Bird flu: X-rayed

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  • Published: Dec 15, 2013
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Bird flu: X-rayed

No need for pandemic panic

Chicken: in the pink! Preferential Recognition of Avian-Like Receptors in Human Influenza A H7N9 Viruses

The emergence of novel strains of avian influenza is a concern for international health agencies. The most recently identified, H7N9, has already killed several dozen people in China. However, X-ray diffraction and glycan arrays have demonstrated that this variant has not yet acquired the necessary receptor binding properties to make it highly infectious between people rather than from infected birds to humans.

Avian influenza type A H7 viruses are endemic in bird populations - although cause no symptoms to birds - but occasionally emerge from their native host species to infect people as variants mutate and become contagious. Human infection with the H7N9 strain was first reported in February 2013 China where more than 100 people had been infected. Initially, about one in five died, one in five had recovered and the others were still critically ill. But the ultimate mortality rate of this outbreak was almost 30 percent. However, there is no evidence that anyone who had been in contact with the first patient had themselves become infected. Unfortunately, studies suggest that this strain is unresponsive to the frontline pharmaceutical intervention against influenza, Tamiflu. On the basis that it seemed to spread rapidly albeit without person to person infection, the World Health Organization has flagged the pathogen as "an unusually dangerous virus for humans."

Mutant flu

Now, an X-ray crystallographic study and binding studies of the hemagglutinin glycoprotein, which is found on the virus surface, by researchers at The Scripps Research Institute (TSRI) in La Jolla, California, USA, suggests that the virus has not yet evolved the necessary structure to allow it to readily infect people. Writing in the journal Science, Rui Xu, Robert de Vries, Xueyong Zhu, Corwin Nycholat, Ryan McBride, Wenli Yu, James Paulson and Ian Wilson, explain that "hemagglutinin glycoprotein, the "H", of most human H7N9 viruses carries the amino acid leucine at position 226. There is evidence that the Leu 226 residue is associated with adaptation of the pandemic influenza viruses H2N2 and H3N2 to the appropriate receptors in people that allow the virus to infect us.

However, experimental analysis of the H7 hemagglutinin in this form of avian influenza shows only a negligible ability to bind to human-type receptors and a much stronger preference for their counterparts in avian-type receptors, the type that are recognized by all avian H7 viruses. The team has now obtained a detailed crystal structure of the H7N9 hemagglutinin and six hemagglutinin-glycan complexes, which they suggest explains the structural characteristics of the virus that endow it with the ability to recognize avian-like receptors but not the human-type receptors. The finding is encouraging news for those concerned with the risk of another global bird flu pandemic. If the virus does not yet have the requisite biochemical machinery to easily infect people, then there is, at the moment, it would seem, a much lower risk of efficient transmission of the disease between people.

"Luckily, H7N9 viruses just don’t yet seem well adapted for binding to human receptors," explains structural and computational biologist, Wilson. Paulson, whose cell and molecular biology lab worked with Wilson and colleagues adds that, "Because publications to date have implied that H7N9 has adapted to human receptors, we felt we should make a clear statement about this." As such, their scientific statement is reported in the 6th December issue of the journal.

One to watch

Early alarm regarding this H7N9 outbreak led to the necessary isolation of patients and public health officials endorsing studies of viral samples by dozens of laboratories across the globe so that evidence could be accumulated regarding its likely behaviour. If the virus had "jumped the species barrier" from bird to human, then a major disease outbreak and potentially a global epidemic might arise. Early tests on the viral isolates from the initial patients, hinted at a leucine-glutamine amino acid switch that was known to have been key to the pandemics that killed millions in 1957-1958 ("Asian flu") and 1968-1969 ("Hong Kong flu"). Animal tests also hinted that could spread among other mammals, mice, ferrets and monkeys.

Flu experts Paulson and Wilson were recruited to the H7N9 work early. Paulson's team focused on how well the viral hemagglutinin could bind different human and avian receptor variants; quickly showing that the proteins have a preference for avian rather than human receptors. Wilson's team performed X-ray diffraction on the protein actually bound to several avian- and human-type receptors, showing that it binds human-type receptors only loosely, whereas binding to avian-type is much snugger.

Aside from those unfortunate enough to have been fatally infected by this virus, for the time being, it would seem, a global pandemic is not about to happen due to H7N9, at least not until it mutates to a much more infectious form. "These results suggest that we should continue to observe H7N9 and see if it undergoes any changes that make it more likely to spread in the human population," Wilson says.

Related Links

Science, 2013, 342, 1230-1235: Preferential Recognition of Avian-Like Receptors in Human Influenza A H7N9 Viruses"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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