Sunday, November 23, 2014

PLoS Path: Genetics, Receptor Binding, and Transmissibility Of Avian H9N2


Photo Credit – FAO


# 9364


While the superstars of avian influenza tend to be those viruses that can infect, and sometimes kill, humans (H5N1, H7N9, H10N8) behind each of these deadly viruses is an obscure `parental’ virus called H9N2 that has lent a good deal of its backbone – it’s internal genes – to the creation of these emerging threats.


I’ve previously described H9N2 as the Professor Moriarty of avian flu viruses. 


Whenever something untoward happens with an avian flu strain – if you look deep enough – you often find clues that H9N2 was the viral `mastermind’ behind it all.


Last May, in EID Journal: H7N9 As A Work In Progress, we looked at a study that found the H7N9 avian virus continues to reassort with local H9N2 viruses, making the H7N9 viruses that circulated in wave 2 genetically distinct from those that were seen during the 1st wave.


Although categorized by their two surface proteins (HA & NA) Influenza A viruses have 8 gene segments (PB2, PB1, PA, HA, NP, NA, M1, M2, NS1, NS2).


Shift, or reassortment, happens when two different influenza viruses co-infect the same host swap genetic material.  New hybrid viruses may be the result of multiple reassortments, with gene contributions coming from several parental viruses.


Of the three avian flu viruses we are currently watching with the most concern – H5N1, H7N9, and H10N8 – all  share several important features (see Study: Sequence & Phylogenetic Analysis Of Emerging H9N2 influenza Viruses In China):


    • They all first appeared in  Mainland China
    • They all  have come about through viral reassortment in poultry
    • And most telling of all, while their HA and NA genes differ - they all carry the internal genes from the avian H9N2 virus


This ubiquitous, yet fairly benign H9N2 virus is apparently very promiscuous, as we keep finding bits and pieces of it turning up in new reassortant viruses.  Last June, in Eurosurveillance: Genetic Tuning Of Avian H7N9 During Interspecies Transmission, we saw evidence of even more influence of H9N2 on the ongoing evolution of H7N9.


Last January, The Lancet carried a report entitled Poultry carrying H9N2 act as incubators for novel human avian influenza viruses by Chinese researchers Di Liu a, Weifeng Shi b & George F Gao that warned:


Several subtypes of avian influenza viruses in poultry are capable of infecting human beings, and the next avian influenza virus that could cause mass infections is not known. Therefore, slaughter of poultry carrying H9N2—the incubators for wild-bird-origin influenza viruses—would be an effective strategy to prevent human beings from becoming infected with avian influenza.

We call for either a shutdown of live poultry markets or periodic thorough disinfections of these markets in China and any other regions with live poultry markets.


In the past, we’ve looked at the propensity of the H9N2 virus to reassort with other avian flu viruses (see PNAS: Reassortment Of H1N1 And H9N2 Avian viruses & PNAS: Reassortment Potential Of Avian H9N2) which have shown the H9N2 capable of producing `biologically fit’ and highly pathogenic reassortant viruses.


And in 2010 (see Study: The Continuing Evolution Of Avian H9N2) we looked at computer modeling (in silica) that warned the H9N2 virus has been slowly evolving towards becoming a `more humanized’ virus.


And while we have only seen a handful of human infections with this virus (see Hong Kong: Isolation & Treatment Of An H9N2 Patient), it is also true that in areas where this virus is most common, testing and surveillance for the virus is extremely limited.  Like so many other novel viruses, we can only guess at is true burden in the human population.


This week, we’ve a new study that finds a diverse set of H9N9 genotypes have been circulating in Chinese poultry between 2009-2013, with the majority sharing a remarkably stable internal-gene-combination”.  This internal gene structure has been `lent’ to the emerging H7N9 and H10N8 viruses as well.

Perhaps most surprising, of 35 viruses tested, all bound preferentially to alpha 2,6 receptor cells -  the type commonly found in the human upper respiratory tract, rather than to alpha 2,3 receptor cells which are found in the gastrointestinal tract of birds.

This is viewed as one of the crucial steps in the adaptation of an avian influenza virus to a mammalian host (see Nature Comms: Host Adaptation Of Avian Influenza Viruses). 


Additionally, six of nine viruses tested in ferrets transmitted via respiratory droplets (two being highly transmissible) and inoculated ferrets readily developing spontaneous viral mutations conducive to greater virulence and better transmission in mammals. 

For more details, follow the link below to read:


Genetics, Receptor Binding Property, and Transmissibility in Mammals of Naturally Isolated H9N2 Avian Influenza Viruses

Xuyong Li equal contributor, Jianzhong Shi equal contributor, Jing Guo equal contributor, Guohua Deng, Qianyi Zhang, Jinliang Wang,  Xijun He, Kaicheng Wang,  Jiming Chen,  Yuanyuan Li,  Jun Fan,  Huiui Kong, Chunyang Gu,  [ ... ], Hualan Chen mail


H9N2 subtype influenza viruses have been detected in different species of wild birds and domestic poultry in many countries for several decades. Because these viruses are of low pathogenicity in poultry, their eradication is not a priority for animal disease control in many countries, which has allowed them to continue to evolve and spread. Here, we characterized the genetic variation, receptor-binding specificity, replication capability, and transmission in mammals of a series of H9N2 influenza viruses that were detected in live poultry markets in southern China between 2009 and 2013.

Thirty-five viruses represented 17 genotypes on the basis of genomic diversity, and one specific “internal-gene-combination” predominated among the H9N2 viruses. This gene combination was also present in the H7N9 and H10N8 viruses that have infected humans in China.

All of the 35 viruses preferentially bound to the human-like receptor, although two also retained the ability to bind to the avian-like receptor. Six of nine viruses tested were transmissible in ferrets by respiratory droplet; two were highly transmissible. Some H9N2 viruses readily acquired the 627K or 701N mutation in their PB2 gene upon infection of ferrets, further enhancing their virulence and transmission in mammals.

Our study indicates that the widespread dissemination of H9N2 viruses poses a threat to human health not only because of the potential of these viruses to cause an influenza pandemic, but also because they can function as “vehicles” to deliver different subtypes of influenza viruses from avian species to humans.

(Continue . . . )