Publikationsserver der Universitätsbibliothek Marburg
Titel:Adaption aviärer Influenzaviren vom Subtyp H5N1 an die Maus durch Mutationen in der Viruspolymerase
Autor:Czudai-Matwich, Volker
Weitere Beteiligte: Klenk, Hans-Dieter (Prof. Dr.)
Veröffentlicht:2012
URI:https://archiv.ub.uni-marburg.de/diss/z2012/0849
URN: urn:nbn:de:hebis:04-z2012-08497
DOI: https://doi.org/10.17192/z2012.0849
DDC: Medizin
Titel (trans.):Adaptation of avian H5N1 Influenzaviruses to mice by mutations in the viral polymerase
Publikationsdatum:2012-10-05
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Anpassung, Mice, Adaptation, Vogelgrippe, Polymerase, Avian Influenzavirus, Polymerase, Mutation, Maus

Zusammenfassung:
Die sporadische Übertragung von HPAIV des Subtyps H5N1 vom Vogel auf den Menschen und andere Säugetiere ist nach wie vor mit einer hohen Mortalität verbunden. Die zugrundeliegenden Mechanismen für die besondere Pathogenität dieser Viren im Vergleich zu anderen HPAIV wie zum Beispiel A/FPV/Rostock/34 (H7N1), sind aber bislang kaum geklärt. Ziel dieser Arbeit war es, anhand des humanen H5N1-Isolats A/Thailand/1(Kan-1)/04 die Auswirkung von zwei Mutationen im PB2-Protein der viralen Polymerase auf die Anpassung und gesteigerte Virulenz von HPAIV des Subtyps H5N1 für Säuger eingehender zu untersuchen. 1. In der vorliegenden Arbeit wurden die Mutationen PB2 D701N und PB2 S714I und PB2 S714R auf ihre Auswirkung auf die Aktivität der viralen Polymerase in Säuger- und Vogelzellen hin untersucht. Es konnte gezeigt werden, dass die eingeführten Mutationen sowohl allein als auch in Kombination zu einer signifikanten Steigerung der Polymerase-Aktivität führen. 2. Des Weiteren wurden rekombinante Viren erzeugt, die die entsprechenden Mutationen im PB2-Protein einzeln oder in Kombination tragen. 3. Die durchgeführten Studien zum viralen Wachstum in verschiedenen Zellen aus Säugern zeigen, dass die Mutation PB2 D701N eine maßgebliche Rolle bei der viralen Replikation in Säugern spielt. Die Mutationen S714I und S714R dagegen führen nur in Kombination mit der Mutation D701N zu einer weiteren Steigerung der Virusreplikation in Säugern. 4. Für die Mutationen S714I und S714R konnte gezeigt werden, dass sie wirtsunabhängig zu einer Steigerung der Polymerase-Aktivität führen. Diese gesteigerte Aktivität resultiert in aviären Zellen aber nicht in einer gesteigerten Virusreplikation. 5. Zur Überprüfung der Bedeutung der eingeführten Mutationen für die Pathogenität der Viren wurden im Rahmen dieser Arbeit auch Studien in der Maus durchgeführt. Es konnte gezeigt werden, dass die Mutation D701N auch in der Maus den größten Einfluss auf die Pathogenität der Viren hat. 6. Darüber hinaus konnte gezeigt werden, dass die Mutationen S714I und S714R in Kombination mit der Mutation D701N die Pathogenität der Viren für die Maus weiter steigern können, dass die Einzelpunktmutanten S714I und S714R aber attenuiert sind. 7. Im Verlauf der Arbeit konnte gezeigt werden, dass die aviär-typischen Viren unter starkem Selektionsdruck stehen und in Zellkultur zum Erwerb adaptiver Mutationen neigen.

Bibliographie / References

  1. Klenk, K., Snow, J., Morgan, K., Bowen, R., Stephens, M., Foster, F., Gordy, P., Beckett, S., Komar, N., Gubler, D., and Bunning, M. (2004). Alligators as West Nile virus amplifiers. Emerg Infect Dis 10(12), 2150-5.
  2. Davis, L. M., and Spackman, E. (2008). Do crocodilians get the flu? Looking for influenza A in captive crocodilians. Journal of Experimental Zoology Part A: Ecological Genetics and Physiology 309A(10), 571-580.
  3. Masunaga, K., Mizumoto, K., Kato, H., Ishihama, A., and Toyoda, T. (1999). Molecular mapping of influenza virus RNA polymerase by site-specific antibodies. Virology 256(1), 130-41.
  4. Modrow, S., Falke, D., and Truyen, U. (2003). "Molekulare Virologie." 2 ed. Spektrum Akademischer Verlag, Heidelberg Berlin.
  5. Beare, A. S., and Webster, R. G. (1991). Replication of avian influenza viruses in humans. Arch Virol 119(1-2), 37-42.
  6. Lang, G., Gagnon, A., and Geraci, J. R. (1981). Isolation of an influenza A virus from seals. Arch Virol 68(3-4), 189-95.
  7. Banks, J., Speidel, E., and Alexander, D. J. (1998). Characterisation of an avian influenza A virus isolated from a human--is an intermediate host necessary for the emergence of pandemic influenza viruses? Arch Virol 143(4), 781-7.
  8. Scholtissek, C., Rohde, W., Von Hoyningen, V., and Rott, R. (1978). On the origin of the human influenza virus subtypes H2N2 and H3N2. Virology 87(1), 13-20.
  9. Webster, R. G., Yakhno, M., Hinshaw, V. S., Bean, W. J., and Murti, K. G. (1978). Intestinal influenza: replication and characterization of influenza viruses in ducks. Virology 84(2), 268-78.
  10. Couceiro, J. N., Paulson, J. C., and Baum, L. G. (1993). Influenza virus strains selectively recognize sialyloligosaccharides on human respiratory epithelium; the role of the host cell in selection of hemagglutinin receptor specificity. Virus Res 29(2), 155-65.
  11. Conenello, G. M., and Palese, P. (2007). Influenza A virus PB1-F2: a small protein with a big punch. Cell Host Microbe 2(4), 207-9.
  12. Mehle, A., and Doudna, J. A. (2008). An Inhibitory Activity in Human Cells Restricts the Function of an Avian-like Influenza Virus Polymerase. Cell Host & Microbe 4(2), 111- 122.
  13. Ruigrok, R. W., Crepin, T., Hart, D. J., and Cusack, S. (2010). Towards an atomic resolution understanding of the influenza virus replication machinery. Curr Opin Struct Biol 20(1), 104-13.
