Published online 13 January 2006 | Nature | doi:10.1038/news060109-14

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Genetic tweak makes virus favour human nose and throat.

Turkish Agriculture Ministry employees collect poultry for culling in the village of Cebeci, Turkey © WHO

Researchers have sequenced the bird flu viruses that killed two people in Turkey in early January, and say that one of them contains a worrying mutation.

This genetic tweak can make the H5N1 virus more adapted to humans than to birds, and more adapted to the nose and throat than to the lungs. This latter effect could help to increase the chances of bird flu being transmitted between people, researchers say.

They add that many more mutations would probably be necessary before the virus is capable of sparking a full-blown pandemic, in which disease spreads like wild fire from person to person.

The samples of H5N1 virus, taken from the first two victims who died of bird flu in Turkey, were sequenced at a World Health Organisation (WHO) collaborating centre at the National Institute for Medical Research in London, UK. The results were announced on Thursday 12 January, along with confirmation of two new cases: bird flu has now also struck Sanliurfa Province, near Turkey's southern border with Syria, and Siirt Province, in the eastern part of Turkey.

The total number of reported human cases has now reached 18 in less than two weeks, three of which have been fatal.

In a bind

The WHO has released details of only one of the mutations found in the viruses. This genetic change results in a substitution of the amino acid serine by another amino acid, asparagine, at a specific position in one of the virus's proteins; a protein that helps the flu virus to bind to receptors on host cells.

This mutation has been observed twice before: in a father and son in Hong Kong in February 2003, and in one fatal case in Vietnam last year. It is known to increase the affinity of the virus for human receptors over poultry ones.

Until samples from the remaining cases are sequenced over the coming week, it is unknown how many of these came from viruses with the same mutation. If many prove to have the same tweak, this may help to account for the relatively large size of Turkey's rapid outbreak. The WHO's current explanation for the spate of cases is simply that people are bringing chickens into their homes during the harsh Turkish winter.

Nose and throat

The mutation also has a secondary effect, which may be more worrying.

There are two subtypes of receptors in the human respiratory tract: alpha 2.3, which occurs mainly in the lower respiratory tract; and alpha 2.6, which occurs mainly in the nose and throat. Human flu viruses typically show a preference for the 2.6 receptors, whereas H5N1 strains typically prefer 2.3.

This is good news for those worried about bird flu, since human-to-human transmission is thought to be more likely via droplets coughed from the nose and throat than from infections lower down. But the mutation found in the Turkey viruses is also known to be able to increase the affinity for H5N1 to the 2.6 receptors, points out Sylvie van der Werf, head of the Laboratory of Molecular Genetics of Respiratory Viruses at the Pasteur Institute in Paris, France.

Van der Werf adds that this affinity will, however, be affected by other genetic changes in the virus, which at present are an unknown factor.

Multiple mutations

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Thankfully, one mutation alone is unlikely to lead to efficient human-to-human transmission. The genetic changes that would allow this to happen are poorly understood, but are thought to require an exact combination of changes in multiple genes.

"Adaptation to humans is a polygenic trait. It requires mutations in each of the eight segments of the virus's genome. Every one has to be correctly optimized to ensure human-to-human transmission," explains Edward Holmes, who is studying virus evolution at Pennsylvania State University in Philadelphia. "You are talking multiple mutations across the entire genome."

That's an improbable, but not impossible event.

Researchers continue to examine the genome of bird flu viruses, and are taking measures to stop the spread of disease among birds and people in Turkey.