Sugars on Cell Surface Are Key to Flu Infections

An influenza virus infects a host cell when hemagglutinin grips onto glycans on the cell surface. NIGMS

Scientists have identified a key factor that determines whether influenza viruses can infect cells of the human upper respiratory tract. The finding offers new insights into how the H5N1 avian flu virus currently circulating in birds would have to change in order to gain a foothold in human populations.

The H5N1 virus has infected several hundred people, but person-to-person transmission has been limited. Chains of sugars called glycans sit on the surface of our cells and control the gates through which different molecules enter. For a virus to gain access to a cell, proteins on the virus's surface must bind to certain glycans.

The binding protein for flu viruses is hemagglutinin. This protein can vary with each flu strain and, as a result, latch onto glycans from different types of cells. Recent studies have shown that the hemagglutinin protein from bird flu viruses can attach to the type of glycans found in human upper airways. However, the virus still doesn't spread effectively between people. To understand why, a team led by Dr. Ram Sasisekharan of the Massachusetts Institute of Technology set out to better understand how flu viruses attach to glycans. They detailed their investigation, which was funded by NIH's National Institute of General Medical Sciences (NIGMS), in the January 6, 2008, online edition of Nature Biotechnology.

Sasisekharan and his team turned to the Consortium for Functional Glycomics (CFG), an initiative supported by NIGMS to explore the interactions between proteins and different types of sugars. Mining data from the CFG glycan array—a tool for quickly screening protein-glycan binding—the team explored the structures of the different sugar chains that coat the cells in the upper respiratory tract. They found that the glycans on these cells can be short and cone-shaped or long and umbrella-shaped.

"Even though these glycans are all linked the same way chemically," Sasisekharan explained, "they have very different shapes."

When the researchers combined this information with data from their experiments, they discovered that the hemagglutinin proteins from human-adapted flu viruses attach specifically to the long glycans of the upper respiratory tract. The hemagglutinins from H5N1 viruses, in contrast, bind mainly to cone-shaped glycans.

These findings suggest that for the H5N1 bird flu virus to infect and spread in humans, it must adapt so that it can latch onto the umbrella-shaped glycans of the upper respiratory tract. NIGMS Director Dr. Jeremy M. Berg said, "The work may improve our ability to monitor the evolution of the H5N1 virus and thwart potential outbreaks." It could also help in the development of vaccines.