory response that quickly."
The 1918 flu research suggests that those fighting the bird flu in the future could try using drugs that reduce inflammation and control the body's immune response, Katze said.
In the Winnipeg research, the first controlled introduction of the 1918 flu to primates, the monkeys were given extra high doses of the flu virus by nose, mouth, eye, and direct injection into the trachea to ensure infection.
The virus had been tested before on mice, but macaques provide better models of how viruses work on humans, the scientists said.
The fate of the monkeys was sealed within hours of their infections, Katze theorized.
In normal flu, the immune system response wanes, but in the 1918 flu "the innate response stayed up and didn't go down," Katze said.
Adolfo Garcia-Sastre, a Mount Sinai microbiology professor who conducted some of the earlier mouse work, cautioned that it may be a mistake to focus so heavily on immune system response. The 1918 flu "induces an overwhelming and probably damaging immune response system" but it is largely because the virus grows so much, he said.
In mice, when the overactive immune response was eliminated, mice died because of high viral levels.
"It's like a vicious circle, you get more viruses, you get more immune response and this results in damage," Garcia-Sastre said.
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