Advertisement

Virologica Sinica

, Volume 33, Issue 6, pp 531–537 | Cite as

The D253N Mutation in the Polymerase Basic 2 Gene in Avian Influenza (H9N2) Virus Contributes to the Pathogenesis of the Virus in Mammalian Hosts

  • Jinfeng Zhang
  • Rong Su
  • Xiaoyun Jian
  • Hongliang An
  • Ronbing Jiang
  • Chris Ka Pun MokEmail author
Research Article
  • 124 Downloads

Abstract

Mutations in the polymerase basic 2 (PB2) gene of avian influenza viruses are important signatures for their adaptation to mammalian hosts. Various adaptive mutations have been identified around the 627 and nuclear localization sequence (NLS) domains of PB2 protein, and these mutations contribute to the replicative ability of avian influenza viruses. However, few studies have focused on adaptive mutations in other regions of PB2. In this study, we investigated the functional roles of the D253N mutation in PB2 in an H9N2 virus. This mutation was found to affect an amino acid residue in the middle domain of the PB2 protein. The virus with the D253N mutation showed higher polymerase activity and transiently increased viral replication in human cells. However, the mutant did not show significant differences in viral replication in the respiratory tract of mice upon infection. Our results supported that the D253N mutation in the middle domain of PB2, similar to mutations at the 627 and NLS domains, specifically contributed to the replication of avian influenza viruses in human cells.

Keywords

Avian influenza virus Mammalian adaptation D253N Polymerase basic 2 (PB2) H9N2 

Notes

Acknowledgements

This project was supported by the Science Research Project of the Guangdong Province (Grant no. 2016A050503047), Health and Medical Research Fund (Grant No. 12111832), Guangzhou Medical University High Level University Construction Project Funding and Research Grants Council of the Hong Kong Special Administrative Region, China, through the Theme Based Research Scheme (Ref: T11-705/14N).

Author Contributions

JZ, RS, and CKPM designed the study, HA and CKPM performed the experiments; JZ, XJ, RJ, and YW analyzed the data, JZ and CKPM wrote the main manuscript. All authors read and approved the final manuscript.

Compliance with Ethical Standards

Conflict of interest

We declare that no authors have conflict interests.

Animal and Human Rights Statement

All institutional and national guidelines for the care and use of laboratory animals were followed.

