A LAB reconstruction of the 1918 flu virus, cause of the deadliest global pandemic ever recorded, is showing frightening similarities with H5N1, the bird flu that killed dozens of people across east Asia last year.
The genetic sequences of the reconstructed 1918 virus show that it was a pure bird flu that adapted to humans, not a hybrid between a bird and a human flu like the relatively mild flu pandemics of 1957 and 1968. That is particularly worrying because H5N1 bird flu is steadily evolving to become more lethal in mammals without combining with a human flu.
First Jeffery Taubenberger at the US Armed Forces Institute of Pathology in Rockville, Maryland, and colleagues isolated and sequenced the virus鈥檚 genes from the preserved tissues of people who died after contracting the 1918 flu. They announced this week that in three previously unsequenced genes coding for the three-protein RNA polymerase complex, which replicates the virus, there are 10 mutations that do not occur in bird viruses but do occur in nearly every human virus (Nature, DOI: 10.1038/nature04230). Taubenberger thinks these may be crucial mutations that allowed the 1918 virus to adapt to humans.
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Ominously, the same mutations have also been turning up in the polymerase genes of H5N1 鈥� and in H7 and H9 flu viruses that have killed people. So far H5N1 has not picked up more than one of the mutations in any of the three proteins at the same time, not several as in the 1918 virus. 鈥淭his is good news,鈥� says Taubenberger. 鈥淏ut that they share any of these changes suggests the possibility of parallel evolution.鈥� It is 鈥渋ntriguing鈥�, he says, that most of the bird flu samples with these mutations also happen to kill humans.
Terrence Tumpey at the US Centers for Disease Control in Atlanta and colleagues took the study further by using Taubenberger鈥檚 sequences to make a complete reconstruction of the virus, plus viruses containing only some of the genes from the 1918 strain (Science, vol 310, p 77). When they administered the reconstructed viruses to mice, the animals died within three days 鈥� more quickly than from any other flu virus ever tested.
The experiments by Tumpey鈥檚 team support the idea that the polymerase complex was important to the 1918 virus鈥檚 success, and that it contributes to its deadliness at least much as the virus鈥檚 surface proteins. The polymerase appears to be important to the lethality of H5N1 as well. In work soon to be published, Erich Hoffman of St Jude Children鈥檚 Research Hospital in Memphis, Tennessee, has found that the H5N1 from human victims in Vietnam owes its deadliness to its polymerase, which he suspects allows it to 鈥渟imply outrun the host鈥檚 immune system鈥�.
鈥淭he sequences show that the 1918 virus was a pure bird flu that adapted to humans鈥�
But there are concerns about the work. If the reconstructed 1918 virus escaped from the lab it could cause widespread illness and death. Despite this, the mouse experiments were performed at only the second-highest level of containment. Critics condemned previous work with partial reconstructions of the 1918 virus on the grounds that the potential risks are not worth running for the small amount it can teach us about the very different viruses that will cause the next pandemic (New Scientist, 23 October 2004, p 6). But the new work suggests that we need to understand as much as possible about the 1918 virus in case H5N1 continues to evolve in a similar way.
