Receptor Shape Matters

Scientists have identified a key molecular feature of respiratory-system cells that may influence the ability of flu viruses to be transmissible from birds to humans and from person to person.

A team of researchers at Massachusetts Institute of Technology, led by biological engineering professor Ram Sasisekharan, reports that the ability of flu virus???s hemagglutinin (HA) surface protein to bind to carbohydrate (glycan) cell-surface receptors is affected as much by receptor shape as by the specific linkage between the receptor???s sugars (Nat. Biotechnol., DOI: 10.1038/nbt1375).

Birds and humans have different receptors for HA. Scientists had thought that the specificity of those HA receptors, which consist of sugar chains capped with sialic acid, depended only on how the terminal sialic acid is linked to the next sugar in the chain. Sasisekharan and coworkers used mass spectrometry, glycan arrays, and detailed conformational analysis to show that an additional important factor is glycan receptor topology.

Flu viruses that infect birds, including the H5N1 strain, bind HA receptors with α2-3-linked sialic acids, whereas viruses that infect humans bind receptors with α2-6-linked sialic acids. The α2-3 glycans adopt a cone-shaped topology, whereas α2-6 glycans can have either a cone- or umbrella-shaped structure. Short α2-6 glycans adopt the cone-shaped structure, whereas longer α2-6 glycans with at least four sugars are more flexible and form the umbrella shape. The MIT study shows that HA from some virus strains binds to both α2-3 and short α2-6 glycans, but that for bird flu virus to be transmissible to and among people, its HA must bind specifically to long α2-6 structures, which are abundant in human respiratory cells.

Ajit Varki, a professor of cellular and molecular medicine at the medical school at the University of California, San Diego, who studies the role of sialic acids in biology, notes that the current research is an important step forward but doesn???t show how the receptor topology affects the infectivity of the viruses.

Earlier research in ferrets has shown that changing the glycan-binding specificity of HA in H1N1 viruses changes their infection or transmission efficiency. This change in specificity now appears to involve loss of binding to umbrella-topology glycans, Sasisekharan points out.

The findings about HA???s binding specificity could aid in monitoring bird flu for the ability to jump into humans. "We now know what to look for," Sasisekharan says???HA specificity for long α2-6 receptors.

Knowing which human receptors interact with flu viruses could also aid development of vaccines and other therapeutics. Such agents could include small molecules that target cell-surface glycans or modulate their biosynthesis during infection, Sasisekharan says. The new results suggest "a whole range of additional therapeutic strategies that can be put into play," he says.