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Archives of Virology

, Volume 162, Issue 11, pp 3517–3522 | Cite as

The virulence factor PA protein of highly pathogenic H5N1 avian influenza virus inhibits NF-κB transcription in vitro

  • Zhu Cui
  • Jiao Hu
  • Xiaoquan Wang
  • Min Gu
  • Xiaowen Liu
  • Shunlin Hu
  • Zenglei Hu
  • Huimou Liu
  • Wenbo Liu
  • Sujuan Chen
  • Daxin Peng
  • Xinan Jiao
  • Xiufan LiuEmail author
Brief Report

Abstract

Nuclear factor kappa B (NF-κB) plays a crucial role in inflammation and immune responses. Our previous studies have demonstrated that the innate immune response affect H5N1 virus virulence in mice. In this study, we first showed that the PA protein of the highly pathogenic avian influenza virus strain CK10 had the strongest inhibitory effect on NF-κB activation when compared with other genes, and that it acted in a dose independent-manner. We then determined the critical amino acids of PA that contribute to this effect. Furthermore, PA also inhibited NF-κB-regulated inflammatory factors, including IL-6, IL-2, Nos-2 and TNF-α. However, the inhibitory effect on NF-κB activation mediated by PA was not associated with nuclear translocation of p65.

Notes

Compliance with ethical standards

Funding

This work was supported by the National Key Research and Development Project of China (2016YFD0501601 and 2016YFD0500202), by the National Natural Science Foundation of China (31502076), by the Special Financial Grant from the China Postdoctoral Science Foundation (2016T90515), by the Jiangsu Provincial Natural Science Foundation of China (BK20150444), by the National Key Technologies R&D Program of China (2015BAD12B01-3), by the Natural Science Foundation of the Higher Education Institutions of Jiangsu Province, China (15KJB230006), by the earmarked fund for Modern Agro-Industry Technology Research System (nycytx-41-G07) and by a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Dai M, McBride R, Dortmans JC, Peng W, Bakkers MJ, de Groot RJ et al (2017) Mutation of the 2nd Sialic acid-binding site resulting in reduced neuraminidase activity preceded emergence of H7N9 influenza A virus. J Virol 91(9). doi: 10.1128/JVI.00049-17
  2. 2.
    Shen Y, Lu H (2017) Global concern regarding the fifth case of human infection with avian influenza A (H7N9) virus in China. Biosci Trends 11(1):120–121CrossRefPubMedGoogle Scholar
  3. 3.
    Cinatl J Jr, Michaelis M, Doerr HW (2007) The threat of avian influenza A (H5N1). Part I: epidemiologic concerns and virulence determinants. Med Microbiol Immunol 196(4):181–190CrossRefPubMedGoogle Scholar
  4. 4.
    Hu J, Hu Z, Song Q, Gu M, Liu X, Wang X et al (2013) The PA-gene-mediated lethal dissemination and excessive innate immune response contribute to the high virulence of H5N1 avian influenza virus in mice. J Virol 87(5):2660–2672CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hu J, Zhao K, Liu X, Wang X, Chen Z, Liu X (2013) Two highly pathogenic avian influenza H5N1 viruses of clade 2.3.2.1 with similar genetic background but with different pathogenicity in mice and ducks. Transbound Emerg Dis 60(2):127–139CrossRefPubMedGoogle Scholar
  6. 6.
    Bonizzi G, Karin M (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25(6):280–288CrossRefPubMedGoogle Scholar
  7. 7.
    Hayden MS, Ghosh S (2012) NF-kappaB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev 26(3):203–234CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Randall RE, Goodbourn S (2008) Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol 89:1–47CrossRefPubMedGoogle Scholar
  9. 9.
    Viemann D, Schmolke M, Lueken A, Boergeling Y, Friesenhagen J, Wittkowski H et al (2011) H5N1 virus activates signaling pathways in human endothelial cells resulting in a specific imbalanced inflammatory response. J Immunol 186(1):164–173CrossRefPubMedGoogle Scholar
  10. 10.
    Schmitz ML, Kracht M, Saul VV (2014) The intricate interplay between RNA viruses and NF-kappaB. Biochim Biophys Acta 1843(11):2754–2764CrossRefPubMedGoogle Scholar
  11. 11.
    Ehrhardt C, Ruckle A, Hrincius ER, Haasbach E, Anhlan D, Ahmann K et al (2013) The NF-kappaB inhibitor SC75741 efficiently blocks influenza virus propagation and confers a high barrier for development of viral resistance. Cell Microbiol 15(7):1198–1211CrossRefPubMedGoogle Scholar
  12. 12.
    Wurzer WJ, Ehrhardt C, Pleschka S, Berberich-Siebelt F, Wolff T, Walczak H et al (2004) NF-kappaB-dependent induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas/FasL is crucial for efficient influenza virus propagation. J Biol Chem 279(30):30931–30937CrossRefPubMedGoogle Scholar
  13. 13.
