Mutant protein may allow flu to kill

It's one of the biggest mysteries in flu: why is it a mild infection in some people, and a killer in others? The 2009 pandemic flu often caused no symptoms at all, yet was deadly in some people. Some of those cases, it now appears, may be down to a protein that normally stops some viruses from invading cells ? but which is mutated in some people.

Paul Kellam of the Sanger Institute in Cambridge, UK, and colleagues bred mice with a mutation that stopped them making a protein called IFITM3. This is normally made by cells in response to interferon, an immune signalling chemical that turns on antiviral defences. We know these are important in flu ? the virus only packs 10 genes, and one is devoted to opposing interferon.

Strains of flu that do not normally make mice very sick ? including the 2009 pandemic virus ? left mice without IFITM3 at death's door. The virus penetrated deeper into their lungs, replicated 10 times more, and induced severe pneumonia, just like bad cases of pandemic flu.

Perhaps most tellingly, people in intensive care with severe pandemic or even seasonal flu in the UK were 17 times more likely than Europeans in general to carry a mutant, non-functional gene for IFITM3.

Most of the people with severe flu didn't have the mutant, but "that isn't really surprising", says Kellam, as "many other factors affect the severity of the disease". But IFITM3 seems significant, given its effect in mice and people ? and in cultured human cells, where it reduced viral replication. The team even found that IFITM3 has become more common in humans since 10,000 years ago, just when we are thought to have first caught flu, from livestock.

The protein affects viruses ? which are normally taken up by the cell inside a bubble of membrane ? including dengue and West Nile as well as flu. It stops them reaching the cell nucleus, and instead routes them to waste disposal. The finding suggests that a drug that mimics IFITM3 might fight all those viruses ? or at least that people who make the mutant form should be prioritised for vaccination.

Meanwhile, more basic biological functions can sometimes save us from flu. An analysis of 193 children who caught the deadly H5N1 bird flu found that, as usual with flu, not everyone had a runny nose. Kids under 5 who did, however, were nearly 10 times less likely to die. The study was published last week.

Journal reference: Nature, DOI: 10.1038/nature10921

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