1887

Abstract

Deletion or truncation of NS1, the principal IFN antagonist of influenza viruses, leads to increased IFN induction during influenza virus infection. We have studied activation of the IFN induction cascade by both wild-type and NS1-defective viruses at the single-cell level using a cell line expressing GFP under the control of the IFN-β promoter and by examining MxA expression. The IFN-β promoter was not activated in all infected cells even during NS1-defective virus infections. Loss of NS1 expression is therefore insufficient to induce IFN in an infected cell, and factors besides NS1 expression status must dictate whether the IFN response is activated. The IFN response was efficiently stimulated in these cells following infection with other viruses; the differential IFN response we observe with influenza viruses is therefore not cell specific but is likely due to differences in the nature of the infecting virus particles and their subsequent replication.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000687
2017-03-01
2024-04-19
Loading full text...

Full text loading...

/deliver/fulltext/jgv/98/3/357.html?itemId=/content/journal/jgv/10.1099/jgv.0.000687&mimeType=html&fmt=ahah

References

  1. Randall RE, Goodbourn S. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol 2008; 89:1–47 [View Article][PubMed]
    [Google Scholar]
  2. Baum A, Sachidanandam R, García-Sastre A. Preference of RIG-I for short viral RNA molecules in infected cells revealed by next-generation sequencing. Proc Natl Acad Sci USA 2010; 107:16303–16308 [View Article][PubMed]
    [Google Scholar]
  3. Rehwinkel J, Tan CP, Goubau D, Schulz O, Pichlmair A et al. RIG-I detects viral genomic RNA during negative-strand RNA virus infection. Cell 2010; 140:397–408 [View Article][PubMed]
    [Google Scholar]
  4. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 2006; 441:101–105 [View Article][PubMed]
    [Google Scholar]
  5. Killip MJ, Smith M, Jackson D, Randall RE. Activation of the interferon induction cascade by influenza a viruses requires viral RNA synthesis and nuclear export. J Virol 2014; 88:3942–3952 [View Article][PubMed]
    [Google Scholar]
  6. Weber M, Sediri H, Felgenhauer U, Binzen I, Bänfer S et al. Influenza virus adaptation PB2-627K modulates nucleocapsid inhibition by the pathogen sensor RIG-I. Cell Host Microbe 2015; 17:309–319 [View Article][PubMed]
    [Google Scholar]
  7. Benitez AA, Panis M, Xue J, Varble A, Shim JV et al. In vivo RNAi screening identifies MDA5 as a significant contributor to the cellular defense against influenza A virus. Cell Rep 2015; 11:1714–1726 [View Article][PubMed]
    [Google Scholar]
  8. Dudek SE, Wixler L, Nordhoff C, Nordmann A, Anhlan D et al. The influenza virus PB1-F2 protein has interferon antagonistic activity. Biol Chem 2011; 392:1135–1144 [View Article][PubMed]
    [Google Scholar]
  9. Varga ZT, Ramos I, Hai R, Schmolke M, García-Sastre A et al. The influenza virus protein PB1-F2 inhibits the induction of type I interferon at the level of the MAVS adaptor protein. PLoS Pathog 2011; 7:e1002067 [View Article][PubMed]
    [Google Scholar]
  10. Graef KM, Vreede FT, Lau YF, McCall AW, Carr SM et al. The PB2 subunit of the influenza virus RNA polymerase affects virulence by interacting with the mitochondrial antiviral signaling protein and inhibiting expression of beta interferon. J Virol 2010; 84:8433–8445 [View Article][PubMed]
    [Google Scholar]
  11. Iwai A, Shiozaki T, Kawai T, Akira S, Kawaoka Y et al. Influenza A virus polymerase inhibits type I interferon induction by binding to interferon beta promoter stimulator 1. J Biol Chem 2010; 285:32064–32074 [View Article][PubMed]
    [Google Scholar]
  12. García-Sastre A, Egorov A, Matassov D, Brandt S, Levy DE et al. Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology 1998; 252:324–330[PubMed] [Crossref]
    [Google Scholar]
  13. Egorov A, Brandt S, Sereinig S, Romanova J, Ferko B et al. Transfectant influenza A viruses with long deletions in the NS1 protein grow efficiently in Vero cells. J Virol 1998; 72:6437–6441[PubMed]
    [Google Scholar]
  14. Kochs G, Koerner I, Thiel L, Kothlow S, Kaspers B et al. Properties of H7N7 influenza A virus strain SC35M lacking interferon antagonist NS1 in mice and chickens. J Gen Virol 2007; 88:1403–1409 [View Article][PubMed]
