Published online 3 January 2008 | Nature | doi:10.1038/news.2008.407

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Barrier to bird flu transmission found in humans

Sugar shape may limit human-to-human spread of avian flu... for now.

An electron micrograph picture shows the H5N1 virus binding to human lung cells.C. Goldsmith, CDC

Umbrella-shaped sugars that decorate proteins in the nose and throat could be preventing widespread human-to-human transmission of avian flu, new research suggests. Whereas normal winter flu viruses easily latch onto these sugars, the H5N1 virus that causes bird flu cannot. This helps to prevent it from colonizing the upper respiratory tract — a key step in triggering an epidemic.

The results could someday lead to new therapeutic approaches to treat or prevent the disease. But more immediately, the findings could also provide health officials with a way to test whether a newly emerging strain is likely to spark a human-to-human epidemic.

There have been rare cases of people catching bird flu from others living in close quarters. Instances of 'clusters' of bird flu in people (see Large bird flu cluster emerges) periodically raise concerns that the virus may be mutating to become more transmittable in humans, potentially starting a pandemic.

A few genetic changes have been identified that are thought to help bird viruses latch onto human — rather than avian — cell receptors more effectively, to survive in the cool nasal regions of the respiratory tract, and to target receptors in the nose and throat rather than the lungs (see Alarms ring over bird flu mutations). Despite these changes, widespread human-to-human transmission hasn't yet kicked in; work in animal models has shown that these mutant H5N1 viruses still are not transmitted efficiently1.

Sticky sweet

When looking for parts of the virus that make it more dangerous to humans, researchers have mainly focused on H5N1's ability to bind characteristic sugar chains found on proteins of the human upper respiratory tract. The composition of those sugars differs between birds and humans, and among different regions of the body. A virus that can't bind to human throat sugars is unlikely to establish an infection there.

But the focus has traditionally been on how the virus interacts with the types of chemical linkages in these sugars, rather than with the sugar’s shape, says Carole Bewley, a virologist at the National Institutes of Health in Bethesda, Maryland, who was not involved with this work. “We tend to draw carbohydrate structures as chemical structures on two-dimensional pieces of paper,” says Bewley. “But that doesn’t really give us an idea of what they look like three-dimensionally. And that’s really a neglected area.”

Now Ram Sasisekharan of the Massachusetts Institute of Technology in Cambridge and his colleagues have found that those three-dimensional structures matter. In a survey of human and avian flu viruses, they observed that avian viruses bind shorter sugar chains that form cone-shaped structures.

Successful human flu viruses, on the other hand, were able to bind larger, umbrella-shaped sugars that are particularly common in the human nose and throat2. The results are published online today by Nature Biotechnology.

Waiting game

The H5N1 strains that were tested all lacked the ability to bind to these umbrella-shaped sugars. But they could develop this ability. Sasisekharan estimates that it may take only two or three amino-acid changes in a single viral protein to allow the virus to latch on to the umbrella-shaped sugars.

“It does not take a lot to switch that specificity,” says Sasisekharan. “The key question is to find out what combination of amino acids it takes to allow that.”

Sasisekharan and his colleagues have thus far only tested nine flu virus strains, including four human flu varieties, two non-H5 avian flu varieties, and three reference avian flu strains provided by the US Centers for Disease Control and Prevention. They have not yet tested recent H5N1 isolates, such as the culprits behind a cluster in Pakistan in late 2007, or a similar cluster found in Turkey in 2006.

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If their finding holds true as more viruses are examined, it will be "incredibly valuable" information, says Bewley. Emerging H5N1 strains could be tested for their ability to bind umbrella-shaped sugars, allowing researchers to quickly pinpoint strains likely to fuel an epidemic.

The findings also suggest that the three-dimensional structure of sugars could be important for transmission of other pathogens, Bewley adds. 

  • References

    1. Chandrasekaran, A. et al. Nat. Biotech. doi:10.1038/nbt1375 (2008).
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