Clues on the 1918 flu epidemic



New clue why 1918 flu epidemic was deadliest Scientists find that year's strain more birdlike than once thought Thursday, February 5, 2004 Posted: 2:19 PM EST (1919 GMT)

WASHINGTON (AP) -- The 1918 flu that killed 20 million people appears to be more birdlike than previously thought, according to findings by U.S. and British researchers that could help explain why it was the deadliest influenza strain ever recorded.

The work doesn't have direct implications for Asia's current outbreak of bird flu, a strain that doesn't seem able to easily infect many people.

But the findings, to be published Friday by the journal Science, do highlight how important it is to monitor flu in poultry since the research suggests it might take fewer genetic adaptations than once thought for a bird virus to begin spreading from person to person.

The research, conducted separately by scientists at the Scripps Institute in La Jolla, California, and at Britain's Medical Research Council, used lung samples preserved from victims of the 1918 flu to reconstruct a protein crucial to their infection.

"These were not little steps but big strides toward understanding, at the structural and molecular level, what it is about these strains that make them dangerous," said Dr. Gregory Poland, a flu specialist at the Mayo Clinic who reviewed the research.

The findings don't completely explain the 1918 strain's virulence, cautioned Michael Perdue, who investigates avian flu at the Agriculture Department's Agricultural Research Service. Other factors than the protein studied, called hemagglutinin, play a role too, he said.

But "this would put together several pieces" of that puzzle, Perdue said. Also, "it suggests the potential is certainly there for rapid transition from an avian to a mammalian strain."

Different influenza strains spread around the world annually. Every so often a strain tough enough to kill millions emerges, and experts believe the world is overdue for another pandemic. Unraveling what made the 1918 flu so vicious could help doctors better react if a similar strain returns.

All flu viruses are thought to have originated in birds. But scientists also have long thought that to cause human epidemics, the viruses first had to jump from birds to pigs, where genetic changes that allow the strains to better spread in mammals occur.

Flu strains that are more birdlike are more dangerous to people because their immune systems haven't been exposed to them before.

Flu in birds, pigs and people Asia's current bird flu, a strain known as H5N1, clearly can jump directly from poultry to people -- at least 15 people have died of it this winter. Most cases have been traced directly to contact with sick birds, although human-to- human transmission has not been ruled out in one instance.

In the new research, scientists reconstructed the three-dimensional structure of the hemagglutinin protein, a protein on the surface of the flu virus that allows it to attach to and penetrate lung cells.

Hemagglutinin from human and bird flu viruses interact with different cell receptors, which is why birds infecting people is rare.

But the new studies show the structure of hemagglutinin from the 1918 flu changed to make it capable of attaching to human cells, yet retained features primarily found in avian viruses, not human or pig strains.

The findings don't rule out a brief stop in pigs before the 1918 flu took off in people, said molecular biologist Ian Wilson, lead investigator of the Scripps team.

But "we want to know how many differences there have to be to an avian flu in order to infect the human," he added. The research suggests not all that many differences are required, if they're in the right spots.

The hemagglutinin from the 1918 virus is in a different family, called H1, than the H5-bird flu now affecting Asia, cautioned the lead British investigator, Sir John Skehel. The two "are quite different," he said, meaning the research won't have an immediate impact on today's bird flu.

Still, the cell receptor properties found to be important for the 1918 flu could point to molecular spots that need particular monitoring to predict when an outbreak of flu in poultry will prove more dangerous to people, Mayo's Poland said.

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Flu Researchers Partially Re-Create Killer Strain of 1918

By ANTONIO REGALADO and BETSY MCKAY Staff Reporters of THE WALL STREET JOURNAL

The great influenza pandemic of 1918-19 snuffed out 20 million to 40 million human lives. Now scientists probing why the germ proved so deadly are taking an unusual step -- they are partly re-creating the killer virus.

Using scraps of genetic material salvaged from 85-year-old hospital samples, and from a body buried under the icy Alaskan permafrost when Woodrow Wilson was president, a research team says it has re-created an influenza bug that is about 60% the same as that from 1918.

