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New Clues about 1918 Influenza Virus

Influenza viruses from the 1918 Spanish flu epidemic recreated in the laboratory.Dr. Terrence Tumpey and Cynthia Goldsmith, Centers for Disease Control and Prevention.

The first comprehensive analysis of an animal’s reaction to the 1918 influenza virus provides new insights into this killer flu. Researchers have found that the virus triggers a hyperactive immune response that may be the key to its lethal effects. The findings also suggest that all eight of the virus’s genes play a role in making the virus so deadly.

Unlike typical seasonal flu, which strikes hardest at the very young, the elderly and those with compromised immune systems, the 1918 flu disproportionately killed young people in the prime of their lives. Modern analyses of 1918 flu victim autopsy samples show extensive damage to lung tissues. Because of this, researchers hypothesized that the 1918 flu virus may have provoked the immune system to create uncontrolled inflammation as it tried to fight off the infection. This reaction could account for the rapid lung failure and death seen in people infected by the virus.

To test this idea, Dr. Terrence Tumpey, working in a biosafety level 3-enhanced laboratory at the U.S. Centers for Disease Control and Prevention in Atlanta, infected mice through their noses with one of four types of virus: seasonal flu virus from a strain that circulated in Texas in 1991; lab-made viruses containing either two or five of eight viral genes from the 1918 virus; or a reconstructed virus containing all eight 1918 flu virus genes.

Lung tissue from three infected mice in each group was removed on days one, three and five after infection and processed to destroy any virus. The mouse genetic material was then extracted and sent to a team led by Dr. Michael G. Katze, an NIH grantee at the University of Washington School of Medicine. Katze and his colleagues used microarrays, which can measure the activity of thousands of genes at once, to see which genes were activated by each of the four viruses.

The team reports in an article published online on September 27 in the journal Nature that mice infected with the reconstructed 1918 virus containing all eight flu genes had the most severe weight loss and the earliest time of death, with most mice dying by five days after infection. The reconstructed 1918 virus caused a much greater immune response than any of the other viruses. Genes involved in promoting inflammation were strongly activated soon after infection with the reconstructed 1918 virus.

“We clearly see a dramatic and uncontrolled immune response in the mouse lungs as early as one day following infection with the reconstructed 1918 virus,” Katze says.

Dr. Anthony S. Fauci, Director of NIH’s National Institute of Allergy and Infectious Diseases, says, “The research provides clues as to why the flu of 1918 was so deadly, and may also help us better understand the disease process that occurs when people are infected by emerging avian influenza viruses, such as the H5N1 strain.”

A fuller picture of the host immune response to the 1918 flu virus could be valuable to scientists working to develop therapies against such viruses as the H5N1 avian influenza. In addition to targeting the viruses themselves, researchers might be able to develop ways to control the human immune system's overactive response to the viruses.