References

  1. Bussey KA, Bousse TL, Desmet EA, Kim B, Takimoto T (2010) PB2 residue 271 plays a key role in enhanced polymerase activity of influenza A viruses in mammalian host cells. J Virol 84:4395–4406CrossRefGoogle Scholar
  2. Chan MC, Cheung CY, Chui WH, Tsao SW, Nicholls JM, Chan YO, Chan RW, Long HT, Poon LL, Guan Y, Peiris JS (2005) Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir Res 6:135CrossRefGoogle Scholar
  3. Chan MC, Chan RW, Chan LL, Mok CK, Hui KP, Fong JH, Tao KP, Poon LL, Nicholls JM, Guan Y, Peiris JS (2013) Tropism and innate host responses of a novel avian influenza A H7N9 virus: an analysis of ex vivo and in vitro cultures of the human respiratory tract. Lancet Respir Med 1:534–542CrossRefGoogle Scholar
  4. Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, Gordon S, Guan Y, Peiris JS (2002) Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 360:1831–1837CrossRefGoogle Scholar
  5. De Filippo K, Neill DR, Mathies M, Bangert M, McNeill E, Kadioglu A, Hogg N (2014) A new protective role for S100A9 in regulation of neutrophil recruitment during invasive pneumococcal pneumonia. FASEB J 28:3600–3608CrossRefGoogle Scholar
  6. de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, Hoang DM, Chau NV, Khanh TH, Dong VC, Qui PT, Cam BV, Ha do Q, Guan Y, Peiris JS, Chinh NT, Hien TT, Farrar J (2006) Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 12:1203–1207CrossRefGoogle Scholar
  7. Gao HN, Lu HZ, Cao B, Du B, Shang H, Gan JH, Lu SH, Yang YD, Fang Q, Shen YZ, et al. (2013) Clinical findings in 111 cases of influenza A (H7N9) virus infection. N Engl J Med 368:2277–2285CrossRefGoogle Scholar
  8. Hatta M, Gao P, Halfmann P, Kawaoka Y (2001) Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293:1840–1842CrossRefGoogle Scholar
  9. Hatta M, Hatta Y, Kim JH, Watanabe S, Shinya K, Nguyen T, Lien PS, Le QM, Kawaoka Y (2007) Growth of H5N1 influenza A viruses in the upper respiratory tracts of mice. PLoS Pathog 3:1374–1379CrossRefGoogle Scholar
  10. Li H, Cao B (2017) Pandemic and avian influenza A viruses in humans: epidemiology, virology, clinical characteristics, and treatment strategy. Clin Chest Med 38:59–70CrossRefGoogle Scholar
  11. Liem NT, Tung CV, Hien ND, Hien TT, Chau NQ, Long HT, Hien NT, le Mai Q, Taylor WR, Wertheim H, Farrar J, Khang DD, Horby P (2009) Clinical features of human influenza A (H5N1) infection in Vietnam: 2004–2006. Clin Infect Dis 48:1639–1646CrossRefGoogle Scholar
  12. Lo CY, Tang YS, Shaw PC (2018) Structure and function of influenza virus ribonucleoprotein. Subcell Biochem 88:95–128CrossRefGoogle Scholar
  13. Mok KP, Wong CH, Cheung CY, Chan MC, Lee SM, Nicholls JM, Guan Y, Peiris JS (2009) Viral genetic determinants of H5N1 influenza viruses that contribute to cytokine dysregulation. J Infect Dis 200:1104–1112CrossRefGoogle Scholar
  14. Mok CK, Yen HL, Yu MY, Yuen KM, Sia SF, Chan MC, Qin G, Tu WW, Peiris JS (2011) Amino acid residues 253 and 591 of the PB2 protein of avian influenza virus A H9N2 contribute to mammalian pathogenesis. J Virol 85:9641–9645CrossRefGoogle Scholar
  15. Mok CK, Lee HH, Chan MC, Sia SF, Lestra M, Nicholls JM, Zhu H, Guan Y, Peiris JM (2013a) Pathogenicity of the novel A/H7N9 influenza virus in mice. MBio pii:e00362–13CrossRefGoogle Scholar
  16. Mok CKP, Lee HHY, Lestra M, Nicholls JM, Chan MCW, Sia SF, Zhu H, Poon LLM, Guan Y, Peiris JSM (2013b) Amino-acid substitutions in polymerase basic protein 2 gene contributes to the pathogenicity of the novel A/H7N9 influenza virus in mammalian hosts. J Virol 88:3568–3576CrossRefGoogle Scholar
  17. Németh T, Mócsai A (2016) Feedback amplification of neutrophil function. Trends Immunol 37:412–424CrossRefGoogle Scholar
  18. Parkos CA (2016) Neutrophil-epithelial interactions: a double-edged sword. Am J Pathol 186:1404–1416CrossRefGoogle Scholar
  19. Perrone LA, Plowden JK, García-Sastre A, Katz JM, Tumpey TM (2008) H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog 4:e1000115CrossRefGoogle Scholar
  20. Sugamata R, Dobashi H, Nagao T, Yamamoto K, Nakajima N, Sato Y, Aratani Y, Oshima M, Sata T, Kobayashi K, Kawachi S, Nakayama T, Suzuki K (2012) Contribution of neutrophil-derived myeloperoxidase in the early phase of fulminant acute respiratory distress syndrome induced by influenza virus infection. Microbiol Immunol 56:171–182CrossRefGoogle Scholar
  21. Wang C, Lee HHY, Yang ZF, Mok CKP, Zhang Z (2016) PB2-Q591K mutation determines the pathogenicity of avian H9N2 influenza viruses for mammlian species. PLoS ONE 11:e0162163CrossRefGoogle Scholar
  22. Yamada S, Hatta M, Staker BL, Watanabe S, Imai M, Shinya K, Sakai-Tagawa Y, Ito M, Ozawa M, Watanabe T, Sakabe S, Li C, Kim JH, Myler PJ, Phan I, Raymond A, Smith E, Stacy R, Nidom CA, Lank SM, Wiseman RW, Bimber BN, O’Connor DH, Neumann G, Stewart LJ, Kawaoka Y (2010) Biological and structural characterization of a host-adapting amino acid in influenza virus. PLoS Pathog 6(8):e1001034CrossRefGoogle Scholar
  23. Zhou J, Wang D, Gao R, Zhao B, Song J, Qi X, Zhang Y, Shi Y, Yang L, Zhu W, et al. (2013) Biological features of novel avian influenza A (H7N9) virus. Nature 499:500–503CrossRefGoogle Scholar

Copyright information

© Wuhan Institute of Virology, CAS 2018

Authors and Affiliations

  1. 1.Laboratory Medicine Center, Foshan Hospital of Traditional Chinese MedicineGuangzhou University of Chinese MedicineFoshanChina
  2. 2.Department of Respiratory Medicine, Foshan Hospital of Traditional Chinese MedicineGuangzhou University of Chinese MedicineFoshanChina
  3. 3.State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
  4. 4.HKU-Pasteur Research Pole, School of Public Health, HKU Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina

Personalised recommendations