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. 2020 Aug 18;9(8):670.
doi: 10.3390/pathogens9080670.

Continuous Reassortment of Clade 2.3.4.4 H5N6 Highly Pathogenetic Avian Influenza Viruses Demonstrating High Risk to Public Health

Huanan Li  1   2   3   4   5 , Qian Li  1   6 , Bo Li  1   2   4   5 , Yang Guo  1   2   4   5 , Jinchao Xing  1   2   4   5 , Qiang Xu  1   2   5 , Lele Liu  1   4 , Jiahao Zhang  1   2   5 , Wenbao Qi  1   2   3   4   5 , Weixin Jia  1   2   3   4   5 , Ming Liao  1   2   3   4   5
Affiliations

Continuous Reassortment of Clade 2.3.4.4 H5N6 Highly Pathogenetic Avian Influenza Viruses Demonstrating High Risk to Public Health

Huanan Li et al. Pathogens. .

Abstract

Since it firstly emerged in China in 2013, clade 2.3.4.4 H5N6 highly pathogenic avian influenza viruses (HPAIVs) has rapidly replaced predominant H5N1 to become the dominant H5 subtype in China, especially in ducks. Not only endemic in China, it also crossed the geographical barrier and emerged in South Korea, Japan, and Europe. Here, we analyzed the genetic properties of the clade 2.3.4.4 H5N6 HPAIVs with full genome sequences available online together with our own isolates. Phylogenetic analysis showed that clade 2.3.4.4 H5N6 HPAIVs continuously reassorted with local H5, H6, and H7N9/H9N2. Species analysis reveals that aquatic poultry and migratory birds became the dominant hosts of H5N6. Adaption to aquatic poultry might help clade 2.3.4.4 H5N6 better adapt to migratory birds, thus enabling it to become endemic in China. Besides, migratory birds might help clade 2.3.4.4 H5N6 transmit all over the world. Clade 2.3.4.4 H5N6 HPAIVs also showed a preference for α2,6-SA receptors when compared to other avian origin influenza viruses. Experiments in vitro and in vivo revealed that clade 2.3.4.4 H5N6 HPAIVs exhibited high replication efficiency in both avian and mammal cells, and it also showed high pathogenicity in both mice and chickens, demonstrating high risk to public health. Considering all the factors together, adaption to aquatic poultry and migratory birds helps clade 2.3.4.4 H5N6 overcome the geographical isolation, and it has potential to be the next influenza pandemic in the world, making it worthy of our attention.

Keywords: clade 2.3.4.4 H5N6; influenza virus; pandemic; pathogenicity; reassort; transmit.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Phylogenetic analysis of H5N6 influenza viruses.
Figure 2
Figure 2
Evolutionary pathway of clade 2.3.4.4 H5N6 HPAIVs. The eight gene segments are PB2, PB1, PA, HA, NP, NA, M, and NS (from top to bottom of the virion). Different colors represent different virus lineages.
Figure 3
Figure 3
Host of clade 2.3.4.4 H5N6 HPAIVs. The eight gene segments are PB2, PB1, PA, HA, NP, NA, M, and NS (from top to bottom of the virion). Different colors represent different virus lineages.
Figure 4
Figure 4
Receptor binding ability and growth curve of clade 2.3.4.4 H5N6 HPAIVs. (a) Receptor reference of clade 2.3.4.4 H5N6 HPAIVs. A 2009 pandemic H1N1 virus (A/Guangdong/776/2015) and a clade 2.3.2 H5N1 virus (A/Guangdong/178/2004) were used as positives controls for SA2,6Gal receptors and SA2,3Gal receptors, respectively. (b) Virus titer of H5N6 AIVs on different cell lines. DF-1, ST, and A549 were inoculated at a MOI of 0.01; supernatants were collected at 12, 24, 36, 48, and 60 hours post-infection (hpi) and stored at -80 °C. The 50% tissue culture infectious dose (TCID50) of different samples were determined in MDCK cells.
Figure 5
Figure 5
Four-week-old female specific pathogen-free (SPF) BALB/c mice were inoculated intranasally with 106 egg infectious doses (EID50) of test viruses or sterile Dulbecco’s Modified Eagle Medium (DMEM) in a volume of 50 µL. Body weight change (a) and survival rate (b) of mice were exhibited. The virus load of lung (c) and brain (d) of infected mice were determined on 3 dpi. The dash line represented the detection limit of this assay. For statistical analysis, a value of 1.5 was assigned if the virus was not detected from the undiluted sample in three embryonated eggs. The data was analyzed in one-way ANOVA test by GraphPad. * meant p < 0.05, ** meant p < 0.01, and ns meant no significant difference, respectively.
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