Advertisement

Virologica Sinica

, Volume 33, Issue 6, pp 515–523 | Cite as

Japanese Encephalitis Virus NS1′ Protein Antagonizes Interferon Beta Production

  • Dengyuan Zhou
  • Fan Jia
  • Qiuyan Li
  • Luping Zhang
  • Zheng Chen
  • Zikai Zhao
  • Min Cui
  • Yunfeng Song
  • Huanchun Chen
  • Shengbo Cao
  • Jing YeEmail author
Research Article
  • 153 Downloads

Abstract

Japanese encephalitis virus (JEV) is a mosquito-borne virus and the major cause of viral encephalitis in Asia. NS1′, a 52-amino acid C-terminal extension of NS1, is generated with a -1 programmed ribosomal frameshift and is only present in members of the Japanese encephalitis serogroup of flaviviruses. Previous studies demonstrated that NS1′ plays a vital role in virulence, but the mechanism is unclear. In this study, an NS1′ defected (rG66A) virus was generated. We found that rG66A virus was less virulent than its parent virus (pSA14) in wild-type mice. However, similar mortality caused by the two viruses was observed in an IFNAR knockout mouse model. Moreover, we found that rG66A virus induced a greater type I interferon (IFN) response than that by pSA14, and JEV NS1′ significantly inhibited the production of IFN-β and IFN-stimulated genes. Taken together, our results reveal that NS1′ plays a vital role in blocking type I IFN production to help JEV evade antiviral immunity and benefit viral replication.

Keywords

Japanese encephalitis virus (JEV) NS1′ Type I interferon (IFN-I) Immune evasion 

Notes

Acknowledgements

This work was supported by the National Key Research and Development Program of China (2016YFD0500407), National Natural Science Foundation of China (31502065 and 31572517), and Fundamental Research Funds for the Central Universities (2013PY051, 2662016Q003, and 2662015PY083).

Author Contributions

JY, SBC, YFS, MC, and HCC conceived and designed the experiments. DYZ, FJ, QYL, LPZ, ZC, and ZKZ performed the experiments. DYZ analyzed the data. DYZ and JY wrote the manuscript and prepared the Figures. JY and SBC checked and finalized the manuscript. All authors read and approved the final manuscript.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interests. All authors read and approved the final manuscript.

Animal and Human Rights Statement

Animal experiments in this study were approved by the Scientific Ethics Committee of Huazhong Agricultural University (permit number HZAUMO-2017-016).

Supplementary material

12250_2018_67_MOESM1_ESM.pdf (127 kb)
Supplementary material 1 (PDF 128 kb)