  14. Herlocher, M. L., Carr, J., Ives, J., Elias, S., Truscon, R., Roberts, N., and Monto, A. S. (2002). Influenza virus carrying an R292K mutation in the neuraminidase gene is not transmitted in ferrets. Antiviral Res 54(2), 99-111.
  15. Ohtsu, Y., Honda, Y., Sakata, Y., Kato, H., and Toyoda, T. (2002). Fine mapping of the subunit binding sites of influenza virus RNA polymerase. Microbiol Immunol 46(3), 167-75.
  16. Butler, D. (2006). Family tragedy spotlights flu mutations. Nature 442(7099), 114-5.
  17. "Medizinische Mikrobiologie." 8 ed. Urban Fischer Verlag, München, Jena.
  18. Gabriel, G., Dauber, B., Wolff, T., Planz, O., Klenk, H. D., and 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), 18590-5.
  19. Kawaoka, Y., and Webster, R. G. (1988). Sequence requirements for cleavage activation of influenza virus hemagglutinin expressed in mammalian cells. Proc Natl Acad Sci U S A 85(2), 324-8.
  20. Huchzermeyer, F. (2003). "Crocodiles: biology, husbandry and diseases." CABI Publishing.
  21. Risk of influenza A (H5N1) infection among health care workers exposed to patients with influenza A (H5N1), Hong Kong. J Infect Dis 181(1), 344-8.
  22. Fedson, D. S. (2009). Was bacterial pneumonia the predominant cause of death in the 1918- 1919 influenza pandemic? J Infect Dis 199(9), 1408-9; author reply 1409-10.
  23. Martin-Benito, J., Area, E., Ortega, J., Llorca, O., Valpuesta, J. M., Carrascosa, J. L., and Ortin, J. (2001). Three-dimensional reconstruction of a recombinant influenza virus ribonucleoprotein particle. EMBO Rep 2(4), 313-7.
  24. Mazza, C., Segref, A., Mattaj, I. W., and Cusack, S. (2002b). Large-scale induced fit recognition of an m(7)GpppG cap analogue by the human nuclear cap-binding complex. EMBO J 21(20), 5548-57.
  25. Blaas, D., Patzelt, E., and Kuechler, E. (1982). Identification of the cap binding protein of influenza virus. Nucleic Acids Res 10(15), 4803-12.
  26. Thierry, F., and Danos, O. (1982). Use of specific single stranded DNA probes cloned in M13 to study the RNA synthesis of four temperature-sensitive mutants of HK/68 influenza virus. Nucleic Acids Res 10(9), 2925-38.
  27. Argos, P. (1988). A sequence motif in many polymerases. Nucleic Acids Res 16(21), 9909-16.
  28. Muller, R., Poch, O., Delarue, M., Bishop, D. H., and Bouloy, M. (1994). Rift Valley fever virus L segment: correction of the sequence and possible functional role of newly identified regions conserved in RNA-dependent polymerases. J Gen Virol 75 ( Pt 6), 1345-52.
  29. Robb, N. C., Smith, M., Vreede, F. T., and Fodor, E. (2009). NS2/NEP protein regulates transcription and replication of the influenza virus RNA genome. Journal of General Virology 90(6), 1398-1407.
  30. Neumann, G., Green, M. A., and Macken, C. A. (2010). Evolution of highly pathogenic avian H5N1 influenza viruses and the emergence of dominant variants. J Gen Virol 91(Pt 8), 1984-95.
  31. Reintroduction of H5N1 highly pathogenic avian influenza virus by migratory water birds, causing poultry outbreaks in 2010-2011 winter season in Japan. J Gen Virol.
  32. Ducatez, M. F., Olinger, C. M., Owoade, A. A., Tarnagda, Z., Tahita, M. C., Sow, A., De Landtsheer, S., Ammerlaan, W., Ouedraogo, J. B., Osterhaus, A. D., Fouchier, R. A., and Muller, C. P. (2007). Molecular and antigenic evolution and geographical spread of H5N1 highly pathogenic avian influenza viruses in western Africa. J Gen Virol 88(Pt 8), 2297-306.
  33. WHO/OIE/FAO (2012). Continued evolution of highly pathogenic avian influenza A (H5N1): updated nomenclature. Influenza Other Respi Viruses 6(1), 1-5.
  34. Green, T. J., Zhang, X., Wertz, G. W., and Luo, M. (2006). Structure of the vesicular stomatitis virus nucleoprotein-RNA complex. Science 313(5785), 357-60.
  35. Rodriguez, A., Perez-Gonzalez, A., and Nieto, A. (2007). Influenza Virus Infection Causes Specific Degradation of the Largest Subunit of Cellular RNA Polymerase II. Journal of Virology 81(10), 5315-5324.
  36. Bertram, S., Glowacka, I., Blazejewska, P., Soilleux, E., Allen, P., Danisch, S., Steffen, I., Choi, S. Y., Park, Y., Schneider, H., Schughart, K., and Pohlmann, S. (2010). TMPRSS2 and TMPRSS4 facilitate trypsin-independent spread of influenza virus in Caco-2 cells. J Virol 84(19), 10016-25.
  37. Billharz, R., Zeng, H., Proll, S. C., Korth, M. J., Lederer, S., Albrecht, R., Goodman, A. G., Rosenzweig, E., Tumpey, T. M., Garcia-Sastre, A., and Katze, M. G. (2009). The NS1 protein of the 1918 pandemic influenza virus blocks host interferon and lipid metabolism pathways. J Virol 83(20), 10557-70.
  38. Cilloniz, C., Pantin-Jackwood, M. J., Ni, C., Goodman, A. G., Peng, X., Proll, S. C., Carter, V. S., Rosenzweig, E. R., Szretter, K. J., Katz, J. M., Korth, M. J., Swayne, D. E., Tumpey, T. M., and Katze, M. G. (2010). Lethal Dissemination of H5N1 Influenza Virus Is Associated with Dysregulation of Inflammation and Lipoxin Signaling in a Mouse Model of Infection. Journal of Virology 84(15), 7613-7624.
  39. Gabriel, G., Abram, M., Keiner, B., Wagner, R., Klenk, H. D., and Stech, J. (2007). Differential Polymerase Activity in Avian and Mammalian Cells Determines Host Range of Influenza Virus. Journal of Virology 81(17), 9601-9604.
