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Mouse adaptation of the H9N2 avian influenza virus causes the downregulation of genes related to innate immune responses and ubiquitin-mediated proteolysis in mice

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Abstract

H9N2 avian influenza viruses sporadically infect humans worldwide. These viruses have also contributed internal genes to H5N1, H5N6, H7N9, and H10N8 viruses, which have been isolated from humans with infections and are a substantial public health threat. To investigate the potential pathogenic mechanism of the H9N2 virus, we performed serial lung-to-lung passage of an avirulent H9N2 avian influenza virus (A/Chicken/Shandong/416/2016 [SD/416]) in mice to increase the pathogenicity of this virus. We generated a mouse-adapted (MA) virus that exhibited increased viral titers in the lungs, caused severe lung damage in mice, and induced body weight loss in mice; however, the avirulent parental virus did not cause any clinical symptoms in infected mice. Global gene expression analysis was performed and indicated that the transcriptional responses of these viruses were distinct. The lungs of mice infected with the MA virus exhibited the downregulation of genes related to innate immunity and ubiquitin-mediated proteolysis, which was not seen in infections with the avirulent parental virus. These data indicated that the MA virus might evade immune surveillance and changed its replication capacity to increase the viral replication level and pathogenicity. Our study demonstrates that host factors play an important role in the adaptive evolution of influenza virus in new hosts.

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Acknowledgements

We thank the National Natural Science Foundation of China, the Natural Science Foundation of Shandong Province, and the State Key Laboratory of Veterinary Biotechnology. This work was supported by the National Natural Science Foundation of China (31702262 and 31702261), the Natural Science Foundation of Shandong Province (ZR2017BC057 and ZR2017BC048), and the State Key Laboratory of Veterinary Biotechnology (SKLVBF201906).

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Correspondence to Jing Guo or Xuyong Li.

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Guo, J., Gao, X., Liu, B. et al. Mouse adaptation of the H9N2 avian influenza virus causes the downregulation of genes related to innate immune responses and ubiquitin-mediated proteolysis in mice. Med Microbiol Immunol (2020). https://doi.org/10.1007/s00430-020-00656-4

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Keywords

  • Influenza virus
  • Adaptation
  • Pathogenicity
  • Gene expression analysis