Skip to main content
SpringerLink
Log in

Molecular Determinants of Pathogenicity in the Polymerase Complex

  • Chapter
  • First Online:
Influenza Pathogenesis and Control - Volume I

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 385))

Abstract

Viral pathogenesis involves numerous interactions between viral and cellular factors. In recent years, the influenza virus polymerase complex has emerged as a major determinant of interspecies transmission and pathogenicity. The viral RNA-dependent RNA polymerase, in concert with the nucleoprotein, mediates transcription and replication of the viral RNA genome in the nucleus of the infected cell. The activity by which the viral polymerase complex performs these processes in mammalian cells is considered to be a major contributor to viral pathogenicity in mammals. In this chapter, we summarise our current understanding on the pathogenicity determinants in the viral polymerase complex and highlight some of its cellular interaction partners. We particularly discuss the role of importin-α isoforms in host adaptation and pathogenesis as well as the role of the viral polymerase in regulating cellular responses to viral infection.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

PB1:

Polymerase basic protein 1

PB2:

Polymerase basic protein 2

PA:

Polymerase acidic protein

NP:

Nucleoprotein

NEP:

Nuclear export protein

NS1:

Non-structural protein 1

NS2:

Non-structural protein 2

vRNA:

Viral RNA

vRNP:

Viral ribonucleoprotein

cRNA:

Complementary RNA

CRM1:

Chromosome region maintenance 1

NLS:

Nuclear localisation signal

Hsp90:

Heat shock protein 90

IFN:

Interferon

RIG-I:

Retinoic acid-inducible gene 1

MAVS:

Mitochondrial antiviral signalling protein

CPSF30:

Cleavage and polyadenylation specificity factor 30

Pol II:

RNA polymerase II

References

  • Arranz R, Coloma R, Chichon FJ, Conesa JJ, Carrascosa JL, Valpuesta JM, Ortin J, Martin-Benito J (2012) The structure of native influenza virion ribonucleoproteins. Science 338(6114):1634–1637

    CAS  PubMed  Google Scholar 

  • Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA (2001) Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci U S A 98(18):10037–10041

    CAS  PubMed  PubMed Central  Google Scholar 

  • Biswas SK, Nayak DP (1994) Mutational analysis of the conserved motifs of influenza a virus polymerase basic protein 1. J Virol 68(3):1819–1826

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bogs J, Kalthoff D, Veits J, Pavlova S, Schwemmle M, Manz B, Mettenleiter TC, Stech J (2011) Reversion of PB2-627E to -627K during replication of an H5N1 Clade 2.2 virus in mammalian hosts depends on the origin of the nucleoprotein. J Virol 85(20):10691–10698

    CAS  PubMed  PubMed Central  Google Scholar 

  • Boivin S, Hart DJ (2011) Interaction of the influenza A virus polymerase PB2 C-terminal region with importin alpha isoforms provides insights into host adaptation and polymerase assembly. J Biol Chem 286(12):10439–10448

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bortz E, Westera L, Maamary J, Steel J, Albrecht RA, Manicassamy B, Chase G, Martinez-Sobrido L, Schwemmle M, Garcia-Sastre A (2011) Host- and strain-specific regulation of influenza virus polymerase activity by interacting cellular proteins. MBio 2(4):e00151–11

    Google Scholar 

  • Bradel-Tretheway BG, Mattiacio JL, Krasnoselsky A, Stevenson C, Purdy D, Dewhurst S, Katze MG (2011) Comprehensive proteomic analysis of influenza virus polymerase complex reveals a novel association with mitochondrial proteins and RNA polymerase accessory factors. J Virol 85(17):8569–8581

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brass AL, Huang IC, Benita Y, John SP, Krishnan MN, Feeley EM, Ryan BJ, Weyer JL, van der Weyden L, Fikrig E, Adams DJ, Xavier RJ, Farzan M, Elledge SJ (2009) The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell 139(7):1243–1254

    PubMed  PubMed Central  Google Scholar 

  • Brown EG, Liu H, Kit LC, Baird S, Nesrallah M (2001) Pattern of mutation in the genome of influenza a virus on adaptation to increased virulence in the mouse lung: identification of functional themes. Proc Natl Acad Sci U S A 98(12):6883–6888

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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(9):4395–4406

    Google Scholar 

  • Carr SM, Carnero E, Garcia-Sastre A, Brownlee GG, Fodor E (2006) Characterization of a mitochondrial-targeting signal in the PB2 protein of influenza viruses. Virology 344(2):492–508

    CAS  PubMed  Google Scholar 

  • Cauldwell AV, Moncorge O, Barclay WS (2013) Unstable polymerase-nucleoprotein interaction is not responsible for avian influenza virus polymerase restriction in human cells. J Virol 87(2):1278–1284

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cauldwell AV, Long JS, Moncorge O, Barclay WS (2014) Viral determinants of influenza a host range. J Gen Virol 95(Pt 6):1193–1210

