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What Made the 1918 Influenza Virus So Deadly?

The 1918 influenza virus was the deadliest in recent history, infecting approximately 30 percent of the world's population and killing up to 40 million individuals, particularly young people.

Recently, NIAID-supported researchers have been unearthing clues into what made the virus so deadly. After retrieving gene sequences of the virus from victims who had been buried in Alaska's permafrost and from preserved tissue samples, researchers Jeffery K. Taubenberger, M.D., Ph.D., Armed Forces Institute of Pathology, Rockville, MD, Terrence Tumpey, Ph.D., USDA Southeast Poultry Research Laboratory, Athens, GA, and Peter Palese, Ph.D., Christopher Basler, Ph.D., and Adolfo García-Sastre, Ph.D., Department of Microbiology, Mount Sinai School of Medicine, New York, NY, and their colleagues were able to construct viruses containing several of the 1918 influenza virus' genes in an effort to winnow it down to its most lethal components. (Because the 1918 virus is considered very dangerous, the work with infectious virus was performed by Dr. Tumpey in a level 3-plus biosafety laboratory to ensure that the virus remained well-contained.)

Using reverse genetics, Drs. Garcia-Sastre, Basler, Taubenberger, Palese, and Tumpey custom-built flu viruses that contained from two to five of the 1918 virus' eight genes, with the remaining genes originating from a flu strain that is adapted to mice. The study was published recently in the Proceedings of the National Academy of Sciences.

The researchers found that all viruses possessing 1918's hemagglutinin (HA) and neuraminidase (NA) genes were highly lethal to mice, a somewhat surprising discovery since genes from a human flu strain normally do not cause disease in mice.

The researchers also found that some drugs that help battle today's flu strains are able to fight the 1918 version too. Viruses that possess the 1918 gene for the matrix (M) protein are vulnerable to the M2 channel-blocking drugs amantadine and rimantadine, and viruses containing the 1918 HA and NA antigens are foiled by NA inhibitors zanamivir and oseltamivir.

What's more, certain vaccines may be able to protect mice against the 1918 virus, the researchers found. Mice that were vaccinated with a strain that resembles the 1918 virus were fully protected against the 1918 virus, while mice vaccinated with strains that differed from the 1918 strain were partially protected.

Another Major Development

In another major development reported recently in Science, Drs. Ian Wilson, D. Phil., Scripps Research Institute, La Jolla, CA, Basler, Garcia-Sastre, Palese, and Taubenberger have shown that the HA protein of the 1918 flu virus may be more like that found in an avian (bird) flu than was previously thought. The findings may help explain why the 1918 flu virus was able to inflict so much damage around the world.

Usually, avian flu strains do not affect humans directly because bird-adapted HA proteins are not able to bind well to human receptors. Until very recently, it was thought that to make the leap to humans successfully, a bird strain must pass through an intermediate animal that contains both bird and human receptors, such as a pig.

Hong Kong's 1997 H5N1 influenza outbreak changed our way of thinking, however. It showed that these very dangerous avian influenza viruses can infect humans directly without passing through an intermediate host. Fortunately, the virus was not adapted to humans and could not be passed from person to person. If a bird strain were able to spread from person to person, the situation could be dire because human immune systems would be unable to protect against the new HA subtype. A global influenza outbreak, or pandemic, could result.

Like a photographer who develops a long-forgotten negative to obtain a glimpse of the past, the research team was able to reconstruct the three-dimensional structure of the 1918 virus' HA antigen, the viral protein that binds to a host's receptors, by piecing together gene fragments from victims' preserved lung tissue. Once the gene was assembled, the protein that the gene encodes could also be constructed, taking shape as microscopic protein crystals.

The researchers discovered that HA's structure was very similar to that found on avian H5 flu viruses, with certain changes enabling it to infect and be transmitted by humans. Though it isn't clear whether the 1918 strain jumped directly to humans or passed through an intermediate animal, the unique, bird-like properties of the 1918 virus may have contributed to its becoming the most vicious influenza strain of the 20th century.

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Last Updated August 12, 2010