Lethal weapon

By Philip Cohen A FLU virus strain that wiped out more than 20 million people in 1918 and 1919 may have turned deadly after hijacking a human protein to help it break into cells. The finding might help health officials spot any future lethal strain before it causes an epidemic. Spanish flu, as it was called, claimed more lives around the world than the First World War. Without antibiotics to help fight secondary bacterial infections, victims often succumbed to pneumonia. But others died within days of infection—too fast for secondary infection to have set in. “It’s a mystery how the virus became so pathogenic,” says Yoshihiro Kawaoka at the University of Wisconsin, Madison. One theory is that the virus was more lethal because it could infect a greater variety of cells. Before a flu virus invades a cell, a protein on its surface called hemagglutinin (HA) must be cut. Only a few host enzymes seem to be able to do this clipping, and infection in humans is normally restricted to the respiratory tract. But if HA is easier to cut, the flu can infect more cells. One flu strain with more clippable HA was responsible for the outbreak of chicken and human influenza in Hong Kong at the end of last year (This Week, 13 December 1997, p 5). But the mutations that create this fragile HA were not found in fragments of the Spanish flu sequenced last year (New Scientist, Science, 29 March 1997, p 20). Kawaoka and his colleague Hideo Goto were studying a similar mystery surrounding the closest living relative of the Spanish flu, a strain isolated in 1933. A laboratory variant of this strain, dubbed WSN/33, can infect a variety of mouse tissues despite having a perfectly normal HA. So the researchers explored another possibility: if HA wasn’t easier to cut, perhaps the virus simply had acquired a more powerful pair of scissors. In this week’s Proceedings of the National Academy of Sciences (vol 95, p 10 224), they reveal how the virus fashions those scissors out of a protein called plasminogen which is common in mammalian blood plasma. Normally plasminogen is unable to cut HA, but in WSN/33 a protein on the viral surface called neuraminidase has acquired two small mutations so that it can pluck plasminogen out of solution. “By bringing plasminogen so close to HA, it forces it to cut,” says Kawaoka. “It’s a very clever idea,” says Jeffrey Taubenberger of the Armed Forces Institute of Pathology in Washington DC, whose team reported the partial Spanish flu virus sequence. However, while following up Kawaoka’s work, his group has shown that the 1918 flu does not contain the same plasminogen-binding mutation as its descendant. But he adds that the 1918 flu may have hijacked plasminogen in some other way. “The flu virus is such a chameleon we need to know all the tricks it can use and be on the lookout for them in future outbreaks,
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