    Google Scholar 

  • Chan WH, Ng AK, Robb NC, Lam MK, Chan PK, Au SW, Wang JH, Fodor E, Shaw PC (2010) Functional analysis of the influenza virus H5N1 nucleoprotein tail loop reveals amino acids that are crucial for oligomerization and ribonucleoprotein activities. J Virol 84(14):7337–7345

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen W, Calvo PA, Malide D, Gibbs J, Schubert U, Bacik I, Basta S, O’Neill R, Schickli J, Palese P, Henklein P, Bennink JR, Yewdell JW (2001) A novel influenza a virus mitochondrial protein that induces cell death. Nat Med 7(12):1306–1312

    CAS  PubMed  Google Scholar 

  • Chen Y, Liang W, Yang S, Wu N, Gao H, Sheng J, Yao H, Wo J, Fang Q, Cui D, Li Y, Yao X, Zhang Y, Wu H, Zheng S, Diao H, Xia S, Chan KH, Tsoi HW, Teng JL, Song W, Wang P, Lau SY, Zheng M, Chan JF, To KK, Chen H, Li L, Yuen KY (2013) Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet 381(9881):1916–1925

    CAS  PubMed  Google Scholar 

  • Chen H, Yuan H, Gao R, Zhang J, Wang D, Xiong Y, Fan G, Yang F, Li X, Zhou J, Zou S, Yang L, Chen T, Dong L, Bo H, Zhao X, Zhang Y, Lan Y, Bai T, Dong J, Li Q, Wang S, Li H, Gong T, Shi Y, Ni X, Li J, Fan J, Wu J, Zhou X, Hu M, Wan J, Yang W, Li D, Wu G, Feng Z, Gao GF, Wang Y, Jin Q, Liu M, Shu Y (2014) Clinical and epidemiological characteristics of a fatal case of avian influenza A H10N8 virus infection: a descriptive study. Lancet 383:714–721

    Google Scholar 

  • Crescenzo-Chaigne B, van der Werf S, Naffakh N (2002) Differential effect of nucleotide substitutions in the 3’ arm of the influenza A virus vRNA promoter on transcription/replication by avian and human polymerase complexes is related to the nature of PB2 amino acid 627. Virology 303(2):240–252

    CAS  PubMed  Google Scholar 

  • 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(10):1203–1207

    Google Scholar 

  • Deng T, Engelhardt OG, Thomas B, Akoulitchev AV, Brownlee GG, Fodor E (2006) Role of ran binding protein 5 in nuclear import and assembly of the influenza virus RNA polymerase complex. J Virol 80(24):11911–11919

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dias A, Bouvier D, Crepin T, McCarthy AA, Hart DJ, Baudin F, Cusack S, Ruigrok RW (2009) The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature 458(7240):914–918

    CAS  PubMed  Google Scholar 

  • Engelhardt OG, Smith M, Fodor E (2005) Association of the influenza A virus RNA-dependent RNA polymerase with cellular RNA polymerase II. J Virol 79(9):5812–5818

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fodor E (2013) The RNA polymerase of influenza a virus: mechanisms of viral transcription and replication. Acta Virol 57(2):113–122

    CAS  PubMed  Google Scholar 

  • Fodor E, Smith M (2004) The PA subunit is required for efficient nuclear accumulation of the PB1 subunit of the influenza a virus RNA polymerase complex. J Virol 78(17):9144–9153

    CAS  PubMed  PubMed Central  Google Scholar 

  • Foeglein A, Loucaides EM, Mura M, Wise HM, Barclay WS, Digard P (2011) Influence of PB2 host-range determinants on the intranuclear mobility of the influenza a virus polymerase. J Gen Virol 92(Pt 7):1650–1661

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fornek JL, Gillim-Ross L, Santos C, Carter V, Ward JM, Cheng LI, Proll S, Katze MG, Subbarao K (2009) A single-amino-acid substitution in a polymerase protein of an H5N1 influenza virus is associated with systemic infection and impaired T-cell activation in mice. J Virol 83(21):11102–11115

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fouchier RA, Schneeberger PM, Rozendaal FW, Broekman JM, Kemink SA, Munster V, Kuiken T, Rimmelzwaan GF, Schutten M, Van Doornum GJ, Koch G, Bosman A, Koopmans M, Osterhaus AD (2004) Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc Natl Acad Sci U S A 101(5):1356–1361

    CAS  PubMed  PubMed Central  Google Scholar 

  • Friedrich B, Quensel C, Sommer T, Hartmann E, Kohler M (2006) Nuclear localization signal and protein context both mediate importin alpha specificity of nuclear import substrates. Mol Cell Biol 26(23):8697–8709

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gabriel G, Dauber B, Wolff T, Planz O, Klenk HD, Stech J (2005) The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host. Proc Natl Acad Sci U S A 102(51):18590–18595

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gabriel G, Herwig A, Klenk HD (2008) Interaction of polymerase subunit PB2 and NP with importin alpha1 is a determinant of host range of influenza a virus. PLoS Pathog 4(2):e11

