Some live poultry markets in China have been closed following the outbreak (Image: Imaginechina/Rex)

In China, nine people have died and more than 20 are seriously ill in the latest outbreak of bird flu, H7N9. And there are fears that the death toll could rise much higher because the virus already has three of the five mutations that we know could allow another bird flu, H5N1, to spread between mammals.

No one knows for sure if the five mutations discovered last year by Ron Fouchier and colleagues at Erasmus Medical Center in Rotterdam, the Netherlands, will do the same thing in H7N9. But we do know that some of the mutations helped viruses from three other flu families go pandemic. For the moment, Chinese authorities tracing contacts of known cases say there is no evidence yet that the infection has spread between humans.

Most recent pandemic viruses have been hybrids of bird and mammalian flu, and therefore relatively mild because mammalian flu tends to be less severe in people than bird flu. Pure bird flu viruses, like H5N1 and H7N9, are potentially more dangerous. The most lethal pandemic we know of, which spread across the world in 1918, was a pure bird flu that acquired mutations that allowed it to spread in humans. Virologists fear H7N9 could be doing that.


Severe or mild?

H7N9 might be unusually severe: it carries a mutation thought to promote deep lung infection, which is also in H5N1, the 1918 flu, and severe cases of the 2009 pandemic. But two known cases of H7N9 only show mild symptoms, so the Chinese authorities are trying to establish how often it makes people seriously ill, in order to estimate the number of unreported mild cases, and therefore the total number of human cases there have already been.

As for H5N1, despite spreading widely in birds in recent years, it has not evolved the ability to spread readily between mammals. Fouchier’s work – which came under fire because of fears that it would allow bioterrorists to engineer an H5N1 pandemic – shows that, in principle, it can spread between ferrets, and with no obvious loss of virulence.

To get transmissible H5N1, Fouchier first had to prime the virus with three mutations known to adapt bird flu to mammals, then allow the virus to evolve the other requisite mutations while infecting the ferrets: as few as two more appeared to be needed. Two of the three deliberately added mutations allow the HA surface protein from bird flu in the H5, H2 and H3 families to bind to cells in mammals’ noses.

This is what allowed flu viruses carrying HA proteins from H2 and H3 bird flu to cause pandemics in 1957 and 1968. The pandemic virus that broke out in 1918 – from the H1 family – had similar mutations with the same effect.

Such binding mutations have never been seen in wild H5N1 – but H7N9 already has one of the two. If H7N9 can bind to mammalian cells, it could adapt even further to mammals, just as Fouchier’s primed H5N1 did in his ferret experiments. We do not yet know for certain that the mutation has the same effect in H7 as in the other flu families, but researchers are gearing up to do the experiments.

Part way there

“If what we know about these mutations in other flu subtypes is also the case for this virus, then it’s already part way there,” says Derek Smith at the University of Cambridge. “That’s why everybody is concerned about this.”

The H7N9 virus has another mutation that Fouchier deliberately gave H5N1 in the ferret experiment – a change in a gene coding for a polymerase protein. The polymerase enzyme, which replicates the virus, is extra-powerful in bird flu, part of what makes these viruses so virulent in mammals – and this mutation allows it to work at mammalian temperatures. It has been present in all pandemic viruses.

H7N9 also has another of Fouchier’s mutations, one that arose as the virus infected ferrets. It removes a sugar group from HA.

That leaves only two more mutations, both in HA, before this H7N9 has all of Fouchier’s five. The virus’s passage through humans parallels the ferret experiment – in which only four sequential infections of ferrets made H5N1 fully transmissible.

“All pandemic viruses have acquired this [mammalian cell] binding and polymerase activity,” says Fouchier. “The H7N9 has these characteristics. So the question is, what else does it need – if anything?”