US scientists have found that the shape of sugar molecules on cell surfaces in the upper respiratory tract determine how easy it is for influenza viruses to infect humans, and suggest that if the deadly strain of H5N1 bird flu were to adapt a way to bind to this shape of sugar molecule it would spread easily from human to human and provoke a world pandemic.

The study, which is funded by the US National Institutes of Health (NIH) is published in the 6th of January early online issue of Nature Biotechnology. The research team that conducted the study was led by Dr Ram Sasisekharan, of the Massachusetts Institute of Technology in Cambridge.

The deadly strain of H5N1 can only pass from bird to human, because it does not have the ability to spread via coughing and sneezing since the virus does not yet have a way of gaining entry to cells in the human upper respiratory tract.

In this study Sasisekharan and colleagues have discovered what makes it possible for some flu viruses to gain a foothold in the cells lining our noses and throats and why other strains find it more difficult.

Dr Jeremy M. Berg, director of the National Institute of General Medical Sciences (the part of NIH that sponsored the research) said:

“Using an approach that combines experimentation and database analysis, Sasisekharan’s team has changed our view of flu viruses and how they must adapt to infect us.”

“The work may improve our ability to monitor the evolution of the H5N1 virus and thwart potential outbreaks,” he added.

The researchers were interested in a group of sugars called glycans. These are long chain molecules of different shapes that sit on the surfaces of cells and control entry into them. They are like gatekeepers of the cells and only let in agents that have the correct protein (rather like a “pass key”). Some viruses can get in because they have the correct protein to bind with the appropriate glycan.

The flu virus has a pass key called hemagglutinin, a protein that is slightly different for each strain of flu, and latches onto glycans for different cell types. The hemagglutinin of flu viruses that transmit easily between humans are able to bind to the glycans of the cells in the upper respiratory tract (the ones that line the nose and throat).

But the bird flu virus does not have the right type of hemagglutinin to gain access to the upper respiratory tract, it can only bind with glycans on the surfaces of lower respiratory tract cells.

However, Sasisekharan had seen some studies that found bird flu hemagglutinin had sometimes been able to bind to glycans on cells in the upper respiratory tract, and was puzzled as to why the virus didn’t spread very well. So he and his team decided to investigate this.

They consulted a database maintained by the Consortium for Functional Glycomics (CFG) which holds information on the interactions between proteins and different types of glycan sugars.

They used the CFG glycan preference array which allowed them to see the different protein-glycan preferences and started to look at the shapes and structures of the glycan chains to see if there was a consistent pattern for the upper respiratory tract sugars.

Sasisekharan said they were surprised by the diversity of shapes:

“Even though these glycans are all linked the same way chemically, they have very different shapes.”

There was however a consistent pattern. Upper respiratory tract glycans tend to be either short and cone-like, or long and umbrella-like.

The hemagglutinin from human-adapted flu viruses attached mainly to the long umbrella glycans that dominate the upper respiratory tract and the bird flu hemagglutinin attached mainly to the short cone glycans that dominate the lower respiratory tract.

The researchers concluded that H5N1 would have to change its hemagglutinin structure so it could latch onto the long umbrella glycans in order to get a foothold in the upper respiratory tract of humans and thereby spread more easily and provoke a pandemic.

Hopefully this new information will alert scientists to keep an eye on how the H5N1 virus evolves, especially in the way it attaches to long glycans.

It will also help to develop new types of therapies for seasonal and pandemic flu, said the researchers.

“Glycan topology determines human adaptation of avian H5N1 virus hemagglutinin.”
Aarthi Chandrasekaran, Aravind Srinivasan, Rahul Raman, Karthik Viswanathan, S Raguram, Terrence M Tumpey, V Sasisekharan & Ram Sasisekharan.
Nature Biotechnology, Published online: 06 January 2008.

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Sources: Journal Abstract, NIH/National Institute of General Medical Sciences press release, Essentials of Glycobiology (1999, Varki, Cummings et al eds).

Written by: Catharine Paddock