    Pauli EK, Schmolke M, Wolff T, Viemann D, Roth J, Bode JG et al (2008) Influenza A virus inhibits type I IFN signaling via NF-kappaB-dependent induction of SOCS-3 expression. PLoS Pathog 4(11):e1000196CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Dam S, Kracht M, Pleschka S, Schmitz ML (2016) The influenza A virus genotype determines the antiviral function of NF-kappaB. J Virol 90(17):7980–7990CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Goulet ML, Olagnier D, Xu Z, Paz S, Belgnaoui SM, Lafferty EI et al (2013) Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity. PLoS Pathog 9(4):e1003298CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Opitz B, Rejaibi A, Dauber B, Eckhard J, Vinzing M, Schmeck B et al (2007) IFNbeta induction by influenza A virus is mediated by RIG-I which is regulated by the viral NS1 protein. Cell Microbiol 9(4):930–938CrossRefPubMedGoogle Scholar
  17. 17.
    Liedmann S, Hrincius ER, Anhlan D, McCullers JA, Ludwig S, Ehrhardt C (2014) New virulence determinants contribute to the enhanced immune response and reduced virulence of an influenza A virus A/PR8/34 variant. J Infect Dis 209(4):532–541CrossRefPubMedGoogle Scholar
  18. 18.
    Sakabe S, Takano R, Nagamura-Inoue T, Yamashita N, Nidom CA, Le Quynh M et al (2013) Differences in cytokine production in human macrophages and in virulence in mice are attributable to the acidic polymerase protein of highly pathogenic influenza A virus subtype H5N1. J Infect Dis 207(2):262–271CrossRefPubMedGoogle Scholar
  19. 19.
    Huang CH, Chen CJ, Yen CT, Yu CP, Huang PN, Kuo RL et al (2013) Caspase-1 deficient mice are more susceptible to influenza A virus infection with PA variation. J Infect Dis 208(11):1898–1905CrossRefPubMedGoogle Scholar
  20. 20.
    DesRochers BL, Chen RE, Gounder AP, Pinto AK, Bricker T, Linton CN et al (2016) Residues in the PB2 and PA genes contribute to the pathogenicity of avian H7N3 influenza A virus in DBA/2 mice. Virology 494:89–99CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Hu J, Hu Z, Song Q, Gu M, Liu X, Wang X et al (2013) The PA-gene-mediated lethal dissemination and excessive innate immune response contribute to the high virulence of H5N1 avian influenza virus in mice. J Virol 87(5):2660–2672CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Hu J, Zhao K, Liu X, Wang X, Chen Z (2013) Two highly pathogenic avian influenza H5N1 viruses of clade 2.3.2.1 with similar genetic background but with different pathogenicity in mice and ducks. Transbound Emerg Dis 60(2):127–139CrossRefPubMedGoogle Scholar
  23. 23.
    Bernasconi D, Amici C, La Frazia S, Ianaro A, Santoro MG (2005) The IkappaB kinase is a key factor in triggering influenza A virus-induced inflammatory cytokine production in airway epithelial cells. J Biol Chem 280(25):24127–24134CrossRefPubMedGoogle Scholar
  24. 24.
    Wei L, Sandbulte MR, Thomas PG, Webby RJ, Homayouni R, Pfeffer LM (2006) NFkappaB negatively regulates interferon-induced gene expression and anti-influenza activity. J Biol Chem 281(17):11678–11684CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Christman JW, Sadikot RT, Blackwell TS (2000) The role of nuclear factor-kappa B in pulmonary diseases. Chest 117(5):1482–1487CrossRefPubMedGoogle Scholar
  26. 26.
    Chen RJ, Yuan HH, Zhang TY, Wang ZZ, Hu AK, Wu LL et al (2014) Heme oxygenase-2 suppress TNF-alpha and IL6 expression via TLR4/MyD88-dependent signaling pathway in mouse cerebral vascular endothelial cells. Mol Neurobiol 50(3):971–978CrossRefPubMedGoogle Scholar
  27. 27.
    Cao T, Zhang T, Wang L, Zhang L, Adachi T, Sato T et al (2010) Ganglioside GD1a suppression of NOS2 expression via ERK1 pathway in mouse osteosarcoma FBJ cells. J Cell Biochem 110(5):1165–1174CrossRefPubMedGoogle Scholar
  28. 28.
    Llavero F, Artaso A, Lacerda HM, Parada LA, Zugaza JL (2016) Lck/PLCgamma control migration and proliferation of interleukin (IL)-2-stimulated T cells via the Rac1 GTPase/glycogen phosphorylase pathway. Cell Signal 28(11):1713–1724CrossRefPubMedGoogle Scholar
  29. 29.
    Zhou B, Yang Z, Feng Q, Liang X, Li J, Zanin M et al (2017) Aurantiamide acetate from baphicacanthus cusia root exhibits anti-inflammatory and anti-viral effects via inhibition of the NF-kappaB signaling pathway in influenza A virus-infected cells. J Ethnopharmacol 199:60–67CrossRefPubMedGoogle Scholar
  30. 30.
    Nieto A, de la Luna S, Barcena J, Portela A, Ortin J (1994) Complex structure of the nuclear translocation signal of influenza virus polymerase PA subunit. J Gen Virol 75(Pt 1):29–36CrossRefPubMedGoogle Scholar
  31. 31.
    Hu J, Liu X (2015) Crucial role of PA in virus life cycle and host adaptation of influenza A virus. Med Microbiol Immunol 204(2):137–149CrossRefPubMedGoogle Scholar
  32. 32.
    Hu J, Hu Z, Mo Y, Wu Q, Cui Z, Duan Z et al (2013) The PA and HA gene-mediated high viral load and intense innate immune response in the brain contribute to the high pathogenicity of H5N1 avian influenza virus in mallard ducks. J Virol 87(20):11063–11075CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria 2017

