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Volume 100, Issue 3

The cellular localization of avian influenza virus PB1-F2 protein alters the magnitude of IFN2 promoter and NFκB-dependent promoter antagonism in chicken cells Open Access

Abstract

The accessory protein, PB1-F2, of influenza A virus (IAV) functions in a chicken host to prolong infectious virus shedding and thus the transmission window. Here we show that this delay in virus clearance by PB1-F2 in chickens is accompanied by reduced transcript levels of type 1 interferon (IFN)-induced genes and NFκB-activated pro-inflammation cytokines. In vitro, two avian influenza isolate-derived PB1-F2 proteins, H9N2 UDL01 and H5N1 5092, exhibited the same antagonism of the IFN and pro-inflammation induction pathways seen in vivo, but to different extents. The two PB1-F2 proteins had different cellular localization in chicken cells, with H5N1 5092 being predominantly mitochondrial-associated and H9N2 UDL being cytoplasmic but not mitochondrial-localized. We hypothesized that PB1-F2 localization might influence the functionality of the protein during infection and that the protein sequence could alter cellular localization. We demonstrated that the sequence of the C-terminus of PB1-F2 determined cytoplasmic localization in chicken cells and this was linked with protein instability. Mitochondrial localization of PB1-F2 resulted in reduced antagonism of an NFκB-dependent promoter. In parallel, mitochondrial localization of PB1-F2 increased the potency of chicken IFN 2 induction antagonism. We suggest that mitochondrial localization of PB1-F2 restricts interaction with cytoplasmic-located IKKβ, reducing NFκB-responsive promoter antagonism, but enhances antagonism of the IFN2 promoter through interaction with the mitochondrial adaptor MAVS. Our study highlights the differential mechanisms by which IAV PB1-F2 protein can dampen the avian host innate signalling response.

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  • Accepted:
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Keyword(s): chicken , IKKβ , influenza virus , MAVS and PB1-F2
© 2019 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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2019-01-23
2024-04-19
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References

