J. Virology: Genetics, Receptor Binding & Virulence (in Mice) Of Avian H10N8

Flu Virus binding to Receptor Cells – Credit CDC

 

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With all of the attention being given to the H7 and H5 avian flu strains this winter (see The Transmission Potential Of A(H7N9) In China & WHO: H5 Currently The Most Obvious Avian Flu Threat) it is easy to forget there are other avian subtypes on our radar as well. 

 

We’ve seen a handful of scattered H9N2 infections over the years, and even a one-off H6N1 in Taiwan in 2013. There’s a reservoir of mixed-host (avian, swine, equine, canine, etc.) H1, H2 & H3 viruses worthy of our attentions, as well.

 

But bringing up the rear are the H10 avian viruses, which have made a splash in the past few years.

 

Last fall, in Avian H10N7 Linked To Dead European Seals, we looked at the die off of thousands of harbor seals due to a combination of avian H10N7 influenza, pneumonia, and bacterial infection.  While known human infections with avian H10 viruses are limited, we’ve discussed them previously on several occasions. 

 

• In 2004, the first known human infections were reported among two Egyptian toddlers, as described in the  WHO/CDS/CSR/RMD report Avian Influenza Virus A (H10N7) Circulating among Humans in Egypt.
• And again, in 2012, in EID Journal: Human Infection With H10N7 Avian Influenza, we looked at a limited outbreak among workers with only mild symptoms at a chicken farm in Australia. 
• And perhaps most concerning, we saw three severe infections with an H10N8 virus in China last winter.

 

A little over a month ago, in TSRI: H10N8 and H6N1 Bind Poorly To Human Receptor Cells, we saw an encouraging report suggesting that neither subtype was poised to pose a serious pandemic threat, although they warned that these viruses bind differently than other avian viruses we’ve seen, and that our understanding of how these viruses mutate isn’t complete enough to warrant complacency.

 

All of which serves a prelude to a new study, published on April 8th in the Journal of Virology, that examines the genetic diversity, and behavior, of eight H10N8 viruses collected between 2009 and 2013. 

 

Worth noting:

• The genetic diversity (5 genotypes) detected among ducks and chickens
• Seven of the eight viruses replicated well in the lungs of mice
• Differences in virulence (in mice) between duck and chicken genotypes
• Dual binding to both Human (a2,6) and avian (a2,3) receptor cells, albeit with marked preference for avian receptors.
• The role that H9N2 has played in its evolution

 

The entire study, including an array of graphs and charts, is available at:

 

Genetics, receptor binding, and virulence in mice of H10N8 influenza viruses isolated from ducks and chickens in live poultry markets in China

Guohua Denga, Jianzhong Shia,  Jing Wanga, Huihui Konga,  Pengfei Cuia, Fang Zhanga,  Dan Tana, Yasuo Suzukib, Liling Liua, Yongping Jianga, Yuntao Guana and Hualan Chena⇑

ABSTRACT

We analyzed eight H10N8 viruses isolated from ducks and chickens in live poultry markets from 2009 to 2013 in China. These viruses showed distinct genetic diversity and formed five genotypes: the four duck isolates formed four different genotypes, whereas the four chicken viruses belong to a single genotype. The viruses bound to both human- and avian-type receptors, and four of the viruses caused 12.7% – 22.5% body weight loss in mice.

SUMMARY

In summary, our genetic studies indicate that the four duck viruses belong to four different genotypes, suggesting that they were introduced into ducks independently; the four chicken viruses belong to one genotype and appear to be hybrids of a duck virus and the local H9N2 viruses (Table 1).

The ability of H10N8 viruses to bind to human-type receptors facilitates their infection of humans, as occurred with the H7N9 viruses (28).

The more efficient replication in mice of the viruses isolated in Jiangxi province than the three duck viruses isolated in Hunan province suggests that the internal genes of the H9N2 viruses may have further increased the replicative ability and virulence of H10N8 viruses in mammals; of cause, the surface proteins may have also contributed to the difference of the virulence.

Although the viruses in our studies were all isolated from healthy birds, two H10 influenza viruses, A/turkey/England/384/79 and A/mandarin duck/Singapore/805/F-72/7/93, were reported to be highly pathogenic in chickens (3, 30). Therefore, it is important to continue monitoring the evolution of H10N8 influenza viruses and to evaluate their potential to cause disease in poultry and pandemics in humans.

 

As we’ve seen with the H5N1 and H7N9 viruses, H10N8 continues to evolve and the ubiquitous H9N2 virus appears to play a substantial role in its evolution.  An LPAI virus in chickens, H10N8 (like H7N9) can spread stealthily between flocks without the typical warning signs that HPAI viruses provide, making it more difficult to detect and eradicate.

 

While the general consensus is that the H10 family of avian viruses aren’t `ready for primetime’, H10N8 has already shown the ability to produce serious (even fatal) illness in humans, which elevates its profile when compared to many other less virulence avian strains.

 

Add in its growing genetic diversity, and its ability to reassort with other avian flu viruses, and H10N8 deservedly holds a second tier position on our list of avian flu viruses to watch.

mBio: Not All LPAI Flu Subtypes Are Created Equally

Credit NIAID

 

 

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Until avian H7N9 showed up a couple of years ago, LPAI (Low Pathogenic Avian Influenza) in birds was considered to constitute a minor human health threat, and our concerns were mostly they would evolve into HPAI (highly pathogenic) strains – with most of that concern focused on H5 and H7 subtypes.

