Bird Flu Hides Deep in the Lungs

This week, two research groups are independently reporting results that help explain why the H5N1 avian influenza virus is so lethal to humans but so difficult to spread. Unlike human influenza viruses, the teams report, H5N1 preferentially infects cells in the lower respiratory tract. Residing deep in the airways, the virus is not easily expelled by coughing and sneezing, the usual route of spread. The results "explain a lot of the mysteries" surrounding H5N1, says K. Y. Yuen, a virologist at the University of Hong Kong.

A better understanding of the virus couldn't be more timely. Endemic in much of Asia, H5N1 has recently spread through Europe and to Africa (ScienceNOW, 9 February). It has killed 98 of the 177 humans it has infected. Flu experts worry that if the virus mutates into a form that could be easily passed among humans, it could spark a pandemic. The two reports, which used different strategies but reached the same conclusion, suggest just what sort of mutation would be needed.

One team, led by Yoshihiro Kawaoka of the University of Wisconsin, Madison, tested various tissues of the human respiratory tract for receptors to which the virus can bind. Human flu viruses preferentially bind to what are known as α 2,6 galactose receptors, which populate the human respiratory tract from the nose to the lungs. Avian viruses prefer α 2,3 galactose receptors, which are common in birds but were thought to be nearly absent in humans. Using marker molecules that bind to one receptor or the other, the team found that humans also have α 2,3 galactose receptors, but only in and around the alveoli, structures deep in the lungs where oxygen is passed to the blood. They describe their findings in the 23 March issue of Nature.

The second team, led by pathologist Thijs Kuiken of Erasmus University in Rotterdam, the Netherlands, used a more direct technique to show that H5N1 readily binds to alveoli but not to tissues higher up in the respiratory tract. Kuiken, whose team will publish its findings online tomorrow in Science, notes that this pattern is consistent with autopsies that have shown heavy damage to the lungs but little involvement of the upper respiratory tract. Among experimental animals, the team reports, cats and ferrets more closely match the human pattern of infection than do mice and macaques. "This is an important factor to consider when planning experiments" to understand the pathology of H5N1, says Kuiken.

Yuen notes that the findings also explain clinical anomalies such as why nasal swabs of H5N1 patients are less reliable than throat swabs in detecting the virus. And they suggest that clinicians need to exercise particular care when performing procedures, such as intubation, that might give the virus a route out of a patient's lungs.

The risk of a pandemic would ratchet up substantially should the virus acquire the ability to bind to receptors in the upper respiratory tract, Kuiken warns. But just how difficult that mutation is to acquire "is something this research did not address," he says.

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