  40. Finkelstein, D. B., Mukatira, S., Mehta, P. K., Obenauer, J. C., Su, X., Webster, R. G., and Naeve, C. W. (2007). Persistent Host Markers in Pandemic and H5N1 Influenza Viruses. Journal of Virology 81(19), 10292-10299.
  41. Moncorge, O., Mura, M., and Barclay, W. S. (2010). Evidence for Avian and Human Host Cell Factors That Affect the Activity of Influenza Virus Polymerase. Journal of Virology 84(19), 9978-9986.
  42. Vreede, F. T., Gifford, H., and Brownlee, G. G. (2008). Role of Initiating Nucleoside Triphosphate Concentrations in the Regulation of Influenza Virus Replication and Transcription. Journal of Virology 82(14), 6902-6910.
  43. Shinya, K., Makino, A., Ozawa, M., Kim, J. H., Sakai-Tagawa, Y., Ito, M., Le, Q. M., and 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), 13015-8.
  44. Naito, T., Momose, F., Kawaguchi, A., and Nagata, K. (2007). Involvement of Hsp90 in assembly and nuclear import of influenza virus RNA polymerase subunits. J Virol 81(3), 1339-49.
  45. Vreede, F. T., and Brownlee, G. G. (2007). Influenza virion-derived viral ribonucleoproteins synthesize both mRNA and cRNA in vitro. J Virol 81(5), 2196-204.
  46. Ortega, J., Martin-Benito, J., Zurcher, T., Valpuesta, J. M., Carrascosa, J. L., and Ortin, J. (2000). Ultrastructural and functional analyses of recombinant influenza virus ribonucleoproteins suggest dimerization of nucleoprotein during virus amplification. J Virol 74(1), 156-63.
  47. Massin, P., van der Werf, S., and Naffakh, N. (2001). Residue 627 of PB2 Is a Determinant of Cold Sensitivity in RNA Replication of Avian Influenza Viruses. Journal of Virology 75(11), 5398-5404.
  48. Shinya, K., Hatta, M., Yamada, S., Takada, A., Watanabe, S., Halfmann, P., Horimoto, T., Neumann, G., Kim, J. H., Lim, W., Guan, Y., Peiris, M., Kiso, M., Suzuki, T., Suzuki, Y., and Kawaoka, Y. (2005). Characterization of a Human H5N1 Influenza A Virus Isolated in 2003. Journal of Virology 79(15), 9926-9932.
  49. Li, Z., Chen, H., Jiao, P., Deng, G., Tian, G., Li, Y., Hoffmann, E., Webster, R. G., Matsuoka, Y., and Yu, K. (2005). Molecular Basis of Replication of Duck H5N1 Influenza Viruses in a Mammalian Mouse Model. Journal of Virology 79(18), 12058-12064.
  50. Klenk, H. D. (2005). Infection of the endothelium by influenza viruses. Thromb Haemost 94(2), 262-5.
  51. Kayali, G., Webby, R. J., Ducatez, M. F., El Shesheny, R. A., Kandeil, A. M., Govorkova, E. A., Mostafa, A., and Ali, M. A. (2011b). The epidemiological and molecular aspects of influenza H5N1 viruses at the human-animal interface in Egypt. PLoS ONE 6(3), e17730.
  52. Gabriel, G., Herwig, A., and Klenk, H.-D. (2008). Interaction of Polymerase Subunit PB2 and NP with Importin α1 Is a Determinant of Host Range of Influenza A Virus. PLoS Pathogens 4(2), e11.
  53. Coloma, R., Valpuesta, J. M., Arranz, R., Carrascosa, J. L., Ortin, J., and Martin-Benito, J. (2009). The structure of a biologically active influenza virus ribonucleoprotein complex. PLoS Pathog 5(6), e1000491.
  54. Cilloniz, C., Shinya, K., Peng, X., Korth, M. J., Proll, S. C., Aicher, L. D., Carter, V. S., Chang, J. H., Kobasa, D., Feldmann, F., Strong, J. E., Feldmann, H., Kawaoka, Y., and Katze, M. G. (2009). Lethal influenza virus infection in macaques is associated with early dysregulation of inflammatory related genes. PLoS Pathog 5(10), e1000604.
  55. Schäfer, W. (1955). Vergleichender sero-immunologische Untersuchungen über die Viren der Influenza und klassischen Geflügelpest. Z Naturforsch B(10b), 81-91.
  56. Guan, Y., Peiris, J. S., Poon, L. L., Dyrting, K. C., Ellis, T. M., Sims, L., Webster, R. G., and Shortridge, K. F. (2003). Reassortants of H5N1 influenza viruses recently isolated from aquatic poultry in Hong Kong SAR. Avian Dis 47(3 Suppl), 911-3.
  57. Songserm, T., Amonsin, A., Jam-on, R., Sae-Heng, N., Pariyothorn, N., Payungporn, S., Theamboonlers, A., Chutinimitkul, S., Thanawongnuwech, R., and Poovorawan, Y. (2006b). Fatal avian influenza A H5N1 in a dog. Emerg Infect Dis 12(11), 1744-7.
  58. Salzberg, S. L., Kingsford, C., Cattoli, G., Spiro, D. J., Janies, D. A., Aly, M. M., Brown, I. H., Couacy-Hymann, E., De Mia, G. M., Dung do, H., Guercio, A., Joannis, T., Maken Ali, A. S., Osmani, A., Padalino, I., Saad, M. D., Savic, V., Sengamalay, N. A., Yingst, S., Zaborsky, J., Zorman-Rojs, O., Ghedin, E., and Capua, I. (2007). Genome analysis linking recent European and African influenza (H5N1) viruses. Emerg Infect Dis 13(5), 713-8.
  59. Kayali, G., El-Shesheny, R., Kutkat, M. A., Kandeil, A. M., Mostafa, A., Ducatez, M. F., McKenzie, P. P., Govorkova, E. A., Nasraa, M. H., Webster, R. G., Webby, R. J., and Ali, M. A. (2011a). Continuing Threat of Influenza (H5N1) Virus Circulation in Egypt. Emerg Infect Dis 17(12), 2306-8.
  60. Rios-Soto, K. R., Song, B., and Castillo-Chavez, C. (2011). Epidemic spread of influenza viruses: The impact of transient populations on disease dynamics. Math Biosci Eng 8(1), 199-222.
  61. Steel, J., Lowen, A. C., Mubareka, S., and 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.
  62. Baum, L. G., and Paulson, J. C. (1990). Sialyloligosaccharides of the respiratory epithelium in the selection of human influenza virus receptor specificity. Acta Histochem Suppl 40, 35-8.
