By Cheryl Pellerin
Washington File Staff Writer

Washington - The first comprehensive analysis of an animal’s immune response to the 1918 influenza virus gives new insights into the killer flu, scientists funded by the U.S. National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) reported online September 27 in the journal Nature.

In addition, researchers funded by the U.S. Department of Agriculture (USDA) Agricultural Research Service (ARS) have found that a relatively benign strain of a common virus became more virulent after passing through older animal hosts.

The ARS study was published in the September 12 print edition of the Proceedings of the National Academy of Sciences.

“Understanding as much as possible about the virus that caused the devastating 1918-1919 influenza pandemic,” NIH Director Dr. Elias Zerhouni said, “is an urgent imperative as we pursue efforts to prepare for - and possibly thwart - the next flu pandemic.”

KILLER FLU

Michael Katze and John Kash of the University of Washington School of Medicine in Seattle found that the 1918 virus triggers a hyperactive immune response that might contribute to the virus’s lethality. (See related article.)

The results suggest that the combination of all eight of the 1918 flu virus genes interacting together accounts for the virus’s exceptional virulence.

The work with the fully reconstructed 1918 virus was conducted by coauthor Terrence Tumpey in a laboratory enhanced to biosafety level 3 at the U.S. Centers for Disease Control and Prevention (CDC) in Georgia.

CDC has established four levels of precautions for biological agents: biosafety level 1 for work involving well-characterized agents not known to cause disease consistently in healthy adults; level 2 for work with agents of moderate potential hazard to people and the environment; level 3 for work with agents that might cause serious or potentially lethal disease; and level 4 for work with dangerous and exotic agents that pose a high individual risk of aerosol-transmitted laboratory infections and life-threatening disease.

“The research provides clues as to why the flu of 1918 was so deadly,” said NIAID Director Dr. Anthony Fauci, “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.”

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 life.

Modern analyses of 1918 flu victim autopsy samples show extreme and extensive damage to lung tissues, leading to the hypothesis that the 1918 flu virus infection provoked an uncontrolled inflammatory response leading to rapid lung failure and death.

VALUABLE FOR H5N1

To test this idea, Tumpey infected mice with one of four types of flu virus - human 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.

An analysis by Katze, Kash and colleagues showed that the immune response to the reconstructed 1918 virus containing all eight flu genes was much greater than to any of the other viruses with all eight genes, Katze said. In particular, genes involved in promoting inflammation were activated strongly and immediately following infection by 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,” he says.

A fuller picture of the host immune response to the 1918 flu virus also could be valuable to scientists working to develop therapies against such viruses as the H5N1 avian influenza, the researchers said. (See related article.)

Besides targeting the flu virus itself, Katze added, researchers might develop new or improved agents aimed at moderating or halting the human immune system’s overactive response to these viruses.

AGING HOSTS AND VIRULENCE

Older adults are more susceptible to viral diseases because their immune systems are less robust than they once were.

A study led by Simin Nikbin Meydani, associate director of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston, suggests a new way of thinking about why older hosts are more susceptible to viruses.

In an animal study, none of a group of younger adult mice infected with a mild strain of a common virus died, but 14 percent of older infected mice did. The scientists then isolated and studied the mild virus from the infected older mice.

The mild viral strain did not affect young adult mice in previous tests, but the scientists found that after it had cycled through an older mouse host, it killed 43 percent of other younger mice later infected and 71 percent of other older mice later infected.

Because the results indicated that the older host environment had allowed the virus to change to a more virulent strain, the scientists performed a DNA sequence analysis on the mild virus after isolating it from the older mice.

They found that a DNA segment related to virulence had mutated, enabling it to match that of a more virulent, disease-causing strain.

The scientists do not know how the viral strain mutated to mimic its virulent cousin in the older mouse hosts, but concluded that because of the world’s increasingly older population, the potential impact of age-associated viral evolution on public health warrants further investigation.

More information about influenza is available on the NIH Web site. U.S. government information about avian and pandemic flu also is available online.

For more information on U.S. and international efforts to combat avian influenza, see Bird Flu.