Two new papers on the virus strain responsible for the 1918/1919 influenza pandemic that came to be known, albeit erroneously, as the Spanish flu, are being published in today's Nature and the Oct. 7 Science.

By resurrecting the virus in one case, and sequencing its polymerase genes, which form the basic viral replication machinery, in the other, the authors have gained clues to the strain's evolution, as well as what made it so deadly.

The authors hope that knowing exactly what makes a given viral strain particularly lethal will help with pandemic preparedness in several ways.

First, the genes responsible for the 1918 strain's lethality are the same as those that make several current strains of bird flu particularly virulent, suggesting that "there are common themes responsible for virulence of influenza viruses," Adolfo Garcia-Sastre, professor of microbiology at the Mount Sinai School of Medicine in New York City and senior author of the Science paper, told reporters at a press conference. Elucidating those common themes means that "now we have good targets for the development of new antiviral drugs."

Jeffrey Taubenberger, chair of the division of molecular pathology at the Armed Forces Institute of Pathology, added that the findings will help with what he termed "molecular-based surveillance" of different viral strains.

"If we can actually identify which amino acids in each protein of the virus are really important in this process of adaptation, in a sense you could provide a checklist for surveillance, to target surveillance to strains that are beginning to show pressures to adapt to humans," he said. Such adaptation to humans is one of the key prerequisites for a viral strain to touch off a pandemic.

The influenza virus genome, which is made of RNA, has eight segments. In the Science paper, titled "Characterization of the Reconstructed 1918 Spanish Influenza Pandemic Virus," researchers at the Centers for Disease Control and Prevention in Atlanta; Mount Sinai School of Medicine in New York; the Armed Forces Institute of Pathology in Rockville, Md.; and the U.S. Department of Agriculture in Athens, Ga., resurrected the 1918 pandemic virus using reverse genetics, and studied its properties in mice, chick embryos and human lung cells to determine what made it so lethal.

The scientists compared the purebred 1918 virus with other engineered viruses containing segments from the Spanish flu virus and segments from other strains. They found that the 1918 viral hemagglutinin (HA) gene, which codes for the protein that helps the virus attach to its host cells (and is the protein against which an immune response is mounted), was responsible for much of the severe lung damage seen from that strain.

"When we replaced the 1918 HA with an HA from a contemporary, garden-variety influenza, this virus is no longer virulent in our model systems," Terence Tumpey, senior microbiologist at the Centers for Disease Control and Prevention and lead author of the Science paper, told reporters. The polymerase genes of the 1918 strain also seemed to be "essential for maximum virus replication," Tumpey added.

The polymerase genes that Tumpey mentioned as being key to explaining the 1918 strain's virulence were the subject of closer scrutiny in today's Nature paper. That paper, authored by researchers from the Armed Forces Institute of Pathology, is the final in a series of papers reporting the gene sequence of the Spanish flu virus; it reported on the gene sequence of the polymerase genes and compared that sequence to two other flu strains that caused pandemics in the 20th century.

Taubenberger is co-author on both papers, taking lead author honors on the Nature paper titled "Characterization of the 1918 influenza virus polymerase genes." He summarized the conclusions of the paper.

"We now think that the best interpretation of the data available to us is that the 1918 virus was an entirely avian-like virus that adapted to humans," he said. "This is a different situation than the last two pandemics we had - the Asian flu in 1957 and the Hong Kong flu in 1968, which were mixtures" of human and bird viruses.

"It suggests that pandemics can form in more than one way," he said.

Given that H5N1 is currently the No. 1 candidate for the next flu pandemic in the opinion of many experts, the scientists were interested in whether it shows similarities to the 1918 virus. Taubenberger said that for a viral strain to cause a pandemic, changes must occur in each of the eight viral segments. Some of the current H5N1 strains do show some such changes. But he added, "the H5N1 strains in general only have one or two of these mutations, where the 1918 strain would have a larger number."

The mechanism of how the 1918 virus became adapted to humans is unclear. Taubenberger said that one possibility is that it ultimately jumped from birds to humans via an intermediate host, perhaps some other type of farm animal. "But we don't have enough genetic information yet about how influenza viruses change from one species to another to begin to look for, in a sense, the fingerprint of an intermediate host in this process."

Though experts disagree on which current flu strain is most likely to start the next pandemic, there is near unanimous agreement that "it's not a question of if; it's a question of when" such a pandemic will come, Julie Gerberding, director of the CDC, told reporters.

Gerberding took pains to point out that it is unlikely the resurrected Spanish flu virus will itself cause the next pandemic, either through escaping from the CDC labs or through use by bioterroists. In addition to stringent safety precautions, the 1918 strain shows antibody cross-reactivity with currently circulating strains. In contrast, pandemics usually occur when a strain begins circulating to which there is no residual immunity in the general population.