  63. Gubareva, L. V., Kaiser, L., Matrosovich, M. N., Soo-Hoo, Y., and Hayden, F. G. (2001). Selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir. J Infect Dis 183(4), 523-31.
  64. Carter, M. J. (2007). A rationale for using steroids in the treatment of severe cases of H5N1 avian influenza. Journal of Medical Microbiology 56(7), 875-883.
  65. Tiley, L. S., Hagen, M., Matthews, J. T., and Krystal, M. (1994). Sequence-specific binding of the influenza virus RNA polymerase to sequences located at the 5' ends of the viral RNAs. J Virol 68(8), 5108-16.
  66. Manz, B., Matrosovich, M., Bovin, N., and Schwemmle, M. (2010). A Polymorphism in the Hemagglutinin of the Human Isolate of a Highly Pathogenic H5N1 Influenza Virus Determines Organ Tropism in Mice. Journal of Virology 84(16), 8316-8321.
  67. Area, E., Martin-Benito, J., Gastaminza, P., Torreira, E., Valpuesta, J. M., Carrascosa, J. L., and Ortin, J. (2004). 3D structure of the influenza virus polymerase complex: localization of subunit domains. Proc Natl Acad Sci U S A 101(1), 308-13.
  68. Perez, D. R., and Donis, R. O. (1995). A 48-amino-acid region of influenza A virus PB1 protein is sufficient for complex formation with PA. J Virol 69(11), 6932-9.
  69. Watanabe, Y., Ibrahim, M. S., Ellakany, H. F., Kawashita, N., Mizuike, R., Hiramatsu, H., Sriwilaijaroen, N., Takagi, T., Suzuki, Y., and Ikuta, K. (2011). Acquisition of human- type receptor binding specificity by new H5N1 influenza virus sublineages during their emergence in birds in Egypt. PLoS Pathog 7(5), e1002068.
  70. Chen, W., Calvo, P. A., Malide, D., Gibbs, J., Schubert, U., Bacik, I., Basta, S., O'Neill, R., Schickli, J., Palese, P., Henklein, P., Bennink, J. R., and Yewdell, J. W. (2001). A novel influenza A virus mitochondrial protein that induces cell death. Nat Med 7(12), 1306- 12.
  71. Alexander, D. J. (2000). A review of avian influenza in different bird species. Vet Microbiol 74(1-2), 3-13.
  72. Almond, J. W. (1977). A single gene determines the host range of influenza virus. Nature 270(5638), 617-8.
  73. Conenello, G. M., Zamarin, D., Perrone, L. A., Tumpey, T., and Palese, P. (2007). A single mutation in the PB1-F2 of H5N1 (HK/97) and 1918 influenza A viruses contributes to increased virulence. PLoS Pathog 3(10), 1414-21.
  74. Engelhardt, O. G., Smith, M., and Fodor, E. (2005). Association of the Influenza A Virus RNA- Dependent RNA Polymerase with Cellular RNA Polymerase II. Journal of Virology 79(9), 5812-5818.
  75. Plotch, S. J., Bouloy, M., Ulmanen, I., and Krug, R. M. (1981). A unique cap(m7GpppXm)- dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription. Cell 23(3), 847-58.
  76. Chen, H., Smith, G. J., Zhang, S. Y., Qin, K., Wang, J., Li, K. S., Webster, R. G., Peiris, J. S., and Guan, Y. (2005). Avian flu: H5N1 virus outbreak in migratory waterfowl. Nature 436(7048), 191-2.
  77. Pereira, H. G., Tumova, B., and Law, V. G. (1965). Avian influenza A viruses. Bull World Health Organ 32(6), 855-60.
  78. Normile, D. (2006). Avian influenza. Evidence points to migratory birds in H5N1 spread. Science 311(5765), 1225.
  79. Schultsz, C., Dong, V. C., Chau, N. V., Le, N. T., Lim, W., Thanh, T. T., Dolecek, C., de Jong, M. D., Hien, T. T., and Farrar, J. (2005). Avian influenza H5N1 and healthcare workers. Emerg Infect Dis 11(7), 1158-9.
  80. Songserm, T., Amonsin, A., Jam-on, R., Sae-Heng, N., Meemak, N., Pariyothorn, N., Payungporn, S., Theamboonlers, A., and Poovorawan, Y. (2006a). Avian influenza H5N1 in naturally infected domestic cat. Emerg Infect Dis 12(4), 681-3.
  81. Keawcharoen, J., Oraveerakul, K., Kuiken, T., Fouchier, R. A., Amonsin, A., Payungporn, S., Noppornpanth, S., Wattanodorn, S., Theambooniers, A., Tantilertcharoen, R., Pattanarangsan, R., Arya, N., Ratanakorn, P., Osterhaus, D. M., and Poovorawan, Y. (2004). Avian influenza H5N1 in tigers and leopards. Emerg Infect Dis 10(12), 2189- 91.
  82. Momose, F., Basler, C. F., O'Neill, R. E., Iwamatsu, A., Palese, P., and Nagata, K. (2001). Cellular splicing factor RAF-2p48/NPI-5/BAT1/UAP56 interacts with the influenza virus nucleoprotein and enhances viral RNA synthesis. J Virol 75(4), 1899-908.
  83. 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., and Cox, N. (1998). Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 279(5349), 393-6.
  84. Hoffmann, E., Stech, J., Leneva, I., Krauss, S., Scholtissek, C., Chin, P. S., Peiris, M., Shortridge, K. F., and Webster, R. G. (2000b). Characterization of the influenza A virus gene pool in avian species in southern China: was H6N1 a derivative or a precursor of H5N1? J Virol 74(14), 6309-15.
  85. Li, X., and Palese, P. (1994). Characterization of the polyadenylation signal of influenza virus RNA. J Virol 68(2), 1245-9.
  86. Bean, W. J., Kawaoka, Y., Wood, J. M., Pearson, J. E., and Webster, R. G. (1985). Characterization of virulent and avirulent A/chicken/Pennsylvania/83 influenza A viruses: potential role of defective interfering RNAs in nature. J Virol 54(1), 151-60.
  87. Mazza, C., Segref, A., Mattaj, I. W., and Cusack, S. (2002a). Co-crystallization of the human nuclear cap-binding complex with a m7GpppG cap analogue using protein engineering.
