1887

Abstract

Avian H9N2 influenza viruses in East Asia are genetically diversified and multiple genotypes (A-W) have been established in poultry. Genotype S strains are currently the most prevalent strains, have caused many human infections and pose a public health threat. In this study, human adaptation mutations in the PB2 polymerase in genotype S strains were identified by database screening. Several PB2 double mutations were identified that acted cooperatively to produce higher genotype S virus polymerase activity and replication in human cells than in avian cells and to increase viral growth and virulence in mice. These mutations were chronologically and phylogenetically clustered in a new group within genotype S viruses. Most of the relevant human virus isolates carry the PB2-A588V mutation together with another PB2 mutation (i.e. K526R, E627V or E627K), indicating a host adaptation advantage for these double mutations. The prevalence of PB2 double mutations in human H9N2 virus isolates has also been found in genetically related human H7N9 and H10N8 viruses. These results suggested that PB2 double mutations in viruses in the field acted cooperatively to increase human adaptation of the currently prevalent H9N2 genotype S strains. This may have contributed to the recent surge of H9N2 infections and may be applicable to the human adaptation of several other avian influenza viruses. Our study provides a better understanding of the human adaptation pathways of genetically related H9N2, H7N9 and H10N8 viruses in nature.

Funding
This study was supported by the:
  • SoSasakawa Scientific Research Grant from the Japan Science Society
    • Principle Award Recipient: YasuhaArai
  • Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
    • Principle Award Recipient: YoheiWatanabe
  • SENSHIN Medical Research Foundation
    • Principle Award Recipient: YoheiWatanabe
  • Uehara Memorial Foundation
    • Principle Award Recipient: YasuhaArai
  • Takeda Science Foundation
    • Principle Award Recipient: YoheiWatanabe
  • Japan Society for the Promotion of Science (Award 21K15455)
    • Principle Award Recipient: YasuhaArai
  • Japan Society for the Promotion of Science (Award 20KK0224)
    • Principle Award Recipient: YoheiWatanabe
  • Japan Society for the Promotion of Science (Award 20K21723)
    • Principle Award Recipient: YoheiWatanabe
  • Japan Society for the Promotion of Science (Award 19H04841)
    • Principle Award Recipient: YoheiWatanabe
  • Japan Society for the Promotion of Science (Award 18K15171)
    • Principle Award Recipient: YasuhaArai
  • Japan Society for the Promotion of Science (Award ID Number P19118)
    • Principle Award Recipient: EmadM. Elgendy
  • Japan Science and Technology Agency (Award JPMJMI19D4)
    • Principle Award Recipient: KazuhikoMatsumoto
  • Japan Science and Technology Agency (Award JPMJCR15F4)
    • Principle Award Recipient: KazuhikoMatsumoto
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2021-06-01
2021-06-19
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