  1. Basuno E, Yusdja Y, Ilham N. Socio-economic impacts of avian influenza outbreaks on small-scale producers in Indonesia. Transbound Emerg Dis 2010; 57:7–10 [View Article][PubMed]
     [Google Scholar]
  2. Govindaraj G, Sridevi R, Nandakumar SN, Vineet R, Rajeev P et al. Economic impacts of avian influenza outbreaks in Kerala, India. Transbound Emerg Dis 2018; 65:e361e372 [View Article][PubMed]
     [Google Scholar]
  3. Qi X, Jiang D, Wang H, Zhuang D, Ma J et al. Calculating the burden of disease of avian-origin H7N9 infections in China. BMJ Open 2014; 4:e004189 [View Article][PubMed]
     [Google Scholar]
  4. Vasin AV, Temkina OA, Egorov VV, Klotchenko SA, Plotnikova MA et al. Molecular mechanisms enhancing the proteome of influenza A viruses: an overview of recently discovered proteins. Virus Res 2014; 185:53–63 [View Article][PubMed]
     [Google Scholar]
  5. Chen W, Calvo PA, Malide D, Gibbs J, Schubert U et al. A novel influenza A virus mitochondrial protein that induces cell death. Nat Med 2001; 7:1306–1312 [View Article][PubMed]
     [Google Scholar]
  6. James J, Howard W, Iqbal M, Nair VK, Barclay WS et al. Influenza A virus PB1-F2 protein prolongs viral shedding in chickens lengthening the transmission window. J Gen Virol 2016; 97:2516–2527 [View Article][PubMed]
     [Google Scholar]
  7. Zell R, Krumbholz A, Eitner A, Krieg R, Halbhuber KJ et al. Prevalence of PB1-F2 of influenza A viruses. J Gen Virol 2007; 88:536–546 [View Article][PubMed]
     [Google Scholar]
  8. Kamal R, Alymova I, York I. Evolution and Virulence of Influenza A Virus Protein PB1-F2. Int J Mol Sci 2017; 19:96 [View Article]
     [Google Scholar]
  9. Klemm C, Boergeling Y, Ludwig S, Ehrhardt C. Immunomodulatory Nonstructural Proteins of Influenza A Viruses. Trends Microbiol 2018; 26:624–636 [View Article][PubMed]
     [Google Scholar]
  10. Košík I, Práznovská M, Košíková M, Bobišová Z, Hollý J et al. The ubiquitination of the influenza A virus PB1-F2 protein is crucial for its biological function. PLoS One 2015; 10:e0118477 [View Article][PubMed]
     [Google Scholar]
  11. Leymarie O, Embury-Hyatt C, Chevalier C, Jouneau L, Moroldo M et al. PB1-F2 attenuates virulence of highly pathogenic avian H5N1 influenza virus in chickens. PLoS One 2014; 9:e100679 [View Article][PubMed]
     [Google Scholar]
  12. de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 2006; 12:1203–1207 [View Article][PubMed]
     [Google Scholar]
  13. Abdel-Ghafar AN, Chotpitayasunondh T, Gao Z, Hayden FG, Nguyen DH et al. Update on avian influenza A (H5N1) virus infection in humans. N Engl J Med 2008; 358:261–273 [View Article][PubMed]
     [Google Scholar]
  14. Yoshizumi T, Ichinohe T, Sasaki O, Otera H, Kawabata S et al. Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity. Nat Commun 2014; 5:4713 [View Article][PubMed]
     [Google Scholar]
  15. Chang P, Kuchipudi SV, Mellits KH, Sebastian S, James J et al. Early apoptosis of porcine alveolar macrophages limits avian influenza virus replication and pro-inflammatory dysregulation. Sci Rep 2015; 5:17999 [View Article][PubMed]
     [Google Scholar]
  16. 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]
  17. Leymarie O, Meyer L, Tafforeau L, Lotteau V, Costa BD et al. Influenza virus protein PB1-F2 interacts with CALCOCO2 (NDP52) to modulate innate immune response. J Gen Virol 2017; 98:1196–1208 [View Article][PubMed]
     [Google Scholar]
  18. Conenello GM, Tisoncik JR, Rosenzweig E, Varga ZT, Palese P et al. A single N66S mutation in the PB1-F2 protein of influenza A virus increases virulence by inhibiting the early interferon response in vivo. J Virol 2011; 85:652–662 [View Article][PubMed]
     [Google Scholar]
  19. Varga ZT, Grant A, Manicassamy B, Palese P. Influenza virus protein PB1-F2 inhibits the induction of type I interferon by binding to MAVS and decreasing mitochondrial membrane potential. J Virol 2012; 86:8359–8366 [View Article][PubMed]
     [Google Scholar]
  20. 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]
  21. Chen S, Cheng A, Wang M. Innate sensing of viruses by pattern recognition receptors in birds. Vet Res 2013; 44:82 [View Article][PubMed]
     [Google Scholar]
  22. Cheng YY, Yang SR, Wang YT, Lin YH, Chen CJ. Amino acid residues 68-71 contribute to influenza A virus PB1-F2 protein stability and functions. Front Microbiol 2017; 8:692 [View Article][PubMed]
     [Google Scholar]