  88. Marcotrigiano, J., Gingras, A. C., Sonenberg, N., and Burley, S. K. (1997). Cocrystal structure of the messenger RNA 5' cap-binding protein (eIF4E) bound to 7-methyl-GDP. Cell 89(6), 951-61.
  89. Suarez, D. L., Perdue, M. L., Cox, N., Rowe, T., Bender, C., Huang, J., and Swayne, D. E. (1998). Comparisons of highly virulent H5N1 influenza A viruses isolated from humans and chickens from Hong Kong. J Virol 72(8), 6678-88.
  90. Perez, J. T., Varble, A., Sachidanandam, R., Zlatev, I., Manoharan, M., Garcia-Sastre, A., and tenOever, B. R. (2010). Cozzarelli Prize Winner: From the Cover: Influenza A virus- generated small RNAs regulate the switch from transcription to replication. Proceedings of the National Academy of Sciences 107(25), 11525-11530.
  91. Yuan, P., Bartlam, M., Lou, Z., Chen, S., Zhou, J., He, X., Lv, Z., Ge, R., Li, X., Deng, T., Fodor, E., Rao, Z., and Liu, Y. (2009). Crystal structure of an avian influenza polymerase PAN reveals an endonuclease active site. Nature 458(7240), 909-913.
  92. He, X., Zhou, J., Bartlam, M., Zhang, R., Ma, J., Lou, Z., Li, X., Li, J., Joachimiak, A., Zeng, Z., Ge, R., Rao, Z., and Liu, Y. (2008). Crystal structure of the polymerase PAC–PB1N complex from an avian influenza H5N1 virus. Nature 454(7208), 1123-1126.
  93. Albertini, A. A., Wernimont, A. K., Muziol, T., Ravelli, R. B., Clapier, C. R., Schoehn, G., Weissenhorn, W., and Ruigrok, R. W. (2006). Crystal structure of the rabies virus nucleoprotein-RNA complex. Science 313(5785), 360-3.
  94. Collins, P. J., Haire, L. F., Lin, Y. P., Liu, J., Russell, R. J., Walker, P. A., Skehel, J. J., Martin, S. R., Hay, A. J., and Gamblin, S. J. (2008). Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants. Nature 453(7199), 1258-61.
  95. Lee, M. T., Bishop, K., Medcalf, L., Elton, D., Digard, P., and Tiley, L. (2002). Definition of the minimal viral components required for the initiation of unprimed RNA synthesis by influenza virus RNA polymerase. Nucleic Acids Res 30(2), 429-38.
  96. Deng, T., Vreede, F. T., and Brownlee, G. G. (2006). Different De Novo Initiation Strategies Are Used by Influenza Virus RNA Polymerase on Its cRNA and Viral RNA Promoters during Viral RNA Replication. Journal of Virology 80(5), 2337-2348.
  97. Guan, Y., Peiris, J. S., Lipatov, A. S., Ellis, T. M., Dyrting, K. C., Krauss, S., Zhang, L. J., Webster, R. G., and Shortridge, K. F. (2002). Emergence of multiple genotypes of H5N1 avian influenza viruses in Hong Kong SAR. Proc Natl Acad Sci U S A 99(13), 8950-5.
  98. Webster, R. G., Bean, W. J., Gorman, O. T., Chambers, T. M., and Kawaoka, Y. (1992). Evolution and ecology of influenza A viruses. Microbiol Rev 56(1), 152-79.
  99. de Jong, M. D., Simmons, C. P., Thanh, T. T., Hien, V. M., Smith, G. J. D., Chau, T. N. B., Hoang, D. M., Van Vinh Chau, N., Khanh, T. H., Dong, V. C., Qui, P. T., Van Cam, B., Ha, D. Q., Guan, Y., Peiris, J. S. M., Chinh, N. T., Hien, T. T., and Farrar, J. (2006). Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nature Medicine 12(10), 1203-1207.
  100. Tindall, K. R., and Kunkel, T. A. (1988). Fidelity of DNA synthesis by the Thermus aquaticus DNA polymerase. Biochemistry 27(16), 6008-13.
  101. Perez, D. R., and Donis, R. O. (2001). Functional Analysis of PA Binding by Influenza A Virus PB1: Effects on Polymerase Activity and Viral Infectivity. Journal of Virology 75(17), 8127-8136.
  102. Li, S. Q., Orlich, M., and Rott, R. (1990). Generation of seal influenza virus variants pathogenic for chickens, because of hemagglutinin cleavage site changes. J Virol 64(7), 3297-303.
  103. Li, K. S., Guan, Y., Wang, J., Smith, G. J., Xu, K. M., Duan, L., Rahardjo, A. P., Puthavathana, P., Buranathai, C., Nguyen, T. D., Estoepangestie, A. T., Chaisingh, A., Auewarakul, P., Long, H. T., Hanh, N. T., Webby, R. J., Poon, L. L., Chen, H., Shortridge, K. F., Yuen, K. Y., Webster, R. G., and Peiris, J. S. (2004). Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature 430(6996), 209- 13.
  104. Xu, X., Subbarao, Cox, N. J., and Guo, Y. (1999). Genetic characterization of the pathogenic influenza A/Goose/Guangdong/1/96 (H5N1) virus: similarity of its hemagglutinin gene to those of H5N1 viruses from the 1997 outbreaks in Hong Kong. Virology 261(1), 15- 9.
  105. Jorba, N., Coloma, R., and Ortin, J. (2009). Genetic trans-complementation establishes a new model for influenza virus RNA transcription and replication. PLoS Pathog 5(5), e1000462.
  106. Germany in 2006 and 2007 suggest at least three separate introductions of H5N1 virus. Vet Microbiol 128(3-4), 243-52.
  107. Moscona, A. (2009). Global transmission of oseltamivir-resistant influenza. N Engl J Med 360(10), 953-6.
  108. Bouloy, M., Plotch, S. J., and Krug, R. M. (1978). Globin mRNAs are primers for the transcription of influenza viral RNA in vitro. Proc Natl Acad Sci U S A 75(10), 4886- 90.
  109. Vey, M., Orlich, M., Adler, S., Klenk, H. D., Rott, R., and Garten, W. (1992). Hemagglutinin activation of pathogenic avian influenza viruses of serotype H7 requires the protease recognition motif R-X-K/R-R. Virology 188(1), 408-13.
