Monkeys infected with a resurrected virus that was responsible for history’s deadliest epidemic have given scientists a better idea of how the 1918 Spanish flu attacked so quickly and relentlessly: by turning victims’ bodies against them.

The research, which found that an over-stimulated immune system killed even as it tried to fight the flu, helps explain why many of the 50 million people who died in the epidemic were healthy young adults. Conventional flu usually claims mostly the very young and very old.

This new look at an old killer gives doctors ideas on how to fight the current bird flu if it develops the ability to spreads from human-to-human, as many scientists fear it will. The 1918 virus, which was reconstructed with reverse genetics, exists today only in two labs where scientists are studying it.

Scientists said they were struck by how suddenly and overwhelmingly the 1918 flu struck seven macaques that were tested in a high-level biosafety lab in Winnipeg, Canada. 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.

Cytokine storm

“Essentially people are drowned by themselves,” said University of Wisconsin virology professor Yoshihiro Kawaoka, lead author of a study published Thursday in the journal Nature.

The experiment was supposed to last 21 days, but after eight days the monkeys were so sick — feverish, in pain and having difficulty breathing — 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 was simply overwhelming, researchers said.

“It’s a very good replicating virus and therefore it can affect more of the immune system and thereby triggers what one refers to as a cytokine storm,” said Peter Palese, chairman of the microbiology department at Mount Sinai School of Medicine in New York, who wasn’t part of the study but has worked on the resurrected virus before. Cytokines transmit messages among cells in the immune system.

No other flu virus is deadly to monkeys, and the speed in its spread and the overwhelming immune system response is only similar to those in the H5N1 bird flu, Kawaoka said.

The bird flu has spread around the world intermittently, but has yet to develop the ability to transmit person-to-person. If it does, scientists believe understanding the 1918 flu may give them clues about how to protect people from it.

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.”

Vicious circle

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-of-its-kind 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 virus was reconstructed from tissues of victims from 1918. Besides the Public Health Agency of Canada’s lab in Winnipeg, it exists only at the Centers for Disease Control in Atlanta.

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. “There was an uncontrolled or aberrant response.”

Adolfo Garcia-Sastre, a Mount Sinai microbiology professor who conducted some of the earlier mouse work, said it may be a mistake to focus so heavily on immune system response. The 1918 flu virus “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.