A street car conductor in Seattle, 1918, preventing passengers from boarding without a mask as a precaution against the spread of Spanish flu.

Credit: Wikipedia

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PARIS: Scientists who resurrected a version of the 1918 flu virus to test on lab mice believe the 20th-century's deadliest pathogen reaped its toll through a combination of runaway tissue inflammation and cell death, a new study shows.

The so-called Spanish flu that swept parts of the world at the end of World War I claimed, by some estimates, as many as 40 million or 50 million lives - nearly three times more than the 1914-1918 conflict itself.

The H1N1 virus could take someone in robust good health and put him in his grave in just three or four days, wrecking lung tissue with such efficiency that the patient would sometimes drown in his own blood.

In this new study, led by John Kash of the University of Washington in Seattle, a team of U.S. researchers went to Alaska to recover tissue samples from a woman victim of Spanish flu whose body had been preserved in permafrost. Teasing out fragments of the virus, they painstakingly recreated the H1N1's eight genes, reviving a killer last seen more than three generations ago.

In a paper published online today in the British journal Nature, the investigators report that they exposed this replica virus to mice, and compared those results with data using three other flu strains. One of the three was a conventional flu strain; another was a conventional strain with two of the 1918 genes; and the third comprised a strain with five 1918 genes.

Mice who had been infected with the full eight-gene 1918 recombinant virus rode the fast track to sickness and death. They outstripped the three other strains for the speed with which they fell sick, the high concentrations of virus in their blood and for their high mortality rate within five days.

Within 24 hours of infection, four key foot-soldiers in the immune system went haywire, unleashing huge inflammation of the lungs, while genes that order cells to commit suicide, a process called apoptosis, were activated.

Post-mortem analysis, carried out at various points during the experiment, showed the mice's lungs were ravaged by a "massive" build up of fluid caused by haemorrhaging and bronchitis, while the lungs' lining, the epithelium, was swiftly destroyed.

"Taken together, our results indicate that enhanced inflammatory and cell-death responses might be contributors" to the severe rates of sickness and death caused by the 1918 virus, the authors say. They caution, though, that further work, on pigs, ferrets and monkeys, is needed to rule out a remote possibility that inflammation and cell-death were the consequence, rather than the cause, of the virus' brutality.

The new work is the latest and most ambitious chapter in the saga of the recreated 1918 virus; previous research has shown it descended entirely from a strain of avian flu, something that is at the heart of today's fears surrounding H5N1 bird flu. The groundbreaking tale has also been punctuated by concern voiced by others that the pathogen could escape from the lab.

Kash and his colleagues stress that the animals were all kept within a Biosafety Level 3 (BSL3) laboratory where all personnel wore protective hoods and backpack air supplies. BSL4, the highest security rating, is reserved for pathogens for which there are no drugs or vaccines.

The 1918 flu mutated into other strains for which many people today may have some immunity; there are also vaccines and antiviral drugs that are believed likely to be effective against the original strain.

Kash also strongly defends the usefulness of the research, saying that finding out the pathways by which H1N1 was able to kill so quickly could help the fight against H5N1 bird flu.

There have been 249 detected cases of humans infected with H5N1, 146 of them fatal, according to the latest toll posted on the World Health Organisation's website. Almost all of these cases have come from direct contact with infected poultry.

The worry is that H5N1 could mutate into a form that is transmitted more easily between humans, unleashing an entirely new form of flu pathogen against which no-one today, as in 1918, would have immunity.