  110. Liu, J., Xiao, H., Lei, F., Zhu, Q., Qin, K., Zhang, X. W., Zhang, X. L., Zhao, D., Wang, G., Feng, Y., Ma, J., Liu, W., Wang, J., and Gao, G. F. (2005). Highly pathogenic H5N1 influenza virus infection in migratory birds. Science 309(5738), 1206.
  111. Alexander, D. J., and Brown, I. H. (2009). History of highly pathogenic avian influenza. Rev Sci Tech 28(1), 19-38.
  112. Claas, E. C. J., Osterhaus, A. D. M. E., van Beek, R., De Jong, J. C., Rimmelzwaan, G. F., Senne, D. A., Krauss, S., Shortridge, K. F., and Webster, R. G. (1998). Human 142 influenza A H5N1 virus related to a highly pathogenic avian influenza virus. The Lancet 351(9101), 472-477.
  113. Du Ry van Beest Holle, M., Meijer, A., Koopmans, M., and de Jager, C. M. (2005). Human-to- human transmission of avian influenza A/H7N7, The Netherlands, 2003. Euro Surveill 10(12), 264-8.
  114. Cheung, C., Poon, L., Lau, A., Luk, W., Lau, Y., Shortridge, K., Gordon, S., Guan, Y., and Peiris, J. (2002). Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? The Lancet 360(9348), 1831-1837.
  115. Stasakova, J., Ferko, B., Kittel, C., Sereinig, S., Romanova, J., Katinger, H., and Egorov, A. (2005). Influenza A mutant viruses with altered NS1 protein function provoke caspase-1 activation in primary human macrophages, resulting in fast apoptosis and release of high levels of interleukins 1beta and 18. J Gen Virol 86(Pt 1), 185-95.
  116. Garcia-Sastre, A., Egorov, A., Matassov, D., Brandt, S., Levy, D. E., Durbin, J. E., Palese, P., and Muster, T. (1998). Influenza A virus lacking the NS1 gene replicates in interferon- deficient systems. Virology 252(2), 324-30.
  117. Bullido, R., Gomez-Puertas, P., Saiz, M. J., and Portela, A. (2001). Influenza A Virus NEP (NS2 Protein) Downregulates RNA Synthesis of Model Template RNAs. Journal of Virology 75(10), 4912-4917.
  118. Gack, M. U., Albrecht, R. A., Urano, T., Inn, K. S., Huang, I. C., Carnero, E., Farzan, M., Inoue, S., Jung, J. U., and Garcia-Sastre, A. (2009). Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe 5(5), 439-49.
  119. Chan, A. Y., Vreede, F. T., Smith, M., Engelhardt, O. G., and Fodor, E. (2006). Influenza virus inhibits RNA polymerase II elongation. Virology 351(1), 210-7.
  120. Nemeroff, M. E., Barabino, S. M., Li, Y., Keller, W., and Krug, R. M. (1998). Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3'end formation of cellular pre-mRNAs. Mol Cell 1(7), 991-1000.
  121. Shapiro, G. I., and Krug, R. M. (1988). Influenza virus RNA replication in vitro: synthesis of viral template RNAs and virion RNAs in the absence of an added primer. J Virol 62(7), 2285-90.
  122. Tomassini, J., Selnick, H., Davies, M. E., Armstrong, M. E., Baldwin, J., Bourgeois, M., Hastings, J., Hazuda, D., Lewis, J., McClements, W., and et al. (1994). Inhibition of cap (m7GpppXm)-dependent endonuclease of influenza virus by 4-substituted 2,4- dioxobutanoic acid compounds. Antimicrob Agents Chemother 38(12), 2827-37.
  123. Palese, P., Schulman, J. L., Bodo, G., and Meindl, P. (1974). Inhibition of influenza and parainfluenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N- trifluoroacetylneuraminic acid (FANA). Virology 59(2), 490-8.
  124. Palese, P., and Compans, R. W. (1976). Inhibition of influenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA): mechanism of action. J Gen Virol 33(1), 159-63.
  125. Boivin, S., and Hart, D. J. (2011). Interaction of the Influenza A Virus Polymerase PB2 C- terminal Region with Importin α Isoforms Provides Insights into Host Adaptation and Polymerase Assembly. Journal of Biological Chemistry 286(12), 10439-10448.
  126. Isolatbezeichnung GenBank Nr. Isolatbezeichnung GenBank Nr.
  127. Dubey, S. C., Dahal, N., Nagarajan, S., Tosh, C., Murugkar, H. V., Rinzin, K., Sharma, B., Jain, R., Katare, M., Patil, S., Khandia, R., Syed, Z., Tripathi, S., Behera, P., Kumar, M., Kulkarni, D. D., and Krishna, L. (2011). Isolation and characterization of influenza A virus (subtype H5N1) that caused the first highly pathogenic avian influenza outbreak in chicken in Bhutan. Vet Microbiol.
  128. Liem, N. T., and Lim, W. (2005). Lack of H5N1 avian influenza transmission to hospital employees, Hanoi, 2004. Emerg Infect Dis 11(2), 210-5.
  129. Seo, S. H., Hoffmann, E., and Webster, R. G. (2002). Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nat Med 8(9), 950-4.
  130. Vong, S., Coghlan, B., Mardy, S., Holl, D., Seng, H., Ly, S., Miller, M. J., Buchy, P., Froehlich, Y., Dufourcq, J. B., Uyeki, T. M., Lim, W., and Sok, T. (2006). Low frequency of poultry-to-human H5NI virus transmission, southern Cambodia, 2005. Emerg Infect Dis 12(10), 1542-7.
  131. Honda, A., Mizumoto, K., and Ishihama, A. (2002). Minimum molecular architectures for transcription and replication of the influenza virus. Proc Natl Acad Sci U S A 99(20), 13166-71.
  132. Murakami, M., Towatari, T., Ohuchi, M., Shiota, M., Akao, M., Okumura, Y., Parry, M. A., and Kido, H. (2001). Mini-plasmin found in the epithelial cells of bronchioles triggers infection by broad-spectrum influenza A viruses and Sendai virus. Eur J Biochem 268(10), 2847-55.
  133. Garten, W., Vey, M., Ohuchi, R., Ohuchi, M., and Klenk, H. D. (1991). Modification of the cleavage activation of the influenza virus hemagglutinin by site-specific mutagenesis. Behring Inst Mitt(89), 12-22.
  134. Toyoda, T., Adyshev, D. M., Kobayashi, M., Iwata, A., and Ishihama, A. (1996). Molecular assembly of the influenza virus RNA polymerase: determination of the subunit-subunit contact sites. J Gen Virol 77 ( Pt 9), 2149-57.
