Influenza experts say the work may also provide clues to a couple of mysteries about the pattern of human H5N1 infections to date, namely whether some people are more genetically susceptible to the virus than others and why children seem to make up a disproportionate percentage of human cases.
The researchers, from the Massachusetts Institute of Technology, identified the shape of cell receptors to which invading avian viruses can attach and where those receptors are found in the upper airways and lungs of humans. The work was published Sunday in the journal Nature Biotechnology.
"I think it's a significant piece of the puzzle in terms of what may be going on in the upper respiratory tract versus the lower with the avian-like viruses," said Michael Perdue, deputy director of the influenza and emerging diseases program of the U.S. Department of Health and Human Services' Biomedical Advanced Research and Development Authority. Perdue was not involved in the research.
The senior author of the study said it gives scientists a way to spot avian flu viruses that are becoming more transmissible to and among people.
"We now really know what to look for," said Ram Sasisekharan, a professor of biological engineering at MIT, in Cambridge, Mass.
Previously, it was thought that the issue of which cells avian and human flu viruses could attach to broke down on simple lines.
Avian viruses were thought to latch onto cells with a type of receptor called alpha 2-3 - found in birds and in the lungs of people. Human flu viruses docked to cells with alpha 2-6 receptors, found in the human upper respiratory tract.
But it became apparent that answer was too simplistic. So Sasisekharan and his colleagues set out to look more precisely at the strings of sugar molecules that make up these receptors.
They found that alpha 2-6 receptors actually come in two shapes - a cone-like shape similar to the alpha 2-3 receptor and a long, umbrella-like shape. The research showed that human flu viruses of the H1N1 and H3N2 subtypes bind to these umbrella-like alpha 2-6 receptors, which predominate in the upper airways. (Results of study of human H2N2 viruses are pending.)
H5N1 viruses currently latch on to cone-like receptors and would have to mutate to be able to dock to the umbrella-like receptors if they are to more easily infect people, Sasisekharan said, likening the process to a lock-and-key scenario.
"It's not any key," said Sasisekharan. "It seems like the shape of the key really matters."
In light of these findings, scientists in future should be checking H5N1 and other non-human flu viruses for that type of alteration, said Terrence Tumpey, an influenza expert with the U.S. Centers for Disease Control who was also a co-author on the paper.
"If there are a couple of mutations that allow it to bind to this umbrella-like topology (configuration) . . . this should sound the alarm bells that we have a virus here that could potentially spread."
But Tumpey and others noted that additional changes would likely be needed before a non-human flu virus could acquire the ability to spread easily among people.
"We think it's necessary but not sufficient," Tumpey said of the change in the docking pattern.
The research cannot be used to predict whether H5N1 viruses will make that switch, or even if they are capable of making that essential change, experts cautioned.
"The manuscript, of course, does not explain whether H5N1 viruses are, or are not closer, to initiating a pandemic, but this observation is a significant one, especially if there are differences among humans with respect to receptor density and prevalence," Adolfo Garcia-Sastre, an influenza expert at Mount Sinai Medical Center in New York, said via e-mail.
Sasisekharan agreed that questions about why H5N1 can infect some people and why clusters of cases occur with some frequency among blood relatives may be answered through study of the concentration of cone-like alpha 2-6 receptors in the airways of people who become infected.
For some time the community of influenza scientists has been debating whether some people are genetically susceptible to the H5N1 virus.
It also could explain why so many of the virus's victims are young children, said Dr. John Nicholls, an anatomical pathologist at the University of Hong Kong.
Nicholls has been studying airway tissues trying to puzzle out receptor patterns. His work suggests the airways of children could have more of the alpha 2-3 receptors H5N1 favours.
While he praised the complex research, Nicholls did raise an important caveat. The highly sophisticated and expensive techniques the MIT researchers employed are not currently in widespread use.
That means that with the existing state of technology, this process is unlikely to provide the rapid answers the World Health Organization would need to determine whether an explosion of new, linked cases - such as a large family cluster that occurred in Karo, Indonesia in 2006 -- was the product of viruses that had mutated to develop the new binding pattern.
"I don't think if they had a Karo cluster . . . I don't think they'd be able to process that and get it done within a week and say: 'Ah, yeah, this is it."' Nicholls said from Hong Kong.
"This is not something which can be done within 24 hours of getting a new virus. This is something which can take a number of weeks at this stage. . . . It's not able to be done . . . in the field in some of these developing countries, no."