It's no small matter to resurrect one of history's most brutal microbes. Although scientists don't yet have all the 1918 genes, they will have them soon. Team members say if they recreate the original bug -- which, according to historical accounts, was capable of killing healthy people in a matter of hours -- they would do so only under the strictest security, and only after serious debate.

Researchers involved in the project say their goal is to determine which genes made the 1918 virus so dangerous. That could put some big historical mysteries to rest and might also help fight outbreaks of new flu strains.

"This is an ideal virus to study, because it was so lethal," says Terrence Tumpey, a scientist at the influenza branch of the Centers for Disease Control and Prevention in Atlanta. Dr. Tumpey carried out the project along with researchers at Mount Sinai School of Medicine in New York and the Armed Forces Institute of Pathology in Rockville, Md.

The mystery of the 1918 pandemic has never seemed so timely and urgent. An outbreak of a deadly avian influenza across Asia has claimed 12 lives after jumping from poultry flocks to humans. (See related article on page D4.) The World Health Organization has warned that the bird virus could erupt into a human pandemic if it's given the chance to mutate into a form easily transmitted between people. Indeed, with his research on the 1918 virus put aside for the moment, Dr. Tumpey is in Vietnam along with other CDC flu experts, helping local authorities battle the outbreak there.

Part of the problem health authorities face coping with that outbreak is that they don't know what makes one flu bug worse than another. The 1918 virus seemed to come out of nowhere, swept around the globe and took a human toll rivaling that of AIDS.

Why the virus killed so easily is one of "the greatest remaining unanswered questions in virology," says Linda Lambert, influenza program officer at the National Institutes of Health in Bethesda, Md.

But until recently, the 1918 flu virus was almost impossible to study. Contemporary doctors didn't save samples of the 1918 virus; indeed, the virus that causes flu wasn't even discovered until 1933.

Researchers subsequently looked for living virus in the bodies of frozen victims buried at high latitudes, but those efforts failed. Then, in 1997, researcher Jeffery Taubenberger at the Armed Forces Institute of Pathology announced he had recovered some genetic sequences of the virus from a tissue sample taken from a World War I-era soldier. The sample had been soaked in the preservative formalin and then embedded in wax. More gene elements were later recovered from lung tissue of the corpse of an Inuit woman buried near Brevig Mission, Alaska, whose population was nearly wiped out by the flu in November 1918.

"The amount of virus still left in these tissues is really infinitesimally small," says Dr. Taubenberger. But since then, his team has managed to reassemble the chemical sequence of six of the 1918 virus's eight genes, and a seventh will be finished shortly. "The virus is broken up in tiny little pieces, and so it's really hard and is taking awhile."

Once the sequence became available, the researchers began using new genetic- engineering techniques to mix them with other flu viruses. Dr. Tumpey showed that adding just two 1918 genes -- the hemaggluttinin and neuraminidase genes - - made a mouse virus "highly lethal." Adding genes from a human flu would normally make a mouse virus much weaker for rodents.

Today, the team reports in the Proceedings of the National Academy of Sciences that they have generated another lethal bug, this time with five of eight genes taken from the 1918 virus.

Such projects have raised concerns over lab safety, even the possibility that custom-made germs could be used for bioterrorism. Dr. Lambert says the NIH is reviewing its rules on how to handle human flu viruses, which until now haven't generally been considered high-risk.

Dr. Tumpey's project was carried out under strict safety standards at the Southeast Poultry Research Laboratory, a Department of Agriculture facility in Athens, Ga., that specializes in handling dangerous animal germs.

Researchers say the germ isn't easily giving up its secrets. Tests in mice do suggest that a vaccine could defeat another pandemic-type virus. And the genetic signatures suggest that the 1918 killer originated in birds, as did other pandemics that hit in 1957 and 1968. But they don't know which birds.

To read the rest of the article you must be a subscriber to the Wall Street Journal.

Write to Antonio Regalado at [email protected] and Betsy McKay at [email protected]

Updated February 3, 2004



CONTENT COPYRIGHT The Associated Press and the Wall Street Journal. THIS CONTENT IS INTENDED SOLELY FOR EDUCATIONAL PURPOSES.



 


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