  135. Hatta, M., Gao, P., Halfmann, P., and Kawaoka, Y. (2001). Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293(5536), 1840-2.
  136. Puthavathana, P., Auewarakul, P., Charoenying, P. C., Sangsiriwut, K., Pooruk, P., Boonnak, K., Khanyok, R., Thawachsupa, P., Kijphati, R., and Sawanpanyalert, P. (2005). Molecular characterization of the complete genome of human influenza H5N1 virus isolates from Thailand. J Gen Virol 86(Pt 2), 423-33.
  137. Mena, I., Jambrina, E., Albo, C., Perales, B., Ortin, J., Arrese, M., Vallejo, D., and Portela, A. (1999). Mutational analysis of influenza A virus nucleoprotein: identification of mutations that affect RNA replication. J Virol 73(2), 1186-94.
  138. Biswas, S. K., and Nayak, D. P. (1994). Mutational analysis of the conserved motifs of influenza A virus polymerase basic protein 1. J Virol 68(3), 1819-26.
  139. Matrosovich, M., and Klenk, H.-D. (2003). Natural and synthetic sialic acid-containing inhibitors of influenza virus receptor binding. Reviews in Medical Virology 13(2), 85- 97.
  140. Matrosovich, M., Matrosovich, T., Garten, W., and Klenk, H. D. (2006). New low-viscosity overlay medium for viral plaque assays. Virol J 3, 63. Matrosovich, M., Zhou, N., Kawaoka, Y., and Webster, R. (1999). The surface glycoproteins of H5 influenza viruses isolated from humans, chickens, and wild aquatic birds have distinguishable properties. J Virol 73(2), 1146-55.
  141. O'Neill, R. E., Jaskunas, R., Blobel, G., Palese, P., and 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), 22701-4.
  142. Whittaker, G., Bui, M., and Helenius, A. (1996a). Nuclear trafficking of influenza virus ribonuleoproteins in heterokaryons. J Virol 70(5), 2743-56.
  143. Palese, P., and Shaw, M. L. (2007). "Orthomyxoviridae: The Viruses and Their Replication." 5th ed. Fields Virology (D. M. Knipe, and P. M. Howley, Eds.), 2. 2 vols. Lippincott Williams & Wilkins, Philadelphia, PA.
  144. Scheiblauer, H., Kendal, A. P., and Rott, R. (1995). Pathogenicity of influenza A/Seal/Mass/1/80 virus mutants for mammalian species. Arch Virol 140(2), 341-8.
  145. Bloom, J. D., Gong, L. I., and Baltimore, D. (2010). Permissive secondary mutations enable the evolution of influenza oseltamivir resistance. Science 328(5983), 1272-5.
  146. Phylogenetic analyses of highly pathogenic avian influenza virus isolates from 150
  147. Scholtissek, C. (1990). Pigs as 'Mixing Vessels' for the Creation of New Pandemic Influenza A Viruses. Med Principles Pract 1990/1991(2), 65-71.
  148. Morens, David M., Taubenberger, Jeffery K., and Fauci, Anthony S. (2008). Predominant Role of Bacterial Pneumonia as a Cause of Death in Pandemic Influenza: Implications for Pandemic Influenza Preparedness. The Journal of Infectious Diseases 198(7), 962-970.
  149. Chan, M. C., Cheung, C. Y., Chui, W. H., Tsao, S. W., Nicholls, J. M., Chan, Y. O., Chan, R. W., Long, H. T., Poon, L. L., Guan, Y., and Peiris, J. S. (2005). Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir Res 6, 135.
  150. Connor, R. J., Kawaoka, Y., Webster, R. G., and Paulson, J. C. (1994). Receptor specificity in human, avian, and equine H2 and H3 influenza virus isolates. Virology 205(1), 17-23.
  151. Bourmakina, and Garcia-Sastre (2003). Reverse genetics studies on the filamentous morphology of influenza A virus. Journal of General Virology 84(3), 517-527.
  152. Steinhauer, D. A. (1999). Role of hemagglutinin cleavage for the pathogenicity of influenza virus. Virology 258(1), 1-20.
  153. Ulmanen, I., Broni, B. A., and Krug, R. M. (1981). Role of two of the influenza virus core P proteins in recognizing cap 1 structures (m7GpppNm) on RNAs and in initiating viral RNA transcription. Proc Natl Acad Sci U S A 78(12), 7355-9.
  154. Sugiyama, K., Obayashi, E., Kawaguchi, A., Suzuki, Y., Tame, J. R. H., Nagata, K., and Park, S.-Y. (2009). Structural insight into the essential PB1–PB2 subunit contact of the influenza virus RNA polymerase. The EMBO Journal 28(12), 1803-1811.
  155. Tarendeau, F., Boudet, J., Guilligay, D., Mas, P. J., Bougault, C. M., Boulo, S., Baudin, F., Ruigrok, R. W. H., Daigle, N., Ellenberg, J., Cusack, S., Simorre, J.-P., and Hart, D. J. (2007). Structure and nuclear import function of the C-terminal domain of influenza virus polymerase PB2 subunit. Nature Structural & Molecular Biology 14(3), 229- 233.
  156. Baudin, F., Bach, C., Cusack, S., and Ruigrok, R. W. (1994). Structure of influenza virus RNP. I. Influenza virus nucleoprotein melts secondary structure in panhandle RNA and exposes the bases to the solvent. EMBO J 13(13), 3158-65.
  157. Ng, A. K. L., Zhang, H., Tan, K., Li, Z., Liu, J. h., Chan, P. K. S., Li, S. M., Chan, W. Y., Au, S. W. N., Joachimiak, A., Walz, T., Wang, J. H., and Shaw, P. C. (2008). Structure of the influenza virus A H5N1 nucleoprotein: implications for RNA binding, oligomerization, and vaccine design. The FASEB Journal 22(10), 3638-3647.
  158. Shih, S. R., and Krug, R. M. (1996). Surprising function of the three influenza viral polymerase proteins: selective protection of viral mRNAs against the cap-snatching reaction catalyzed by the same polymerase proteins. Virology 226(2), 430-5.
  159. Corden, J. L. (1990). Tails of RNA polymerase II. Trends Biochem Sci 15(10), 383-7.
  160. Li, M. L., Rao, P., and Krug, R. M. (2001). The active sites of the influenza cap-dependent endonuclease are on different polymerase subunits. EMBO J 20(8), 2078-86.