    PubMed  PubMed Central  Google Scholar 

  • Gabriel G, Klingel K, Otte A, Thiele S, Hudjetz B, Arman-Kalcek G, Sauter M, Shmidt T, Rother F, Baumgarte S, Keiner B, Hartmann E, Bader M, Brownlee GG, Fodor E, Klenk HD (2011) Differential use of importin-alpha isoforms governs cell tropism and host adaptation of influenza virus. Nat Commun 2:156

    PubMed  PubMed Central  Google Scholar 

  • Gabriel G, Czudai-Matwich V, Klenk HD (2013) Adaptive mutations in the H5N1 polymerase complex. Virus Res 178(1):53–62

    CAS  PubMed  Google Scholar 

  • Gao Y, Zhang Y, Shinya K, Deng G, Jiang Y, Li Z, Guan Y, Tian G, Li Y, Shi J, Liu L, Zeng X, Bu Z, Xia X, Kawaoka Y, Chen H (2009) Identification of amino acids in HA and PB2 critical for the transmission of H5N1 avian influenza viruses in a mammalian host. PLoS Pathog 5(12):e1000709

    PubMed  PubMed Central  Google Scholar 

  • Garten RJ, Davis CT, Russell CA, Shu B, Lindstrom S, Balish A, Sessions WM, Xu X, Skepner E, Deyde V, Okomo-Adhiambo M, Gubareva L, Barnes J, Smith CB, Emery SL, Hillman MJ, Rivailler P, Smagala J, de Graaf M, Burke DF, Fouchier RA, Pappas C, Alpuche-Aranda CM, Lopez-Gatell H, Olivera H, Lopez I, Myers CA, Faix D, Blair PJ, Yu C, Keene KM, Dotson PD Jr, Boxrud D, Sambol AR, Abid SH, St George K, Bannerman T, Moore AL, Stringer DJ, Blevins P, Demmler-Harrison GJ, Ginsberg M, Kriner P, Waterman S, Smole S, Guevara HF, Belongia EA, Clark PA, Beatrice ST, Donis R, Katz J, Finelli L, Bridges CB, Shaw M, Jernigan DB, Uyeki TM, Smith DJ, Klimov AI, Cox NJ (2009) Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science 325(5937):197–201

    CAS  PubMed  PubMed Central  Google Scholar 

  • Graef KM, Vreede FT, Lau YF, McCall AW, Carr SM, Subbarao K, Fodor E (2010) 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 84(17):8433–8445

    CAS  PubMed  PubMed Central  Google Scholar 

  • Guilligay D, Tarendeau F, Resa-Infante P, Coloma R, Crepin T, Sehr P, Lewis J, Ruigrok RW, Ortin J, Hart DJ, Cusack S (2008) The structural basis for cap binding by influenza virus polymerase subunit PB2. Nat Struct Mol Biol 15(5):500–506

    CAS  PubMed  Google Scholar 

  • Hale BG, Randall RE, Ortin J, Jackson D (2008) The multifunctional NS1 protein of influenza a viruses. J Gen Virol 89(Pt 10):2359–2376

    CAS  PubMed  Google Scholar 

  • Hao L, Sakurai A, Watanabe T, Sorensen E, Nidom CA, Newton MA, Ahlquist P, Kawaoka Y (2008) Drosophila RNAi screen identifies host genes important for influenza virus replication. Nature 454(7206):890–893

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hatta M, Gao P, Halfmann P, Kawaoka Y (2001) Molecular basis for high virulence of Hong Kong H5N1 influenza a viruses. Science 293(5536):1840–1842

    CAS  PubMed  Google Scholar 

  • 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(10):1374–1379

    CAS  PubMed  Google Scholar 

  • He X, Zhou J, Bartlam M, Zhang R, Ma J, Lou Z, Li X, Li J, Joachimiak A, Zeng Z, Ge R, Rao Z, Liu Y (2008) Crystal structure of the polymerase PA(C)-PB1(N) complex from an avian influenza H5N1 virus. Nature 454(7208):1123–1126

    CAS  PubMed  Google Scholar 

  • Herfst S, Chutinimitkul S, Ye J, de Wit E, Munster VJ, Schrauwen EJ, Bestebroer TM, Jonges M, Meijer A, Koopmans M, Rimmelzwaan GF, Osterhaus AD, Perez DR, Fouchier RA (2010) Introduction of virulence markers in PB2 of pandemic swine-origin influenza virus does not result in enhanced virulence or transmission. J Virol 84(8):3752–3758

    CAS  PubMed  PubMed Central  Google Scholar 

  • Herfst S, Schrauwen EJ, Linster M, Chutinimitkul S, de Wit E, Munster VJ, Sorrell EM, Bestebroer TM, Burke DF, Smith DJ, Rimmelzwaan GF, Osterhaus AD, Fouchier RA (2012) Airborne transmission of influenza A/H5N1 virus between ferrets. Science 336(6088):1534–1541

    CAS  PubMed  Google Scholar 

  • Hudjetz B, Gabriel G (2012) Human-like PB2 627K influenza virus polymerase activity is regulated by importin-alpha1 and -alpha7. PLoS Pathog 8(1):e1002488

