How pandemic flu viruses gain the ability to infect humans

24 April 2013

Researchers at NIMR have shown how structural changes mediate the transmissibility of flu viruses in humans. The research is published in Nature.

The ease with which flu viruses are transmitted is determined in large part by how they bind to receptors on the surface of host cells. This is true for transmission both from avian and animal species to humans as well as from human to human. Hence there is a need to understand the species specificity of flu viruses, and this is a longterm aim of flu researchers at NIMR.

Biologically, the natural reservoir of flu is wild fowl, their cells carry a receptor molecule that is related to the one found in human airways but its chemistry is a bit different. To switch from birds to humans the virus needs to adapt its binding protein so that it prefers human-type receptors. Individual binding sites on haemagglutinin (HA), the protein on the surface of the virus that mediates interaction with host cells, binds single receptor ligands with low affinity. However, multiple HA/ligand interactions result in very high avidity for the virus binding to cells carrying preferred ligands, but not to less preferred ones.

Steve Gamblin (pictured), John Skehel, John McCauley (Director of NIMR's WHO Influenza Centre), Stephen Martin and their colleagues, made quantitative biophysical measurements of the receptor-binding properties of haemagglutinin (HA) from a mutant virus of the H5N1 subtype that acquired the ability to be transmissible between infected and naive ferrets. These indicate a small increase in affinity for human receptor and a marked decrease in affinity for avian receptor. From analysis of virus and HA binding data they derived an algorithm that predicts virus avidity from the affinity of individual HA–receptor interactions. It reveals that the transmissible-mutant virus has a 200-fold preference for binding human over avian receptors. The crystal structure of the transmissible-mutant HA in complex with receptor analogues show that this mutant, in contrast to the wild-type H5N1 virus, binds human receptor like other known human pandemic viruses.

Our data shows how virus avidity can be simply predicted from the binding strength of a single interaction. One consequence of this is that virus avidity can be established without the need to generate and work with infectious material. Using this approach, we showed how laboratory-engineered ferret-transmissible (the usual surrogate for human transmission) flu virus has acquired the ability to infect human cells.

Steve Gamblin

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Comparison of H5 and H2 HA complexes with human receptor.

Original article

Xiaoli Xiong, Peter J. Coombs, Stephen R. Martin, Junfeng Liu, Haixia Xiao, John W. McCauley, Kathrin Locher, Philip A. Walker, Patrick Collins, Yoshihiro Kawaoka, John J. Skehel & Steven J. Gamblin (2013)

Receptor binding by a ferret-transmissible H5 avian influenza virus

Nature, Epub ahead of print.  Publisher abstract

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