Wednesday, April 19, 2017

Emerg. Microbes & Inf.: Pathogenicity & Transmission Of A Swine Influenza A(H6N6) Virus - China


Although we tend to think first of H7N9 - and then of H5N1 and H5N6 - as the only serious novel flu threats in China, in truth the field of novel flu threats is much larger, and grows larger with each passing year.

A few of the  `oddball' flu viruses in China we've covered in the past 12 months include:
Sci Rpts: Characterization of Avian H7N2 in Wild Birds and Pikas in Qinghai-Tibet Plateau Area

EID Journal: Reassortant EAH1N1 Virus Infection In A Child - Hunan China, 2016

J. Virol: A Single Mutation Enhances H9N2 Binding To Human-Like Sialic Acid Receptors
Front. Microbiol.: A Novel H1N2 Reassorted Influenza Virus In Chinese Pigs
Nature: Emergence Of Novel Reassortant H3N6 In Hunan Province

While we worry about avian influenza - swine carry and spread a variety of H1, H2, and H3 Swine Influenza Viruses (SIVs) - which just happen to be only subtypes of influenza that have sparked human pandemics over the past 100+ years (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?).
All of which puts swine high on the list of possible pandemic flu incubators.  Swine viruses - being at least partially mammalian adapted - are viewed as having `less far to jump' to infect humans.
But a 2013 survey of the Epidemic Status of Swine Influenza Virus in China also documented the presence of avian H3N8, H4N8, H5N1, H6N6, and H9N2 in Chinese pigs. 

Swine possess both avian-like (SAα2,3Gal) and human-like (SAα2,6Gal) receptor cells in their respiratory tract, making them susceptible to a wide variety of avian, human, and swine influenza viruses.
This allows them to act as a `mixing vessels', which can lead to the creation of new hybrid flu viruses.
As the diversity of the pool of flu viruses circulating in pigs increases, so do the odds of generating new biologically fit novel virus. Over time, reassortants of reassorted viruses are generated, and we end up with viruses with multiple parental contributions.
Notable among the viruses circulating in China's swine population is H6N6, which emerged in 2010, and has played an important role in the creation of HPAI H5N6, which this year has expanded its range to South Korea, Japan, and Taiwan. 
While H6 viruses don't tend to get a lot of attention, in May of 2013, the Taiwan CDC Reported A Human Infection With Avian H6N1) - the first ever detected - in a 20-year-old female, hospitalized with pneumonia.

This was followed in 2014 by the discovery of  Influenza A(H6N1) In Dogs, Taiwan, which surprisingly found a seroprevalence of more than 2% in the dogs tested.
After years of relative obscurity, avian H6 viruses are now a topic of considerable interest to flu researchers (see EID Journal: Seropositivity For H6 Influenza Viruses In China &  Study: Adaptation Of H6N1 From Avian To Human Receptor-Binding).
Last year, in Arch Virol: Novel Reassortant H6N6 Isolated From Chinese Poultry, we looked at a study that found novel reassortant H6N6 avian viruses circulating widely in Chinese poultry.  The authors noted `H6 subtype avian influenza viruses (AIVs) possess the ability to cross the species barrier to infect mammals and pose a threat to human health.'
Today we've a recently published study that looks at the evolution, pathogenicity, and circulation  of H6N6 in China's pig population.
Among their findings, they demonstrate that H6N6 binds to both α2,6-linked and α2,3-linked sialic acids, an important trait for any species jumping flu virus to acquire. 
While not currently viewed as ready for prime time, H6N6 is circulating in a host environment rich with other influenza subtypes, which over time could provide it ample opportunities to reassort into a much greater human health threat. 

The full (open access) report is available at the link below. I've only included some excepts.  Follow the link to read:
Pathogenicity and transmission of a swine influenza A(H6N6) virus
Hailiang Sun1, Bryan S Kaplan2, Minhui Guan1, Guihong Zhang3, Jianqiang Ye1, Li-Ping Long1, Sherry Blackmon1, Chun-Kai Yang1, Meng-Jung Chiang4, Hang Xie4, Nan Zhao1, Jim Cooley5, David F Smith6, Ming Liao3, Carol Cardona7, Lei Li8, George Peng Wang8, Richard Webby2 and Xiu-Feng Wan1


Subtype H6 influenza A viruses (IAVs) are commonly detected in wild birds and domestic poultry and can infect humans. In 2010, a H6N6 virus emerged in southern China, and since then, it has caused sporadic infections among swine. We show that this virus binds to α2,6-linked and α2,3-linked sialic acids. Mutations at residues 222 (alanine to valine) and 228 (glycine to serine) of the virus hemagglutinin (HA) affected its receptor-binding properties. 

Experiments showed that the virus has limited transmissibility between ferrets through direct contact or through inhalation of infectious aerosolized droplets. The internal genes of the influenza A(H1N1)pdm09 virus, which is prevalent in swine worldwide, increases the replication efficiency of H6N6 IAV in the lower respiratory tract of ferrets but not its transmissibility between ferrets. These findings suggest H6N6 swine IAV (SIV) currently poses a moderate risk to public health, but its evolution and spread should be closely monitored.



Together, the demonstrated promiscuous nature of H6 AIVs, their prevalence in southern China, and the case of H6N1 virus infection in a human in southern China 15 raise concerns that the H6N6 SIV emerging in that area’s swine population could become or contribute to an enzootic influenza strain causing human infections. Such a transition could occur through the commonplace evolutionary events in influenza viruses, such as acquisition of adapted mutations or entire gene segments from currently co-circulating SIVs.
Phylogenetic analyses showed that the H6N6 virus is genetically different from the H6N1 virus that infected a human in Taiwan. These findings suggest that the H6 IAVs in southern China are genetically diverse,16, 17, 18 and active evolutionary events that are still ongoing among the H6 AIVs have led to the emergence of an H6N1 virus in a human15, 43, 44 and to H6N6 viruses in swine.20 Virus mutation and reassortment rates have been key measures in virologic risk assessments of influenza.45 The presence of genetically diverse H6 IAVs and active evolutionary events increases the possibility for a virus of this subtype to develop pandemic potential and present a risk to public health.


In summary, our findings suggest that subtype H6N6 virus can bind to α2,6-linked sialic acids, indicating H6N6 virus as a virus with zoonotic potential. Although H6N6 SIV has limited transmissibility between ferrets and probably cannot yet be transmitted between ferrets through infectious aerosolized droplets, the virus could evolve into a more transmissible H6 virus through additional adaptation and reassortment. Thus, evolution of this H6N6 virus and other H6 AIVs should be closely monitored.