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hutchinson EC, Fodor E (2013) Transport of the influenza virus genome from nucleus to nucleus. Viruses 5(10):2424–2446

    CAS  PubMed  PubMed Central  Google Scholar 

  • Imai M, Watanabe T, Hatta M, Das SC, Ozawa M, Shinya K, Zhong G, Hanson A, Katsura H, Watanabe S, Li C, Kawakami E, Yamada S, Kiso M, Suzuki Y, Maher EA, Neumann G, Kawaoka Y (2012) Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 486(7403):420–428

    CAS  PubMed  PubMed Central  Google Scholar 

  • Iwai A, Shiozaki T, Kawai T, Akira S, Kawaoka Y, Takada A, Kida H, Miyazaki T (2010) Influenza a virus polymerase inhibits type I interferon induction by binding to interferon beta promoter stimulator 1. J Biol Chem 285(42):32064–32074

    CAS  PubMed  PubMed Central  Google Scholar 

  • Iwasaki A, Peiris M (2013) Innate immunity. In: Webster R, Monto A, Braciale T, Lamb R (eds) Textbook of influenza, Wiley-Blackwell, UK, pp 269–282

    Google Scholar 

  • Jagger BW, Wise HM, Kash JC, Walters KA, Wills NM, Xiao YL, Dunfee RL, Schwartzman LM, Ozinsky A, Bell GL, Dalton RM, Lo A, Efstathiou S, Atkins JF, Firth AE, Taubenberger JK, Digard P (2012) An overlapping protein-coding region in influenza a virus segment 3 modulates the host response. Science 337(6091):199–204

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jorba N, Juarez S, Torreira E, Gastaminza P, Zamarreno N, Albar JP, Ortin J (2008) Analysis of the interaction of influenza virus polymerase complex with human cell factors. Proteomics 8(10):2077–2088

    CAS  PubMed  Google Scholar 

  • Kageyama T, Fujisaki S, Takashita E, Xu H, Yamada S, Uchida Y, Neumann G, Saito T, Kawaoka Y, Tashiro M (2013) Genetic analysis of novel avian A(H7N9) influenza viruses isolated from patients in China, February to April 2013. Euro Surveill 18(15):20453

    CAS  PubMed  Google Scholar 

  • Karlas A, Machuy N, Shin Y, Pleissner KP, Artarini A, Heuer D, Becker D, Khalil H, Ogilvie LA, Hess S, Maurer AP, Muller E, Wolff T, Rudel T, Meyer TF (2010) Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication. Nature 463(7282):818–822

    CAS  PubMed  Google Scholar 

  • Kim JH, Hatta M, Watanabe S, Neumann G, Watanabe T, Kawaoka Y (2010) Role of host-specific amino acids in the pathogenicity of avian H5N1 influenza viruses in mice. J Gen Virol 91(Pt 5):1284–1289

    CAS  PubMed  PubMed Central  Google Scholar 

  • Konig R, Stertz S, Zhou Y, Inoue A, Hoffmann HH, Bhattacharyya S, Alamares JG, Tscherne DM, Ortigoza MB, Liang Y, Gao Q, Andrews SE, Bandyopadhyay S, De Jesus P, Tu BP, Pache L, Shih C, Orth A, Bonamy G, Miraglia L, Ideker T, Garcia-Sastre A, Young JA, Palese P, Shaw ML, Chanda SK (2010) Human host factors required for influenza virus replication. Nature 463(7282):813–817

    PubMed  PubMed Central  Google Scholar 

  • Krug RM, Fodor E (2013) The virus genome and its replication, 2nd edn. In: Webster RG, Monto AS, Braciale TJ, and Lamb R (eds) Textbook of influenza, Wiley-Blackwell, UK, pp 57–66

    Google Scholar 

  • Krug RM, Garcia-Sastre A (2013) The NS1 protein: a master regulator of host and viral functions, 2nd edn. In: Webster R, Monto A, Braciale T, Lamb R (eds) Textbook of influenza, Wiley-Blackwell, UK, pp 114–132

    Google Scholar 

  • Kuzuhara T, Kise D, Yoshida H, Horita T, Murazaki Y, Nishimura A, Echigo N, Utsunomiya H, Tsuge H (2009a) Structural basis of the influenza a virus RNA polymerase PB2 RNA-binding domain containing the pathogenicity-determinant lysine 627 residue. J Biol Chem 284(11):6855–6860

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kuzuhara T, Kise D, Yoshida H, Horita T, Murazaki Y, Utsunomiya H, Tsuge H (2009b) Crystallization and X-ray diffraction analysis of the RNA primer/promoter-binding domain of influenza a virus RNA-dependent RNA polymerase PB2. Acta Crystallogr Sect F Struct Biol Cryst Commun 65(Pt 2):144–146

    CAS  PubMed  PubMed Central  Google Scholar 

  • Labadie K, Dos Santos Afonso E, Rameix-Welti MA, van der Werf S, Naffakh N (2007) Host-range determinants on the PB2 protein of influenza a viruses control the interaction between the viral polymerase and nucleoprotein in human cells. Virology 362(2):271–282