  23. Chen CJ, Chen GW, Wang CH, Huang CH, Wang YC et al. Differential localization and function of PB1-F2 derived from different strains of influenza A virus. J Virol 2010; 84:10051–10062 [View Article][PubMed]
     [Google Scholar]
  24. Gibbs JS, Malide D, Hornung F, Bennink JR, Yewdell JW. The influenza A virus PB1-F2 protein targets the inner mitochondrial membrane via a predicted basic amphipathic helix that disrupts mitochondrial function. J Virol 2003; 77:7214–7224 [View Article][PubMed]
     [Google Scholar]
  25. Yamada H, Chounan R, Higashi Y, Kurihara N, Kido H. Mitochondrial targeting sequence of the influenza A virus PB1-F2 protein and its function in mitochondria. FEBS Lett 2004; 578:331–336 [View Article][PubMed]
     [Google Scholar]
  26. Reuter A, Soubies S, Härtle S, Schusser B, Kaspers B et al. Antiviral activity of lambda interferon in chickens. J Virol 2014; 88:2835–2843 [View Article][PubMed]
     [Google Scholar]
  27. Liniger M, Summerfield A, Zimmer G, Mccullough KC, Ruggli N. Chicken cells sense influenza A virus infection through MDA5 and CARDIF signaling involving LGP2. J Virol 2012; 86:705–717 [View Article][PubMed]
     [Google Scholar]
  28. Reis AL, Mccauley JW. The influenza virus protein PB1-F2 interacts with IKKβ and modulates NF-κB signalling. PLoS One 2013; 8:e63852 [View Article][PubMed]
     [Google Scholar]
  29. Miodek A, Sauriat-Dorizon H, Chevalier C, Delmas B, Vidic J et al. Direct electrochemical detection of PB1-F2 protein of influenza A virus in infected cells. Biosens Bioelectron 2014; 59:6–13 [View Article][PubMed]
     [Google Scholar]
  30. Miodek A, Vidic J, Sauriat-Dorizon H, Richard CA, Le Goffic R et al. Electrochemical detection of the oligomerization of PB1-F2 influenza A virus protein in infected cells. Anal Chem 2014; 86:9098–9105 [View Article][PubMed]
     [Google Scholar]
  31. Wei P, Li W, Zi H, Cunningham M, Guo Y et al. Epidemiological and molecular characteristics of the PB1-F2 proteins in H7N9 influenza viruses, Jiangsu. Biomed Res Int 2015; 2015:1–8 [View Article][PubMed]
     [Google Scholar]
  32. Holmes EC, Lipman DJ, Zamarin D, Yewdell JW. Comment on "Large-scale sequence analysis of avian influenza isolates". Science 2006; 313:1573b [View Article][PubMed]
     [Google Scholar]
  33. Marais R, Light Y, Paterson HF, Marshall CJ. Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J 1995; 14:3136–3145 [View Article][PubMed]
     [Google Scholar]
  34. Horner SM, Liu HM, Park HS, Briley J, Gale M. Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus. Proc Natl Acad Sci USA 2011; 108:14590–14595 [View Article][PubMed]
     [Google Scholar]
  35. Carpenter AE, Jones TR, Lamprecht MR, Clarke C, Kang IH et al. CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol 2006; 7:R100 [View Article][PubMed]
     [Google Scholar]
  36. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001; 29:45e–45 [View Article][PubMed]
     [Google Scholar]
  37. Spackman E, Senne DA, Myers TJ, Bulaga LL, Garber LP et al. Development of a real-time reverse transcriptase PCR assay for type A influenza virus and the avian H5 and H7 hemagglutinin subtypes. J Clin Microbiol 2002; 40:3256–3260 [View Article][PubMed]
     [Google Scholar]
  38. Berger Rentsch M, Zimmer G. A vesicular stomatitis virus replicon-based bioassay for the rapid and sensitive determination of multi-species type I interferon. PLoS One 2011; 6:e25858 [View Article][PubMed]
     [Google Scholar]
  39. Moncorgé O, Long JS, Cauldwell AV, Zhou H, Lycett SJ et al. Investigation of influenza virus polymerase activity in pig cells. J Virol 2013; 87:384–394 [View Article][PubMed]
     [Google Scholar]
  40. Giotis ES, Robey RC, Skinner NG, Tomlinson CD, Goodbourn S et al. Chicken interferome: avian interferon-stimulated genes identified by microarray and RNA-seq of primary chick embryo fibroblasts treated with a chicken type I interferon (IFN-α). Vet Res 2016; 47:75 [View Article][PubMed]
     [Google Scholar]
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The cellular localization of avian influenza virus PB1-F2 protein alters the magnitude of IFN2 promoter and NFκB-dependent promoter antagonism in chicken cells
J. Gen. Virol. 100, 414 (2019); https://doi.org/10.1099/jgv.0.001220
/content/journal/jgv/10.1099/jgv.0.001220
/content/journal/jgv/10.1099/jgv.0.001220
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