Influenza
Why Spanish flu was so lethal
By American Association for the Advancement of Science
Oct 6, 2005 - 11:03:00 PM

The Spanish flu virus is more closely related to avian flu viruses than other human flu viruses. 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. 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 Garc�a-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. 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.



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