    Google Scholar 

  • Le QM, Sakai-Tagawa Y, Ozawa M, Ito M, Kawaoka Y (2009) Selection of H5N1 influenza virus PB2 during replication in humans. J Virol 83(10):5278–5281

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li J, Ishaq M, Prudence M, Xi X, Hu T, Liu Q, Guo D (2009) Single mutation at the amino acid position 627 of PB2 that leads to increased virulence of an H5N1 avian influenza virus during adaptation in mice can be compensated by multiple mutations at other sites of PB2. Virus Res 144(1–2):123–129

    Google Scholar 

  • Llompart CM, Nieto A, Rodriguez-Frandsen A (2014) Specific residues of PB2 and PA influenza virus polymerase subunits confer the ability for RNA polymerase II degradation and virus pathogenicity in mice. J Virol 88:3443–3454

    Google Scholar 

  • Maines TR, Jayaraman A, Belser JA, Wadford DA, Pappas C, Zeng H, Gustin KM, Pearce MB, Viswanathan K, Shriver ZH, Raman R, Cox NJ, Sasisekharan R, Katz JM, Tumpey TM (2009) Transmission and pathogenesis of swine-origin 2009 A(H1N1) influenza viruses in ferrets and mice. Science 325(5939):484–487

    CAS  PubMed  PubMed Central  Google Scholar 

  • Manz B, Brunotte L, Reuther P, Schwemmle M (2012) Adaptive mutations in NEP compensate for defective H5N1 RNA replication in cultured human cells. Nat Commun 3:802

    PubMed  Google Scholar 

  • Manz B, Schwemmle M, Brunotte L (2013) Adaptation of avian influenza a virus polymerase in mammals to overcome the host species barrier. J Virol 87(13):7200–7209

    PubMed  PubMed Central  Google Scholar 

  • Massin P, van der Werf S, Naffakh N (2001) Residue 627 of PB2 is a determinant of cold sensitivity in RNA replication of avian influenza viruses. J Virol 75(11):5398–5404

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mayer D, Molawi K, Martinez-Sobrido L, Ghanem A, Thomas S, Baginsky S, Grossmann J, Garcia-Sastre A, Schwemmle M (2007) Identification of cellular interaction partners of the influenza virus ribonucleoprotein complex and polymerase complex using proteomic-based approaches. J Proteome Res 6(2):672–682

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mehle A, Doudna JA (2008) An inhibitory activity in human cells restricts the function of an avian-like influenza virus polymerase. Cell Host Microbe 4(2):111–122

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mehle A, Doudna JA (2009) Adaptive strategies of the influenza virus polymerase for replication in humans. Proc Natl Acad Sci U S A 106(50):21312–21316

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mehle A, McCullers J (2013). Structure and function of the influenza virus replication machinery and PB1-F2. In: Webster R, Monto A, Braciale T, Lamb R (eds) Textbook of influenza, Wiley-Blackwell, UK, pp 133–145

    Google Scholar 

  • Moeller A, Kirchdoerfer RN, Potter CS, Carragher B, Wilson IA (2012) Organization of the influenza virus replication machinery. Science 338(6114):1631–1634

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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(18):9641–9645

    Google Scholar 

  • Moncorge O, Mura M, Barclay WS (2010) Evidence for avian and human host cell factors that affect the activity of influenza virus polymerase. J Virol 84(19):9978–9986

    CAS  PubMed  PubMed Central  Google Scholar 

  • Munster VJ, de Wit E, van den Brand JM, Herfst S, Schrauwen EJ, Bestebroer TM, van de Vijver D, Boucher CA, Koopmans M, Rimmelzwaan GF, Kuiken T, Osterhaus AD, Fouchier RA (2009) Pathogenesis and transmission of swine-origin 2009 A(H1N1) influenza virus in ferrets. Science 325(5939):481–483

    CAS  PubMed  Google Scholar 

  • Murakami Y, Nerome K, Yoshioka Y, Mizuno S, Oya A (1988) Difference in growth behavior of human, swine, equine, and avian influenza viruses at a high temperature. Arch Virol 100(3–4):231–244

    CAS  PubMed  Google Scholar 

  • Muramoto Y, Noda T, Kawakami E, Akkina R, Kawaoka Y (2013) Identification of novel influenza a virus proteins translated from PA mRNA. J Virol 87(5):2455–2462

    CAS  PubMed  PubMed Central  Google Scholar 

  • Murphy BR, Hinshaw VS, Sly DL, London WT, Hosier NT, Wood FT, Webster RG, Chanock RM (1982a) Virulence of avian influenza a viruses for squirrel monkeys. Infect Immun 37(3):1119–1126

    CAS  PubMed  PubMed Central  Google Scholar 

  • Murphy BR, Sly DL, Tierney EL, Hosier NT, Massicot JG, London WT, Chanock RM, Webster RG, Hinshaw VS (1982b) Reassortant virus derived from avian and human influenza a viruses is attenuated and immunogenic in monkeys. Science 218(4579):1330–1332

