Friday, June 16, 2017

PLoS Pathogens: Three Mutations Switch H7N9 To Human-type Receptor Specificity


Although it has already received a good deal of coverage in the mainstream media over the past 24 hours, I'd be remiss if I didn't post the link to yesterday's PLos Pathogens study, and offer a little context. 

First, the link and abstract, then I'll return with some comments of my own.

Three mutations switch H7N9 influenza to human-type receptor specificity

Robert P. de Vries , Wenjie Peng , Oliver C. Grant, Andrew J. Thompson,  Xueyong Zhu,    Kim M. Bouwman,    Alba T. Torrents de la Pena,  Marielle J. van Breemen,    Iresha N. Ambepitiya Wickramasinghe,    Cornelis A. M. de Haan,    Wenli Yu,    Ryan McBride,    Rogier W. Sanders,  [ ... ],    James C. Paulson

    Published: June 15, 2017


The avian H7N9 influenza outbreak in 2013 resulted from an unprecedented incidence of influenza transmission to humans from infected poultry. The majority of human H7N9 isolates contained a hemagglutinin (HA) mutation (Q226L) that has previously been associated with a switch in receptor specificity from avian-type (NeuAcα2-3Gal) to human-type (NeuAcα2-6Gal), as documented for the avian progenitors of the 1957 (H2N2) and 1968 (H3N2) human influenza pandemic viruses.

While this raised concern that the H7N9 virus was adapting to humans, the mutation was not sufficient to switch the receptor specificity of H7N9, and has not resulted in sustained transmission in humans.
To determine if the H7 HA was capable of acquiring human-type receptor specificity, we conducted mutation analyses. Remarkably, three amino acid mutations conferred a switch in specificity for human-type receptors that resembled the specificity of the 2009 human H1 pandemic virus, and promoted binding to human trachea epithelial cells.
Author summary

Influenza A virus of the H7N9 subtype continues to cross the species barrier from poultry to humans. This zoonotic ability is remarkable as the virus retains specificity to avian-type receptors. To effectively transmit between humans, the virus needs to acquire human-type receptor specificity.
In this study, we show that recombinant H7 proteins need three amino acid mutations to change specificity to human-type receptors. Although we are not allowed to assess if these mutations would lead to efficient transmission in the ferret model, this knowledge will aid in surveillance. If these amino acid mutations are observed to arise during natural selection in humans, timely actions could be taken.
         (Continue . . . )

For an influenza virus to infect a host, the virus must bind (attach) itself to the surface of a cell (see graphic at top of blog).  

RBD's or receptor binding domains, are that part of the virus that allows it to attach to receptor cells in a host's body.  Different viruses are attracted to different types of cells, which explains why some viruses that affect man, don't affect other species, and why we don't get influenza in our big toe.

Receptor cells have stalks of sugar (carbohydrate) molecules on their surface. These carbohydrate molecules -  called `glycans' - form a dense sugary coating to all animal cell membranes. The composition of these stalks varies between types of cells and hosts.

When a virus meets a compatible receptor cell, they bind.  And infection ensues.

Avian influenza viruses, like the H7N9 virus, bind preferentially to the alpha 2,3 receptor cells found in the gastrointestinal tract of birds, while `humanized’ flu viruses  - like H3N2 and H1N1 - have an affinity for the alpha 2,6 receptor cells most commonly found in the human respiratory system. . 
While there are some α2-3 cells deep in the lungs of humans – which may explain the high rate of pneumonia in the unlucky few who do contract avian flu -  for an influenza to be truly successful in a human host, it needs to a able to bind to the α2-6  receptor cells in the upper airway.
The ability to bind to human α2-6 receptor cells is considered the single biggest obstacle that an avian flu virus must overcome in order to successfully jump to humans.
But it isn’t the only one.
Avian viruses also typically replicate at the higher temperatures found in birds, and would need to adapt to the lower (roughly 33C) temps found in the upper human respiratory tract. And there are undoubtably others as well.
The three-amino-acid mutations combinations (V186G/K-K193T-G228S or V186N-N224K-G228S) identified in this study have not been seen in nature, although a couple individual mutations (186G and 193N) have been reported in a few H7 isolates. 
Whether they will ever spontaneously arrange themselves in the wild, and whether that alone would be enough to trigger efficient human-to-human transmission, is unknown. It would be a heck of a start, however.
And there may be other amino-acid combinations that could produce similar results.
The value of this study is that it may provide us with some early warning signs, should these mutations start cropping up in H7 isolates, that the virus is evolving towards a more `humanized' strain.

It is worth noting that over the past 130 years we've only seen human influenza epidemics caused by H1, H2, and H3 viruses, leading some scientists to wonder: Are Influenza Pandemic Viruses Members Of An Exclusive Club?
Since 130 years is far too short of a time span to draw conclusions from, and one should never say `never', I wouldn't bet against an H5 or H7 avian virus someday winning the genetic lottery.
But it is probably safe to say that H1, H2, and H3 viruses have `less far to go', to make the jump to humans, and swine and avian versions continue to circulate around the globe.    
Meaning that while we watch avian H7N9 and H5N6 for signs of adaptation, we could just as easily be blindsided by one of the H1-H2-H3 viruses (see When H2N2 Predictions Go Viral and  MMWR: Investigation Into H3N2v Outbreak In Ohio & Michigan - Summer 2016).
Suffice to say, there are pandemic threats aplenty, including some I'd wager we don't even have on our radar.  All of which makes yesterday's HHS Pandemic Influenza Plan - 2017 Update - and the preparations of businesses and individuals - all the more important. 

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