    [Google Scholar]
  15. Qian XY, Chien CY, Lu Y, Montelione GT, Krug RM. An amino-terminal polypeptide fragment of the influenza virus NS1 protein possesses specific RNA-binding activity and largely helical backbone structure. RNA 1995; 1:948–956[PubMed]
    [Google Scholar]
  16. Newby CM, Sabin L, Pekosz A. The RNA binding domain of influenza A virus NS1 protein affects secretion of tumor necrosis factor alpha, interleukin-6, and interferon in primary murine tracheal epithelial cells. J Virol 2007; 81:9469–9480 [View Article][PubMed]
    [Google Scholar]
  17. Donelan NR, Basler CF, García-Sastre A. A recombinant influenza A virus expressing an RNA-binding-defective NS1 protein induces high levels of beta interferon and is attenuated in mice. J Virol 2003; 77:13257–13266[PubMed] [Crossref]
    [Google Scholar]
  18. Steidle S, Martínez-Sobrido L, Mordstein M, Lienenklaus S, García-Sastre A et al. Glycine 184 in nonstructural protein NS1 determines the virulence of influenza A virus strain PR8 without affecting the host interferon response. J Virol 2010; 84:12761–12770 [View Article][PubMed]
    [Google Scholar]
  19. Gack MU, Albrecht RA, Urano T, Inn KS, Huang IC et al. Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe 2009; 5:439–449 [View Article][PubMed]
    [Google Scholar]
  20. Guo Z, Chen LM, Zeng H, Gomez JA, Plowden J et al. NS1 protein of influenza A virus inhibits the function of intracytoplasmic pathogen sensor, RIG-I. Am J Respir Cell Mol Biol 2007; 36:263–269 [View Article][PubMed]
    [Google Scholar]
  21. Mibayashi M, Martínez-Sobrido L, Loo YM, Cárdenas WB, Gale M Jr et al. Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. J Virol 2007; 81:514–524 [View Article][PubMed]
    [Google Scholar]
  22. Opitz B, Rejaibi A, Dauber B, Eckhard J, Vinzing M et al. IFNbeta induction by influenza A virus is mediated by RIG-I which is regulated by the viral NS1 protein. Cell Microbiol 2007; 9:930–938 [View Article][PubMed]
    [Google Scholar]
  23. Twu KY, Noah DL, Rao P, Kuo RL, Krug RM. The CPSF30 binding site on the NS1A protein of influenza A virus is a potential antiviral target. J Virol 2006; 80:3957–3965 [View Article][PubMed]
    [Google Scholar]
  24. Noah DL, Twu KY, Krug RM. Cellular antiviral responses against influenza A virus are countered at the posttranscriptional level by the viral NS1A protein via its binding to a cellular protein required for the 3′ end processing of cellular pre-mRNAS. Virology 2003; 307:386–395[PubMed] [Crossref]
    [Google Scholar]
  25. das K, Ma LC, Xiao R, Radvansky B, Aramini J et al. Structural basis for suppression of a host antiviral response by influenza A virus. Proc Natl Acad Sci USA 2008; 105:13093–13098 [View Article][PubMed]
    [Google Scholar]
  26. Hayman A, Comely S, Lackenby A, Murphy S, McCauley J et al. Variation in the ability of human influenza A viruses to induce and inhibit the IFN-beta pathway. Virology 2006; 347:52–64 [View Article][PubMed]
    [Google Scholar]
  27. Kuo RL, Zhao C, Malur M, Krug RM. Influenza A virus strains that circulate in humans differ in the ability of their NS1 proteins to block the activation of IRF3 and interferon-β transcription. Virology 2010; 408:146–158 [View Article][PubMed]
    [Google Scholar]
  28. Chen S, Short JA, Young DF, Killip MJ, Schneider M et al. Heterocellular induction of interferon by negative-sense RNA viruses. Virology 2010; 407:247–255 [View Article][PubMed]
    [Google Scholar]
  29. Killip MJ, Fodor E, Randall RE. Influenza virus activation of the interferon system. Virus Res 2015; 209:11–22 [View Article][PubMed]
    [Google Scholar]
  30. Killip MJ, Young DF, Ross CS, Chen S, Goodbourn S et al. Failure to activate the IFN-β promoter by a paramyxovirus lacking an interferon antagonist. Virology 2011; 415:39–46 [View Article][PubMed]
    [Google Scholar]
  31. Killip MJ, Young DF, Gatherer D, Ross CS, Short JA et al. Deep sequencing analysis of defective genomes of parainfluenza virus 5 and their role in interferon induction. J Virol 2013; 87:4798–4807 [View Article][PubMed]
    [Google Scholar]
  32. Killip MJ, Young DF, Precious BL, Goodbourn S, Randall RE. Activation of the beta interferon promoter by paramyxoviruses in the absence of virus protein synthesis. J Gen Virol 2012; 93:299–307 [View Article][PubMed]
