Friday, March 02, 2018

JVI: K193T Mutation Enhances Human-type Receptor Binding In Ferret Transmissible H5N1


Last summer, in PLoS Pathogens: Three Mutations Switch H7N9 To Human-type Receptor Specificity, we looked at research out of The Scripps Research Institute on the amino acid changes that would enhance the ability of avian H7N9 to bind to, and infect, cells lining the human respiratory tract.

As I explained back then:
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.
Those researchers identified a pair of three-amino-acid mutations (V186G/K-K193T-G228S or V186N-N224K-G228S) that enhanced H7N9's ability bind to human receptor cells. 
While these specific combinations have not been reported in nature, a couple individual mutations (186G and 193N) have been seen in sporadic  H7 isolates.
Most of these same authors are back with a new study, which focuses instead on the amino acid changes that would enhance the binding of previously described ferret transmissible avian H5N1 to human receptor cells.
They find that one of the same amino acid swap outs mentioned above - K193T - has a similar impact on this genetically modified H5N1 virus. 
The bulk of their study - published this week in the Journal of Virology - is behind a pay wall, but we have the following abstract to look at.

Enhanced human-type receptor binding by ferret transmissible H5N1 with a K193T mutation


All human influenza pandemics have originated from avian influenza viruses. Although multiple changes are needed for an avian virus to be able to transmit between humans, binding to human-type receptors is essential. Several research groups have reported mutations in H5N1 viruses that exhibit specificity to human-type receptors and promote respiratory droplet transmission between ferrets.
Upon detailed analysis we have found that these mutants exhibit significant differences in fine receptor specificity compared to human H1N1 and H3N2 and retain avian-type receptor binding. We have recently shown that human influenza viruses preferentially bind to α2-6 sialylated branched N-linked glycans, where the sialic acids on each branch can bind to receptor sites on two protomers of the same HA trimer. In this binding mode the glycan projects over the 190-helix at the top of the receptor-binding pocket, which in H5N1 would create stearic clash with lysine at 193.
Thus we hypothesized that a K193T mutation, would improve binding to branched N-linked receptors. Indeed, adding the K193T mutation to the H5 HA of a respiratory droplet transmissible virus dramatically improves both binding to human trachea epithelial cells and specificity for extended α2-6 sialylated N-linked glycans recognized by human influenza viruses. 

IMPORTANCE Infections by avian H5N1 viruses are associated with a high mortality rate in several species including humans. Fortunately H5N1 viruses do not transmit between humans because they don't bind to human-type receptors.
In 2012, three seminal papers have shown how these viruses can be engineered to transmit between ferrets, the human model for influenza virus infection. Receptor binding, amongst others, was changed, and now binds to human-type receptors. Receptor specificity was still markedly different compared to human influenza viruses.
Here we report an additional mutation in ferret transmissible H5N1 that increases human-type receptor binding. K193T seems to be a common receptor specificity determinant as it increases human-type receptor binding in multiple subtypes. The K193T mutation can now be used as a marker during surveillance of emerging viruses to assess potential pandemic risk.
         (Continue . . . . ) 

It takes more than just enhanced receptor binding to turn an avian flu virus into a human pandemic threat, but it is considered the most important hurdle for the virus to jump.
Whether this K193T mutation will occur naturally in H5N1 - along with the other requisite changes - is probably a long shot. But we know there are an awful lot of HPAI H5 viruses out there, throwing the genetic dice every day.
While we continue to watch a growing number of avian viruses with pandemic potential (including H5N1, H5N6, H5N8, H6N1, H7N4, H7N7, H7N9, H9N2, H10N8 . . . )  - as far back as we can realistically look (about 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 with influenza one should never say `never',  we continue to watch these viruses carefully.
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 many swine and avian versions of these subtypes continue to circulate around the globe.    
Meaning that while we watch novel H5 and H7 avian flu viruses 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).
Given that influenza pandemics occur several times each century, we ignore pandemic planning and preparedness at our considerable peril.  Some recent blogs on these topics include:
CDC EID Journal: All About IRAT
ECDC: Low Uptake Of Flu Vaccine In Europe Jeopardizes Pandemic Preparedness

The Challenge Of Promoting Pandemic Preparedness

WHO Guidance For Surveillance During An Influenza Pandemic

ECDC: Guide To Revising The Influenza Pandemic Preparedness Plan

Smithsonian Livestream: “The Next Pandemic: Are We Prepared?"


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