    CAS  PubMed  Google Scholar 

  • Naito T, Momose F, Kawaguchi A, Nagata K (2007) Involvement of Hsp90 in assembly and nuclear import of influenza virus RNA polymerase subunits. J Virol 81(3):1339–1349

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ng AK, Zhang H, Tan K, Li Z, Liu JH, Chan PK, Li SM, Chan WY, Au SW, Joachimiak A, Walz T, Wang JH, Shaw PC (2008) Structure of the influenza virus A H5N1 nucleoprotein: implications for RNA binding, oligomerization, and vaccine design. FASEB J 22(10):3638–3647

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ng AK, Chan WH, Choi ST, Lam MK, Lau KF, Chan PK, Au SW, Fodor E, Shaw PC (2012) Influenza polymerase activity correlates with the strength of interaction between nucleoprotein and PB2 through the host-specific residue K/E627. PLoS One 7(5):e36415

    CAS  PubMed  PubMed Central  Google Scholar 

  • Obayashi E, Yoshida H, Kawai F, Shibayama N, Kawaguchi A, Nagata K, Tame JR, Park SY (2008) The structural basis for an essential subunit interaction in influenza virus RNA polymerase. Nature 454(7208):1127–1131

    CAS  PubMed  Google Scholar 

  • Ocana-Macchi M, Ricklin ME, Python S, Monika GA, Stech J, Stech O, Summerfield A (2012) Avian influenza a virus PB2 promotes interferon type I inducing properties of a swine strain in porcine dendritic cells. Virology 427(1):1–9

    CAS  PubMed  Google Scholar 

  • O’Neill RE, Palese P (1995) NPI-1, the human homolog of SRP-1, interacts with influenza virus nucleoprotein. Virology 206(1):116–125

    PubMed  Google Scholar 

  • O’Neill RE, Jaskunas R, Blobel G, Palese P, Moroianu J (1995) Nuclear import of influenza virus RNA can be mediated by viral nucleoprotein and transport factors required for protein import. J Biol Chem 270(39):22701–22704

    PubMed  Google Scholar 

  • Paterson D, Fodor E (2012) Emerging roles for the influenza a virus nuclear export protein (NEP). PLoS Pathog 8(12):e1003019

    CAS  PubMed  PubMed Central  Google Scholar 

  • Paterson D, te Velthuis AJ, Vreede FT, Fodor E (2014) Host restriction of influenza virus polymerase activity by PB2 627E is diminished on short viral templates in a nucleoprotein-independent manner. J Virol 88(1):339–344

    CAS  PubMed  PubMed Central  Google Scholar 

  • Peiris M, Yuen KY, Leung CW, Chan KH, Ip PL, Lai RW, Orr WK, Shortridge KF (1999) Human infection with influenza H9N2. Lancet 354(9182):916–917

    CAS  PubMed  Google Scholar 

  • Poch O, Sauvaget I, Delarue M, Tordo N (1989) Identification of four conserved motifs among the RNA-dependent polymerase encoding elements. EMBO J 8(12):3867–3874

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rameix-Welti MA, Tomoiu A, Dos Santos Afonso E, van der Werf S, Naffakh N (2009) Avian Influenza a virus polymerase association with nucleoprotein, but not polymerase assembly, is impaired in human cells during the course of infection. J Virol 83(3):1320–1331

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rehwinkel J, Tan CP, Goubau D, Schulz O, Pichlmair A, Bier K, Robb N, Vreede F, Barclay W, Fodor E, Reis e Sousa C (2010) RIG-I detects viral genomic RNA during negative-strand RNA virus infection. Cell 140(3):397–408

    CAS  PubMed  Google Scholar 

  • Resa-Infante P, Gabriel G (2013) The nuclear import machinery is a determinant of influenza virus host adaptation. Bioessays 35(1):23–27

    CAS  PubMed  Google Scholar 

  • Resa-Infante P, Jorba N, Zamarreno N, Fernandez Y, Juarez S, Ortin J (2008) The host-dependent interaction of alpha-importins with influenza PB2 polymerase subunit is required for virus RNA replication. PLoS One 3(12):e3904

    PubMed  PubMed Central  Google Scholar 

  • Resa-Infante P, Jorba N, Coloma R, Ortin J (2011) The influenza virus RNA synthesis machine: advances in its structure and function. RNA Biol 8(2):207–215

    CAS  PubMed  PubMed Central  Google Scholar 

  • Richard M, Schrauwen EJ, de Graaf M, Bestebroer TM, Spronken MI, van Boheemen S, de Meulder D, Lexmond P, Linster M, Herfst S, Smith DJ, van den Brand JM, Burke DF, Kuiken T, Rimmelzwaan GF, Osterhaus AD, Fouchier RA (2013) Limited airborne transmission of H7N9 influenza a virus between ferrets. Nature 501(7468):560–563

    CAS  PubMed  Google Scholar 

  • Rodriguez A, Perez-Gonzalez A, Nieto A (2007) Influenza virus infection causes specific degradation of the largest subunit of cellular RNA polymerase II. J Virol 81(10):5315–5324