    [Google Scholar]
  33. Kochs G, García-Sastre A, Martínez-Sobrido L. Multiple anti-interferon actions of the influenza A virus NS1 protein. J Virol 2007; 81:7011–7021 [View Article][PubMed]
    [Google Scholar]
  34. Kuo RL, Krug RM. Influenza A virus polymerase is an integral component of the CPSF30–NS1A protein complex in infected cells. J Virol 2009; 83:1611–1616 [View Article][PubMed]
    [Google Scholar]
  35. Steidle S, Martínez-Sobrido L, Mordstein M, Lienenklaus S, García-Sastre A et al. Glycine 184 in nonstructural protein NS1 determines the virulence of influenza A virus strain PR8 without affecting the host interferon response. J virol 2010; 84:12761–12770 [Crossref]
    [Google Scholar]
  36. Wang W, Riedel K, Lynch P, Chien CY, Montelione GT et al. RNA binding by the novel helical domain of the influenza virus NS1 protein requires its dimer structure and a small number of specific basic amino acids. RNA 1999; 5:195–205[PubMed] [Crossref]
    [Google Scholar]
  37. Min JY, Krug RM. The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: inhibiting the 2′–5′ oligo (A) synthetase/RNase L pathway. Proc Natl Acad Sci USA 2006; 103:7100–7105 [View Article][PubMed]
    [Google Scholar]
  38. Jackson D, Killip MJ, Galloway CS, Russell RJ, Randall RE. Loss of function of the influenza A virus NS1 protein promotes apoptosis but this is not due to a failure to activate phosphatidylinositol 3-kinase (PI3K). Virology 2010; 396:94–105 [View Article][PubMed]
    [Google Scholar]
  39. Strähle L, Marq JB, Brini A, Hausmann S, Kolakofsky D et al. Activation of the beta interferon promoter by unnatural Sendai virus infection requires RIG-I and is inhibited by viral C proteins. J Virol 2007; 81:12227–12237 [View Article][PubMed]
    [Google Scholar]
  40. Kallfass C, Lienenklaus S, Weiss S, Staeheli P. Visualizing the beta interferon response in mice during infection with influenza A viruses expressing or lacking nonstructural protein 1. J Virol 2013; 87:6925–6930 [View Article][PubMed]
    [Google Scholar]
  41. von Recum-Knepper J, Sadewasser A, Weinheimer VK, Wolff T. Fluorescence-activated cell sorting-based analysis reveals an asymmetric induction of interferon-stimulated genes in response to seasonal influenza A virus. J Virol 2015; 89:6982–6993 [View Article][PubMed]
    [Google Scholar]
  42. Weber M, Gawanbacht A, Habjan M, Rang A, Borner C et al. Incoming RNA virus nucleocapsids containing a 5′-triphosphorylated genome activate RIG-I and antiviral signaling. Cell Host Microbe 2013; 13:336–346 [View Article][PubMed]
    [Google Scholar]
  43. Frensing T, Pflugmacher A, Bachmann M, Peschel B, Reichl U. Impact of defective interfering particles on virus replication and antiviral host response in cell culture-based influenza vaccine production. Appl Microbiol Biotechnol 2014; 98:8999–9008 [View Article][PubMed]
    [Google Scholar]
  44. Ngunjiri JM, Buchek GM, Mohni KN, Sekellick MJ, Marcus PI. Influenza virus subpopulations: exchange of lethal H5N1 virus NS for H1N1 virus NS triggers de novo generation of defective-interfering particles and enhances interferon-inducing particle efficiency. J Interferon Cytokine Res 2013; 33:99–107 [View Article][PubMed]
    [Google Scholar]
  45. Scott PD, Meng B, Marriott AC, Easton AJ, Dimmock NJ. Defective interfering influenza A virus protects in vivo against disease caused by a heterologous influenza B virus. J Gen Virol 2011; 92:2122–2132 [View Article][PubMed]
    [Google Scholar]
  46. Scott PD, Meng B, Marriott AC, Easton AJ, Dimmock NJ. Defective interfering virus protects elderly mice from influenza. Virol J 2011; 8:212 [View Article][PubMed]
    [Google Scholar]
  47. Pérez-Cidoncha M, Killip MJ, Oliveros JC, Asensio VJ, Fernández Y et al. An unbiased genetic screen reveals the polygenic nature of the influenza virus anti-interferon response. J Virol 2014; 88:4632–4646 [View Article][PubMed]
    [Google Scholar]
  48. Tapia K, Kim WK, Sun Y, Mercado-López X, Dunay E et al. Defective viral genomes arising in vivo provide critical danger signals for the triggering of lung antiviral immunity. PLoS Pathog 2013; 9:e1003703 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000687
Loading
/content/journal/jgv/10.1099/jgv.0.000687
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error