References

  1. Amorim JH, Alves RP, Boscardin SB, Ferreira LC (2014) The dengue virus non-structural 1 protein: risks and benefits. Virus Res 181:53–60CrossRefGoogle Scholar
  2. Ashour J, Laurent-Rolle M, Shi PY, Garcia-Sastre A (2009) NS5 of dengue virus mediates STAT2 binding and degradation. J Virol 83:5408–5418CrossRefGoogle Scholar
  3. Best SM (2017) The many faces of the flavivirus NS5 protein in antagonism of type I interferon signaling. J Virol 91:e01970-16CrossRefGoogle Scholar
  4. Blitvich BJ, Scanlon D, Shiell BJ, Mackenzie JS, Hall RA (1999) Identification and analysis of truncated and elongated species of the flavivirus NS1 protein. Virus Res 60:67–79CrossRefGoogle Scholar
  5. Dalrymple NA, Cimica V, Mackow ER (2015) Dengue virus NS proteins inhibit RIG-I/MAVS signaling by blocking TBK1/IRF3 phosphorylation: dengue virus serotype 1 NS4A Is a unique interferon-regulating virulence determinant. mBio 6:e00553-00515CrossRefGoogle Scholar
  6. Daniels BP, Snyder AG, Olsen TM, Orozco S, Oguin TH, Tait SWG, Martinez J, Gale M, Loo YM, Oberst A (2017) RIPK3 restricts viral pathogenesis via cell death-independent neuroinflammation. Cell 169:301–313CrossRefGoogle Scholar
  7. Firth AE, Atkins JF (2009) A conserved predicted pseudoknot in the NS2A-encoding sequence of West Nile and Japanese Encephalitis flaviviruses suggests NS1′ may derive from ribosomal frameshifting. Virol J 6:14CrossRefGoogle Scholar
  8. Ginsburg AS, Meghani A, Halstead SB, Yaich M (2017) Use of the live attenuated Japanese Encephalitis vaccine SA 14-14-2 in children: a review of safety and tolerability studies. Hum Vaccin Immunother 13:2222–2231CrossRefGoogle Scholar
  9. Grant A, Ponia SS, Tripathi S, Balasubramaniam V, Miorin L, Sourisseau M, Schwarz MC, Sanchez-Seco MP, Evans MJ, Best SM, Garcia-Sastre A (2016) Zika virus targets human STAT2 to inhibit type I interferon signaling. Cell Host Microbe 19:882–890CrossRefGoogle Scholar
  10. Igarashi A, Tanaka M, Morita K, Takasu T, Ahmed A, Akram DS, Waqar MA (1994) Detection of West Nile and Japanese Encephalitis viral genome sequences in cerebrospinal fluid from acute encephalitis cases in Karachi, Pakistan. Microbiol Immunol 38:827–830CrossRefGoogle Scholar
  11. Johansen CA, van den Hurk AF, Pyke AT, Zborowski P, Phillips DA, Mackenzie JS, Ritchie SA (2001) Entomological investigations of an outbreak of Japanese Encephalitis virus in the Torres Strait, Australia, in 1998. J Med Entomol 38:581–588CrossRefGoogle Scholar
  12. Mackenzie JS (2005) Emerging zoonotic encephalitis viruses: lessons from Southeast Asia and Oceania. J Neurovirol 11:434–440CrossRefGoogle Scholar
  13. Mackenzie JS, Gubler DJ, Petersen LR (2004) Emerging flaviviruses: the spread and resurgence of Japanese Encephalitis, West Nile and Dengue viruses. Nat Med 10:S98–S109CrossRefGoogle Scholar
  14. Melian EB, Hinzman E, Nagasaki T, Firth AE, Wills NM, Nouwens AS, Blitvich BJ, Leung J, Funk A, Atkins JF, Hall R, Khromykh AA (2010) NS1′ of flaviviruses in the Japanese Encephalitis virus serogroup is a product of ribosomal frameshifting and plays a role in viral neuroinvasiveness. J Virol 84:1641–1647CrossRefGoogle Scholar
  15. Mitchell CJ, Savage HM, Smith GC, Flood SP, Castro LT, Roppul M (1993) Japanese Encephalitis on Saipan: a survey of suspected mosquito vectors. Am J Trop Med Hyg 48:585–590CrossRefGoogle Scholar
  16. Morita K, Nabeshima T, Buerano CC (2015) Japanese encephalitis. Rev Sci Tech 34:441–452CrossRefGoogle Scholar
  17. Muller DA, Young PR (2013) The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker. Antiviral Res 98:192–208CrossRefGoogle Scholar
  18. Rastogi M, Sharma N, Singh SK (2016) Flavivirus NS1: a multifaceted enigmatic viral protein. Virol J 13:131CrossRefGoogle Scholar
  19. Snell LM, Brooks DG (2015) New insights into type I interferon and the immunopathogenesis of persistent viral infections. Curr Opin Immunol 34:91–98CrossRefGoogle Scholar
  20. Sucharit S, Surathin K, Shrestha SR (1989) Vectors of Japanese Encephalitis virus (JEV): species complexes of the vectors. Southeast Asian J Trop Med Public Health 20:611–621Google Scholar
  21. Teijaro JR (2016) Type I interferons in viral control and immune regulation. Curr Opin Virol 16:31–40CrossRefGoogle Scholar
  22. Turtle L, Driver C (2018) Risk assessment for Japanese Encephalitis vaccination. Hum Vaccin Immunother 14:213–217CrossRefGoogle Scholar
  23. Turtle L, Solomon T (2018) Japanese encephalitis—the prospects for new treatments. Nat Rev Neurol 14:298–313CrossRefGoogle Scholar
  24. Unni SK, Ruzek D, Chhatbar C, Mishra R, Johri MK, Singh SK (2011) Japanese encephalitis virus: from genome to infectome. Microb Infect 13:312–321CrossRefGoogle Scholar
  25. Urosevic N (2003) Is flavivirus resistance interferon type I-independent? Immunol Cell Biol 81:224–229CrossRefGoogle Scholar
  26. van den Hurk AF, Ritchie SA, Mackenzie JS (2009) Ecology and geographical expansion of Japanese Encephalitis virus. Annu Rev Entomol 54:17–35CrossRefGoogle Scholar
  27. Wang J, Li X, Gu J, Fan Y, Zhao P, Cao R, Chen P (2015) The A66G back mutation in NS2A of JEV SA14-14-2 strain contributes to production of NS1′ protein and the secreted NS1′ can be used for diagnostic biomarker for virulent virus infection. Infect Genet Evol 36:116–125CrossRefGoogle Scholar
  28. Ye Q, Li XF, Zhao H, Li SH, Deng YQ, Cao RY, Song KY, Wang HJ, Hua RH, Yu YX, Zhou X, Qin ED, Qin CF (2012) A single nucleotide mutation in NS2A of Japanese encephalitis-live vaccine virus (SA14-14-2) ablates NS1′ formation and contributes to attenuation. J Gen Virol 93:1959–1964CrossRefGoogle Scholar
  29. Young LB, Melian EB, Khromykh AA (2013) NS1′ colocalizes with NS1 and can substitute for NS1 in West Nile virus replication. J Virol 87:9384–9390CrossRefGoogle Scholar
  30. Young LB, Melian EB, Setoh YX, Young PR, Khromykh AA (2015) Last 20 aa of the West Nile virus NS1′ protein are responsible for its retention in cells and the formation of unique heat-stable dimers. J Gen Virol 96:1042–1054CrossRefGoogle Scholar
  31. Zhang HL, Ye HQ, Liu SQ, Deng CL, Li XD, Shi PY, Zhang B (2017) West Nile Virus NS1 antagonizes interferon beta production by targeting RIG-I and MDA5. J Virol 91:e02396-16CrossRefGoogle Scholar

Copyright information

© Wuhan Institute of Virology, CAS and Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.State Key Laboratory of Agricultural MicrobiologyHuazhong Agricultural UniversityWuhanChina
  2. 2.Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary MedicineHuazhong Agricultural UniversityWuhanChina
  3. 3.The Cooperative Innovation Center for Sustainable Pig ProductionHuazhong Agricultural UniversityWuhanChina
  4. 4.Wuhan Institute of Physics and Mathematics (WIPM)Chinese Academy of SciencesWuhanChina

Personalised recommendations