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rodriguez A, Perez-Gonzalez A, Hossain MJ, Chen LM, Rolling T, Perez-Brena P, Donis R, Kochs G, Nieto A (2009) Attenuated strains of influenza a viruses do not induce degradation of RNA polymerase II. J Virol 83(21):11166–11174

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ruigrok RW, Crepin T, Hart DJ, Cusack S (2010) Towards an atomic resolution understanding of the influenza virus replication machinery. Curr Opin Struct Biol 20(1):104–113

    CAS  PubMed  Google Scholar 

  • Salomon R, Franks J, Govorkova EA, Ilyushina NA, Yen HL, Hulse-Post DJ, Humberd J, Trichet M, Rehg JE, Webby RJ, Webster RG, Hoffmann E (2006) The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04. J Exp Med 203(3):689–697

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shapira SD, Gat-Viks I, Shum BO, Dricot A, de Grace MM, Wu L, Gupta PB, Hao T, Silver SJ, Root DE, Hill DE, Regev A, Hacohen N (2009) A physical and regulatory map of host-influenza interactions reveals pathways in H1N1 infection. Cell 139(7):1255–1267

    PubMed  PubMed Central  Google Scholar 

  • Shaw ML (2011) The host interactome of influenza virus presents new potential targets for antiviral drugs. Rev Med Virol 21(6):358–369

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shaw M, Palese P (2013) Orthomyxoviridae, 6th edn. In: Knipe D, Howley P (eds) Fields virology, vol 1. Lippincott Williams and Wilkins, Philadelphia, pp 1151–1185

    Google Scholar 

  • Shi M, Jagger BW, Wise HM, Digard P, Holmes EC, Taubenberger JK (2012) Evolutionary conservation of the PA-X open reading frame in segment 3 of influenza a virus. J Virol 86(22):12411–12413

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shinya K, Hamm S, Hatta M, Ito H, Ito T, Kawaoka Y (2004) PB2 amino acid at position 627 affects replicative efficiency, but not cell tropism, of Hong Kong H5N1 influenza A viruses in mice. Virology 320(2):258–266

    CAS  PubMed  Google Scholar 

  • Shinya K, Makino A, Ozawa M, Kim JH, Sakai-Tagawa Y, Ito M, Le QM, Kawaoka Y (2009) Ostrich involvement in the selection of H5N1 influenza virus possessing mammalian-type amino acids in the PB2 protein. J Virol 83(24):13015–13018

    Google Scholar 

  • Song MS, Pascua PN, Lee JH, Baek YH, Park KJ, Kwon HI, Park SJ, Kim CJ, Kim H, Webby RJ, Webster RG, Choi YK (2011) Virulence and genetic compatibility of polymerase reassortant viruses derived from the pandemic (H1N1) 2009 influenza virus and circulating influenza a viruses. J Virol 85(13):6275–6286

    CAS  PubMed  PubMed Central  Google Scholar 

  • Steel J, Lowen AC, Mubareka S, Palese P (2009) Transmission of influenza virus in a mammalian host is increased by PB2 amino acids 627K or 627E/701N. PLoS Pathog 5(1):e1000252

    PubMed  PubMed Central  Google Scholar 

  • Subbarao K, Klimov A, Katz J, Regnery H, Lim W, Hall H, Perdue M, Swayne D, Bender C, Huang J, Hemphill M, Rowe T, Shaw M, Xu X, Fukuda K, Cox N (1998) Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 279(5349):393–396

    CAS  PubMed  Google Scholar 

  • Subbarao EK, London W, Murphy BR (1993) A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J Virol 67(4):1761–1764

    Google Scholar 

  • Sugiyama K, Obayashi E, Kawaguchi A, Suzuki Y, Tame JR, Nagata K, Park SY (2009) Structural insight into the essential PB1-PB2 subunit contact of the influenza virus RNA polymerase. EMBO J 28(12):1803–1811

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sui B, Bamba D, Weng K, Ung H, Chang S, Van Dyke J, Goldblatt M, Duan R, Kinch MS, Li WB (2009) The use of random homozygous gene perturbation to identify novel host-oriented targets for influenza. Virology 387(2):473–481

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tarendeau F, Boudet J, Guilligay D, Mas PJ, Bougault CM, Boulo S, Baudin F, Ruigrok RW, Daigle N, Ellenberg J, Cusack S, Simorre JP, Hart DJ (2007) Structure and nuclear import function of the C-terminal domain of influenza virus polymerase PB2 subunit. Nat Struct Mol Biol 14(3):229–233

    CAS  PubMed  Google Scholar 

  • Tarendeau F, Crepin T, Guilligay D, Ruigrok RW, Cusack S, Hart DJ (2008) Host determinant residue lysine 627 lies on the surface of a discrete, folded domain of influenza virus polymerase PB2 subunit. PLoS Pathog 4(8):e1000136

