Study suggests why bird flu slow to infect humans

Mar 23, 2006 (CIDRAP News) – A new study suggests that the reason the H5N1 avian influenza virus infects humans relatively rarely and does not spread from person to person is that it lacks the right key to unlock many cells in the upper respiratory tract.

The virus is better equipped to infect cells deep in the lungs, because some of those cells have a different kind of receptor molecule from those in the upper airways, according to the study by a team led by Yoshihiro Kawaoka of the University of Wisconsin-Madison and the University of Tokyo. It was published online yesterday by Nature.

"Our findings may provide a rational explanation for why H5N1 viruses at present rarely infect and spread between humans although they can replicate efficiently in the lungs," Kawaoka and his colleagues write.

"Deep in the respiratory system, [cell] receptors for avian viruses, including avian H5N1 viruses, are present," Kawaoka explained in a University of Wisconsin news release. "But these receptors are rare in the upper portion of the respiratory system. For the viruses to be transmitted efficiently, they have to multiply in the upper portion of the respiratory system so that they can be transmitted by coughing and sneezing."

He added, however, that mutations could enable the virus to infect cells in the upper airway, which could help set the stage for a flu pandemic.

Global health agencies have documented 184 human cases of avian flu, with 103 deaths, since the H5N1 virus began spreading widely among birds in late 2003. Given its ability to cause severe human illness, the virus's failure to infect many more people or spread from person to person has puzzled scientists. Kawaoka's study appears to offer the best explanation so far.

Flu viruses use a protein called hemagglutinin to latch onto receptor molecules on the surface of host cells. The article explains that avian flu viruses prefer a cell receptor molecule consisting of sialic acid linked to galactose by an alpha-2,3 linkage, called SA-alpha2,3Gal, whereas human flu viruses prefer receptors consisting of sialic acid with an alpha2,6 linkage to galactose (called SA-alpha2,6Gal).

The authors sought to determine the distribution of these two kinds of receptors in the human respiratory tract. By exposing respiratory tract cells in laboratory cultures to lectins—plant proteins that bind preferentially to different cell-surface molecules—they determined that the human-type receptors were dominant in the nose, nasal sinuses, throat, trachea, and bronchi. They found few of the avian-type receptors in the upper airways, but there were "substantial" numbers in the alveoli, the small air sacks in the lungs.

The researchers then exposed respiratory tract cells to human and avian flu viruses. They found that human-derived viruses, preferring the "2,6" receptor, efficiently infected cells from both the bronchial lining and alveoli, whereas avian viruses, preferring the "2,3" receptor, infected alveolar cells but not bronchial cells, according to the report. The experiment included an H5N1 virus and two other avian flu viruses, an H3N2 and an H4N6.

"Our findings indicate that although H5N1 viruses preferentially recognizing SAalpha2,3Gal can be transmitted from birds to humans, they can replicate efficiently only in cells in the lower region of the respiratory tract, where the avian-virus receptor is prevalent," the report states.

This may help explain the "inefficient" human-to-human transmission of H5N1 viruses seen so far, the article continues. But a mutation in the hemagglutinin molecule could enable the virus to "recognize" the human type receptor. Then it could grow in the upper respiratory tract, where sneezing and coughing could spread it to others, the authors say.

However, they add, "Changes in other viral proteins, including PB2, may be required to confer pandemic potential on avian viruses that can efficiently replicate in humans."

In the news release, Kawaoka commented, "No one knows whether the virus will evolve into a pandemic strain, but flu viruses constantly change. Certainly, multiple mutations need to be accumulated for the H5N1 virus to become a pandemic strain."

The news release says the finding suggests the world may have more time to prepare for an eventual pandemic of avian flu, though most scientists agree that a pandemic will occur sooner or later.

The finding also puts scientists in a better position to look for the kinds of mutations that could lead a pandemic strain of H5N1, the news release says.

"Identification of H5N1 viruses with the ability to recognize human receptors would bring us one step closer to a pandemic strain," Kawaoka commented in the release. He added that the human receptors "can serve as molecular markers for the pandemic potential of the isolates."

Shinya K, Ebina M, Yamada S, et al. Avian flu: influenza virus receptors in the human airway. Nature 2006 Mar 23;440:435-6 [Abstract]

See also:

Mar 22 University of Wisconsin news release
http://www.news.wisc.edu/releases/12345.html

 

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