Study of sugars on cell surface identifies key factor in flu infection

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Study of sugars on cell surface identifies key factor in flu

infection

Science Centric

6 January 2008

Science Centric - Sofia,Sofia Town,Bulgaria*

http://www.sciencecentric.com/news/08010602.htm

Scientists have identified a key factor that determines the ability

of influenza viruses to infect cells of the human upper respiratory

tract — a necessary step for sustaining spread between people. The

research, described in the 6 January online edition of Nature

Biotechnology and funded by the National Institutes of Health (NIH),

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. To trigger a widespread

outbreak, experts agree that the bird flu virus must infect the

cells lining our noses and throats. We then would spread the virus

to others through coughing or sneezing. The latest study, led by Ram

Sasisekharan, PhD, of the Massachusetts Institute of Technology in

Cambridge, refines this notion: The virus can gain access only

through a subset of the sugar molecules coating the cells of our

upper airways. `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,' said M. Berg,

PhD, director of the National Institute of General Medical Sciences,

the NIH component that supported the research. `The work may improve

our ability to monitor the evolution of the H5N1 virus and thwart

potential outbreaks.'

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. The protein

can vary with each flu strain and, as a result, latch on to glycans

from different types of cells. While the protein from human-adapted

flu viruses favours the sugars dotting the cells of the nose and

throat, the one from bird flu viruses opts for glycans on cells

deeper in the respiratory tract.

Sasisekharan noted that recent studies have shown that the

hemagglutinin protein from bird flu viruses has on occasion attached

to glycans of the upper airways. The surprising finding, he

explained, is that the virus didn't always spread effectively.

`This was a conundrum,' said Sasisekharan.

To solve it, he 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 preferences, Sasisekharan began to explore

the structures of the different sugar chains coating upper

respiratory tract cells.

`We found remarkable diversity,' he said. `Even though these glycans

are all linked the same way chemically, they have very different

shapes.'

According to the results, glycans of upper respiratory tract cells

come in two main varieties: short and cone-shaped, and long and

umbrella-shaped.

When the researchers combined this information with data from

experiments and the glycan array, they found that the hemagglutinin

protein from human-adapted flu viruses attached specifically to the

long glycans of the upper respiratory tract. They also confirmed

that the hemagglutinin from H5N1 viruses bound mainly to the cone-

shaped glycans found in the lower respiratory tract.

These findings suggest that for the H5N1 bird flu virus to infect

people and sustain its spread in humans, it must adapt so that it

can latch onto the umbrella-shaped glycans of the upper respiratory

tract.

`Until now, we had an incomplete understanding of avian flu

hemagglutinin and how the protein must adapt to humans,' said

Sasisekharan.

The new knowledge may unlock strategies for tracking mutations in

the avian flu virus that allow it to bind to long glycans, point to

new therapeutic targets for both seasonal and pandemic flu, and

expand our basic knowledge of glycans and their diversity.

In addition to Sasisekharan, authors of the paper include MIT

researchers Aarthi Chandrasekaran (PhD candidate); Aravind

Srinivasan, PhD; Rahul Raman, PhD; Karthik Viswanathan, PhD; S.

Raguram, Ph.D; and V. Sasisekharan, PhD; as well as Terrance M.

Tumpey, PhD, of the U.S. Centres for Disease Control and Prevention.

Source: NIH, NIGMS