New possibilities for flu antiviral and vaccine research emerge from 'Spanish flu' virus

09/29/05

Findings reported in Science help explain why Spanish flu was so lethal

The 1918 Spanish flu was a global disaster, killing an estimated 20 to 50 million people, many of them otherwise healthy adults. By partially reconstructing the Spanish flu virus, researchers have now discovered at least part of what made the virus so lethal, thus providing essential information for influenza drug and vaccine research.

The research appears in the 7 October issue of the journal Science, published by AAAS, the nonprofit science society.

The Spanish flu virus is more closely related to avian flu viruses than other human flu viruses. Many experts say that it is only a matter of time before an avian flu outbreak occurs in humans and develops into a global pandemic, potentially costing millions of lives.

Therapies against a new flu strain would need to disarm the parts of the virus that do the most damage to the body. In order to learn which components of the virus would be the best targets for such therapies, Terrence Tumpey of the Centers for Disease Control and Prevention and his colleagues revisited the 1918 Spanish flu virus.

Their results may also provide a benchmark for measuring the potential virulence of future flu strains as they emerge.

Using the virus' genome sequence, whose final three genes are being published simultaneously this week in Nature, Tumpey's group created a live virus with all eight of the Spanish flu viral genes. The genome sequence information was recovered in fragments from lung autopsy materials and lung tissues from a flu victim who was buried in the Alaskan permafrost in 1918.

The virus is contained at the Centers for Disease Control and Prevention (CDC), following stringent safety conditions designated for flu viruses and heightened security elements mandated by the CDC's Select Agent program.

"We felt we had to recreate the virus and run these experiments to understand the biological properties that made the 1918 virus so exceptionally deadly. We wanted to identify the specific genes responsible for its virulence, with the hope of designing antivirals or other interventions that would work against virulent pandemic or epidemic influenza viruses," said Tumpey.

"Science is publishing this study because it provides information necessary for developing drugs and vaccines that could help prevent another global flu pandemic. We carefully considered the implications of publishing this research and concluded that the knowledge we're gaining to potentially protect public health far outweighs the risk of working with this virus," said Donald Kennedy, editor-in-chief of Science.

"We were comforted to learn that this also was the conclusion of Dr. Anthony Fauci of the U.S. National Institute of Allergy and Infectious Diseases, Dr. Julie Gerberding of the Centers for Disease Control and Prevention, and Dr. Amy Patterson of the Office of Biotechnology Activities within the Office of Science Policy at the U.S. National Institutes of Health. Dr. Patterson is the spokesperson for the National Science Advisory Board for Biodefense (NSABB), which provides guidance and advice on the implications for dual use research and publication," Kennedy said.

To make the virus, the researchers used an approach called "reverse genetics," which involves transferring gene sequences of viral RNA into bacteria and then inserting combinations of the genes -- often after manipulating them -- into cell lines, where they combine to form a virus.

For the Science study, Jeffery Taubenberger of the Armed Forces Institute of Pathology provided the coding sequences for the eight Spanish flu genes to Christopher Basler, Peter Palese, Adolfo Garca-Sastre and their colleagues at the Mount Sinai School of Medicine. They spliced these sequences together with noncoding DNA from a closely related virus, since this portion of the genome wasn't available for the Spanish flu virus.

Then, they sent the bacteria containing the viral gene sequences to Tumpey, who inserted them into the cells to produce the virus.

The researchers also produced variations of the virus for comparison, with certain Spanish flu genes replaced by the corresponding genes from other flu viruses. Then they studied the viruses' effects in mice, chick embryos and human lung cells and identified the constellation of genes that was responsible for the Spanish flu virus' extreme virulence.

One gene associated with high virulence was the HA gene, which encodes the hemagglutinin surface protein that helps the virus attach to cells and replicate properly. This gene seemed to be responsible for much of the severe lung damage reported in people infected with the Spanish flu. The three genes encoding the viral "polymerase" enzymes, which form the virus' basic replication machinery, were also found to be important for high virulence.

"Given that HA is responsible for so much pathology in the lung, if we could identify the mechanism for how that happens and then block it, perhaps it would be useful for antiviral development. With the identification of the polymerase genes contributing to disease, that represents another set of genes that might also be a good target for prophylactic and therapeutic interventions," Tumpey said.

Although more research needs to be done on antivirals and vaccines for a future flu pandemic, Tumpey noted some encouraging signs. The FDA-approved flu antiviral drugs, oseltamivir and amantadine, have been shown to be effective against viruses carrying certain genes from the Spanish flu virus. And, vaccines containing the Spanish flu HA gene, as well as another gene from this virus, were protective in mice.

Source: Eurekalert & others

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