 

H7N9 showed us that an avian influenza could be LPAI in birds and yet extremely pathogenic in humans.

Furthermore, in the summer of 2013 Taiwan reported the first known human infection with an avian H6N1 virus, and a few months later mainland China reported the first three cases of H10N8 (two fatal), further widening the range of avian subtypes capable of causing serious illness in humans.

 

Suddenly, there seemed to be more to keep an eye on than just HPAI H5 and H7.

 

All of which brings us to a fascinating study, published yesterday in the open-access journal mBio, that attempts to compare the pathogenicity of different HA Subtype LPAI flu strains in mammals, and finds some subtypes are far more virulent than others.

Researchers constructed identical LPAI avian flu viruses – differing each only by their hemagglutinin protein (H1-H16) - and tested them in mice and against human cell cultures.

They found the H1, H6, H7, H10, and H15 HA genes demonstrated enhanced virulence in mice and were destructive to human bronchial epithelial cells (in vitro), while chimeric H2, H3, H5, H9, H11, H13, H14 and H16 subtypes caused no significant disease.

 

Leading the study is noted NIAID virologist Jeffrey Taubenberger, who was the first to sequence the the genome of the 1918 Spanish Flu virus.  First some excerpts from the mBio article (follow the link to read in its entirety), followed by a link and excerpt from the press release.

 

Contemporary Avian Influenza A Virus Subtype H1, H6, H7, H10, and H15 Hemagglutinin Genes Encode a Mammalian Virulence Factor Similar to the 1918 Pandemic Virus H1 Hemagglutinin

Li Qi^a, Lindsey M. Pujanauski^a, A. Sally Davis^a, Louis M. Schwartzman^a, Daniel S. Chertow^a,b,  David Baxter^c, Kelsey Scherler^c, Kevan L. Hartshorn^d,  Richard D. Slemons^e,  Kathie-Anne Walters^c,  John C. Kash^a,  Jeffery K. Taubenberger^a

ABSTRACT

Zoonotic avian influenza virus infections may lead to epidemics or pandemics. The 1918 pandemic influenza virus has an avian influenza virus-like genome, and its H1 hemagglutinin was identified as a key mammalian virulence factor. A chimeric 1918 virus expressing a contemporary avian H1 hemagglutinin, however, displayed murine pathogenicity indistinguishable from that of the 1918 virus. Here, isogenic chimeric avian influenza viruses were constructed on an avian influenza virus backbone, differing only by hemagglutinin subtype expressed. Viruses expressing the avian H1, H6, H7, H10, and H15 subtypes were pathogenic in mice and cytopathic in normal human bronchial epithelial cells, in contrast to H2-, H3-, H5-, H9-, H11-, H13-, H14-, and H16-expressing viruses. Mouse pathogenicity was associated with pulmonary macrophage and neutrophil recruitment. These data suggest that avian influenza virus hemagglutinins H1, H6, H7, H10, and H15 contain inherent mammalian virulence factors and likely share a key virulence property of the 1918 virus. Consequently, zoonotic infections with avian influenza viruses bearing one of these hemagglutinins may cause enhanced disease in mammals.

IMPORTANCE Influenza viruses from birds can cause outbreaks in humans and may contribute to the development of pandemics. The 1918 pandemic influenza virus has an avian influenza virus-like genome, and its main surface protein, an H1 subtype hemagglutinin, was identified as a key mammalian virulence factor. In a previous study, a 1918 virus expressing an avian H1 gene was as virulent in mice as the reconstructed 1918 virus. Here, a set of avian influenza viruses was constructed, differing only by hemagglutinin subtype. Viruses with the avian H1, H6, H7, H10, and H15 subtypes caused severe disease in mice and damaged human lung cells. Consequently, infections with avian influenza viruses bearing one of these hemagglutinins may cause enhanced disease in mammals, and therefore surveillance for human infections with these subtypes may be important in controlling future outbreaks.

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From the  American Society for Microbiology we get the following press release:

 

Some flu viruses potentially more dangerous than others

WASHINGTON, DC - November 18, 2014 - Certain subtypes of avian influenza viruses have the potential to cause more severe disease in humans than other avian influenza subtypes and should be monitored carefully to prevent spread of disease, according to a study published this week in mBio®, the online open-access journal of the American Society for Microbiology.

The work, directed by researchers at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., found that flu viruses expressing the low pathogenicity avian H1, H6, H7, H10 or H15 hemagglutinins (genes that encode the major surface protein for the virus) led to fatal infections in mice and caused more cell damage in normal human lung cells grown in culture as compared to avian influenza viruses with other subtypes. The 1918 H1 subtype hemagglutinin has been already identified as a key virulence factor in the pandemic influenza virus of 1918. That virus, which caused the so-called "Spanish flu," spread rapidly around the world, resulting in approximately 50 million deaths.

"Viruses with these avian hemagglutinins have some type of inherent virulence motif to them, in that they induce a marked inflammatory response in mammals including human cells in culture," said senior study author Jeffery K. Taubenberger, MD, PhD, chief of the Viral Pathogenesis and Evolution Section of NIAID's Laboratory of Infectious Diseases. In 2013-2014 there have been close to 400 cases of avian influenza H7N9 infections in people in China, many severe, along with small numbers of severe human infections with H10N8 and H6N1 subtypes. "From a public health and epidemiology standpoint, it's useful to know that avian viruses of these subtypes (for example, H6, H7, or H10) might lead to more severe infections in humans and is something to look out for."

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