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PA-X I94V mutation modulates the pathogenicity of the highly pathogenic H7N9 influenza A virus in mice and chickens

Xia Chen1, Haozhan Liu2, Liyi Jiang1

  • 1Key Laboratory of Avian Bioproducts Development，Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Yangzhou University, China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China; Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agri-food Safety and Quality, Ministry of Agriculture of China (26116120), College of Veterinary Medicine, Yangzhou University, Yangzhou, China.

Veterinary Microbiology
|May 6, 2026
PubMed

Insights

The PA-X I94V mutation in influenza A virus (IAV) enhances pathogenicity in mice but reduces virulence in chickens. This specific mutation in PA-X, not PA, drives H7N9 virus adaptation and virulence in mammals.

Area of Science:

  • Virology
  • Molecular Biology
  • Pathogenesis

Background:

  • Influenza A virus (IAV) continuously evolves, posing significant threats to human and animal health.
  • Recent H5N1 and H7N9 IAV strains exhibit high variation at site 94 of the PA/PA-X gene.
  • The I94V mutation is prevalent in human H7N9 viruses, but its role in pathogenicity across hosts is unclear.

Purpose of the Study:

  • To investigate the role of the PA I94V mutation in H7N9 viral pathogenicity in mammalian and avian species.
  • To determine the specific contribution of PA-X I94V versus PA-I94V in host adaptation and viral fitness.
  • To elucidate the molecular mechanisms underlying the effect of PA-X I94V on viral replication and host response.

Main Methods:

  • Comparative analysis of viral pathogenicity and fitness in mouse and chicken models.
  • Phenotypic comparison of wild-type, PA-X-deficient, and PA-X-deficient viruses with PA I94V mutation.
  • Assessment of viral polymerase activity, replication efficiency in mammalian cells, and host shutoff activity.

Main Results:

  • PA/PA-X I94V mutation increased pathogenicity and viral fitness in mice but attenuated virulence in chickens.
  • PA-X I94V, not PA-I94V, was identified as the key driver of H7N9 virulence, as its effect was abolished in PA-X-deficient viruses.
  • PA-X I94V significantly enhanced viral polymerase activity, replication in mammalian cells, and modulated host shutoff mechanisms, including inhibition of antiviral and cell death responses.

Conclusions:

  • The PA-X I94V mutation plays a critical role in the host adaptation and pathogenesis of H7N9 influenza A virus.
  • PA-X I94V directly modulates viral virulence by enhancing polymerase activity and replication in mammalian hosts.
  • This mutation impacts host antiviral responses, offering insights into influenza virus evolution and disease mechanisms.
Keywords:
Avian influenza virusChickensH7N9 subtypeHost adaptationHost shutoffMicePA-X

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