    PubMed  PubMed Central  Google Scholar 

  • Vreede FT, Fodor E (2010) The role of the influenza virus RNA polymerase in host shut-off. Virulence 1(5):436–439

    PubMed  PubMed Central  Google Scholar 

  • Vreede FT, Chan AY, Sharps J, Fodor E (2010) Mechanisms and functional implications of the degradation of host RNA polymerase II in influenza virus infected cells. Virology 396(1):125–134

    CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe T, Watanabe S, Kawaoka Y (2010) Cellular networks involved in the influenza virus life cycle. Cell Host Microbe 7(6):427–439

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wise HM, Foeglein A, Sun J, Dalton RM, Patel S, Howard W, Anderson EC, Barclay WS, Digard P (2009) A complicated message: identification of a novel PB1-related protein translated from influenza a virus segment 2 mRNA. J Virol 83(16):8021–8031

    CAS  PubMed  PubMed Central  Google Scholar 

  • Woodfin BM, Kazim AL (1993) Interaction of the amino-terminus of an influenza virus protein with mitochondria. Arch Biochem Biophys 306(2):427–430

    CAS  PubMed  Google Scholar 

  • Xu C, Hu WB, Xu K, He YX, Wang TY, Chen Z, Li TX, Liu JH, Buchy P, Sun B (2012) Amino acids 473V and 598P of PB1 from an avian-origin influenza A virus contribute to polymerase activity, especially in mammalian cells. J Gen Virol 93(Pt 3):531–540

    Google Scholar 

  • 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):e1001034

    PubMed  PubMed Central  Google Scholar 

  • Ye Q, Krug RM, Tao YJ (2006) The mechanism by which influenza a virus nucleoprotein forms oligomers and binds RNA. Nature 444(7122):1078–1082

    CAS  PubMed  Google Scholar 

  • York A, Fodor E (2013) Biogenesis, assembly, and export of viral messenger ribonucleoproteins in the influenza a virus infected cell. RNA Biol 10(8):1274–1282

    CAS  PubMed  PubMed Central  Google Scholar 

  • York A, Hengrung N, Vreede FT, Huiskonen JT, Fodor E (2013) Isolation and characterization of the positive-sense replicative intermediate of a negative-strand RNA virus. Proc Natl Acad Sci U S A 110(45):E4238–E4245

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yuan P, Bartlam M, Lou Z, Chen S, Zhou J, He X, Lv Z, Ge R, Li X, Deng T, Fodor E, Rao Z, Liu Y (2009) Crystal structure of an avian influenza polymerase PA(N) reveals an endonuclease active site. Nature 458(7240):909–913

    CAS  PubMed  Google Scholar 

  • Zhao Z, Yi C, Zhao L, Wang S, Zhou L, Hu Y, Zou W, Chen H, Jin M (2013) PB2 588I enhances the 2009 H1N1 pandemic influenza virus virulence by increasing viral replication and exacerbating PB2 inhibition of interferon-beta expression. J Virol 88(4):2260–2267

    Google Scholar 

  • Zhou B, Pearce MB, Li Y, Wang J, Mason RJ, Tumpey TM, Wentworth DE (2013a) Asparagine substitution at PB2 residue 701 enhances the replication, pathogenicity, and transmission of the 2009 pandemic H1N1 influenza a virus. PLoS One 8(6):e67616

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou J, Wang D, Gao R, Zhao B, Song J, Qi X, Zhang Y, Shi Y, Yang L, Zhu W, Bai T, Qin K, Lan Y, Zou S, Guo J, Dong J, Dong L, Wei H, Li X, Lu J, Liu L, Zhao X, Huang W, Wen L, Bo H, Xin L, Chen Y, Xu C, Pei Y, Yang Y, Zhang X, Wang S, Feng Z, Han J, Yang W, Gao GF, Wu G, Li D, Wang Y, Shu Y (2013b) Biological features of novel avian influenza a (H7N9) virus. Nature 499(7459):500–503

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Edward Hutchinson and Anna Otte for critical reading of the manuscript and Narin Hengrung and Aartjan te Velthuis for their assistance with the figures. Work in the laboratory of the authors was supported by the German Research Foundation (Emmy-Noether Programme to GG), the European Union (Flu-Pharm to GG) and the Medical Research Council (programme grant MR/K000241/1 to EF).

Author information

Authors and Affiliations

  1. Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany

    Gülsah Gabriel

  2. Sir William Dunn School of Pathology, University of Oxford, Oxford, UK

    Ervin Fodor

Authors
  1. Gülsah Gabriel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ervin Fodor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gülsah Gabriel .

Editor information

Editors and Affiliations

  1. Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA

    Richard W. Compans

  2. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA

    Michael B. A. Oldstone

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Gabriel, G., Fodor, E. (2014). Molecular Determinants of Pathogenicity in the Polymerase Complex. In: Compans, R., Oldstone, M. (eds) Influenza Pathogenesis and Control - Volume I. Current Topics in Microbiology and Immunology, vol 385. Springer, Cham. https://doi.org/10.1007/82_2014_386

Download citation

Publish with us

Policies and ethics

Search

Navigation