Abstract
H9N2 is the most prevalent low pathogenic avian influenza virus (LPAIV) in domestic poultry in the world. Two distinct H9N2 poultry lineages, G1-like (A/quail/Hong Kong/G1/97) and Y280-like (A/Duck/Hong Kong/Y280/1997) viruses, are usually associated with binding affinity for both α 2,3 and α 2,6 sialic acid receptors (avian and human receptors), raising concern whether these viruses possess pandemic potential. To explore the impact of mouse adaptation on the transmissibility of a Y280-like virus A/Chicken/Hubei/214/2017(H9N2) (abbreviated as WT), we performed serial lung-to-lung passages of the WT virus in mice. The mouse-adapted variant (MA) exhibited enhanced pathogenicity and advantaged transmissibility after passaging in mice. Sequence analysis of the complete genomes of the MA virus revealed a total of 16 amino acid substitutions. These mutations distributed across 7 segments including PB2, PB1, PA, NP, HA, NA and NS1 genes. Furthermore, we generated a panel of recombinant or mutant H9N2 viruses using reverse genetics technology and confirmed that the PB2 gene governing the increased pathogenicity and transmissibility. The combinations of 340 K and 588 V in PB2 were important in determining the altered features. Our findings elucidate the specific mutations in PB2 contribute to the phenotype differences and emphasize the importance of monitoring the identified amino acid substitutions due to their potential threat to human health.
Highlights
H9N2 is the most prevalent low pathogenic avian influenza virus (LPAIV) in domestic poultry in the world
We studied the pathogenicity of the mouse-adapted variant (MA)
The WT-inoculated mice experienced no substantial body weight loss and had nonlethal infections (Fig. 1A,B). These results show that a series of lungto-lung passages of the H9N2 virus resulted in substantially increased virulence in mice
Summary
H9N2 is the most prevalent low pathogenic avian influenza virus (LPAIV) in domestic poultry in the world. The methods rely upon mammalian adaptation through serial passage, reassortment between an AIV and a human influenza virus, point mutations in genes, or a combination of the above[19]. A highly pathogenic strain of H7N1 avian influenza virus became capable of airborne transmission in mammals after 10 serial passages[20]. The capacity of AIVs to transmit among mammals appears to require multiple viral features, such as human receptor binding, increased polymerase activity and high thermostability of HA20,21,23–25. The G1 and Y280 poultry lineages are usually associated with both avian and human receptor binding affinity and could potentially transmit between mammals[8]. To explore which gene-specific mutations contribute to altered phenotype, we generated recombinant and mutant viruses using reverse genetics technology
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