Authors and Affiliations

  • Zhu Cui
    • 1
    • 2
    • 4
  • Jiao Hu
    • 1
    • 2
    • 4
  • Xiaoquan Wang
    • 1
    • 2
    • 4
  • Min Gu
    • 1
    • 2
    • 4
  • Xiaowen Liu
    • 1
    • 2
    • 4
  • Shunlin Hu
    • 1
    • 2
    • 4
  • Zenglei Hu
    • 1
    • 2
    • 4
  • Huimou Liu
    • 1
    • 2
    • 4
  • Wenbo Liu
    • 1
    • 2
    • 4
  • Sujuan Chen
    • 1
    • 2
    • 4
  • Daxin Peng
    • 1
    • 2
    • 4
  • Xinan Jiao
    • 2
    • 3
    • 4
  • Xiufan Liu
    • 1
    • 2
    • 4
    Email author
  1. 1.Animal Infectious Disease Laboratory, School of Veterinary MedicineYangzhou UniversityYangzhouChina
  2. 2.Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and ZoonosisYangzhou UniversityYangzhouChina
  3. 3.Jiangsu Key Laboratory of ZoonosisYangzhou UniversityYangzhouChina
  4. 4.Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agri-food Safety and Quality, Ministry of Agriculture of China (26116120)Yangzhou UniversityYangzhouChina

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