  161. Duan, L., Bahl, J., Smith, G., Wang, J., Vijaykrishna, D., Zhang, L., Zhang, J., Li, K., Fan, X., and Cheung, C. (2008). The development and genetic diversity of H5N1 influenza virus in China, 1996–2006. Virology 380(2), 243-254.
  162. Dugan, V. G., Chen, R., Spiro, D. J., Sengamalay, N., Zaborsky, J., Ghedin, E., Nolting, J., Swayne, D. E., Runstadler, J. A., Happ, G. M., Senne, D. A., Wang, R., Slemons, R. D., Holmes, E. C., and Taubenberger, J. K. (2008). The evolutionary genetics and emergence of avian influenza viruses in wild birds. PLoS Pathog 4(5), e1000076.
  163. Lupiani, B., and Reddy, S. M. (2009). The history of avian influenza. Comp Immunol Microbiol Infect Dis 32(4), 311-23.
  164. Resa-Infante, P., Jorba, N., Zamarreno, N., Fernandez, Y., Juarez, S., and 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.
  165. Resa-Infante, P., Jorba, N., Coloma, R., and Ortin, J. (2011). The influenza virus RNA synthesis machine: advances in its structure and function. RNA Biol 8(2), 207-15.
  166. Ye, Q., Krug, R. M., and Tao, Y. J. (2006). The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA. Nature 444(7122), 1078-1082.
  167. Hinshaw, V. S., Webster, R. G., and Turner, B. (1980). The perpetuation of orthomyxoviruses and paramyxoviruses in Canadian waterfowl. Can J Microbiol 26(5), 622-9.
  168. Salomon, R., Franks, J., Govorkova, E. A., Ilyushina, N. A., Yen, H. L., Hulse-Post, D. J., Humberd, J., Trichet, M., Rehg, J. E., Webby, R. J., Webster, R. G., and 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), 689-97.
  169. Whittaker, G., Bui, M., and Helenius, A. (1996b). The role of nuclear import and export in influenza virus infection. Trends Cell Biol 6(2), 67-71.
  170. Obayashi, E., Yoshida, H., Kawai, F., Shibayama, N., Kawaguchi, A., Nagata, K., Tame, J. R. H., and Park, S.-Y. (2008). The structural basis for an essential subunit interaction in influenza virus RNA polymerase. Nature 454(7208), 1127-1131.
  171. Guilligay, D., Tarendeau, F., Resa-Infante, P., Coloma, R., Crepin, T., Sehr, P., Lewis, J., Ruigrok, R. W., Ortin, J., Hart, D. J., and Cusack, S. (2008). The structural basis for cap binding by influenza virus polymerase subunit PB2. Nat Struct Mol Biol 15(5), 500-6.
  172. Kandun, I. N., Wibisono, H., Sedyaningsih, E. R., Yusharmen, Hadisoedarsuno, W., Purba, W., Santoso, H., Septiawati, C., Tresnaningsih, E., Heriyanto, B., Yuwono, D., Harun, S., Soeroso, S., Giriputra, S., Blair, P. J., Jeremijenko, A., Kosasih, H., Putnam, S. D., Samaan, G., Silitonga, M., Chan, K. H., Poon, L. L., Lim, W., Klimov, A., Lindstrom, S., Guan, Y., Donis, R., Katz, J., Cox, N., Peiris, M., and Uyeki, T. M. (2006). Three Indonesian clusters of H5N1 virus infection in 2005. N Engl J Med 355(21), 2186-94.
  173. Beaton, A. R., and Krug, R. M. (1986). Transcription antitermination during influenza viral template RNA synthesis requires the nucleocapsid protein and the absence of a 5' capped end. Proc Natl Acad Sci U S A 83(17), 6282-6.
  174. Honda, A., Mizumoto, K., and Ishihama, A. (1999). Two separate sequences of PB2 subunit constitute the RNA cap-binding site of influenza virus RNA polymerase. Genes Cells 4(8), 475-85.
  175. Mukaigawa, J., and Nayak, D. P. (1991). Two signals mediate nuclear localization of influenza virus (A/WSN/33) polymerase basic protein 2. J Virol 65(1), 245-53.
  176. Johnson, N. P., and Mueller, J. (2002). Updating the accounts: global mortality of the 1918- 1920 "Spanish" influenza pandemic. Bull Hist Med 76(1), 105-15.
  177. Zur Erstellung der humanen und aviäre PB2-Konsensus-Sequenz wurden die im Folgenden aufgelisteten Aminosäure-Sequenzen aus der Datenbank http://www. ncbi.nlm.nih.gov/genomes/FLU/FLU.html herangezogen: Humane H5N1 Isolate 2001-2011
  178. Caton, A. J., and Robertson, J. S. (1980). Structure of the host-derived sequences present at the 5' ends of influenza virus mRNA. Nucleic Acids Res 8(12), 2591-603.
  179. Beaton, A. R., and Krug, R. M. (1981). Selected host cell capped RNA fragments prime influenza viral RNA transcription in vivo. Nucleic Acids Res 9(17), 4423-36.
  180. Wong, K. K., Bull, R. A., Rockman, S., Scott, G., Stelzer-Braid, S., and Rawlinson, W. (2011). Correlation of polymerase replication fidelity with genetic evolution of influenza A/Fujian/411/02(H3N2) viruses. J Med Virol 83(3), 510-6.
  181. Wagner, R., Matrosovich, M., and Klenk, H.-D. (2002). Functional balance between haemagglutinin and neuraminidase in influenza virus infections. Reviews in Medical Virology 12(3), 159-166.
  182. Cros, J. F., Garcia-Sastre, A., and Palese, P. (2005). An unconventional NLS is critical for the nuclear import of the influenza A virus nucleoprotein and ribonucleoprotein. Traffic 6(3), 205-13.
  183. Kiss, I., German, P., Sami, L., Antal, M., Farkas, T., Kardos, G., Kecskemeti, S., Dan, A., and Belak, S. (2006). Application of real-time RT-PCR utilising lux (light upon extension) fluorogenic primer for the rapid detection of avian influenza viruses. Acta Vet Hung 54(4), 525-33.
  184. de Jong, J. C., Claas, E. C., Osterhaus, A. D., Webster, R. G., and Lim, W. L. (1997). A pandemic warning? Nature 389(6651), 554.
  185. Dias, A., Bouvier, D., Crépin, T., McCarthy, A. A., Hart, D. J., Baudin, F., Cusack, S., and Ruigrok, R. W. H. (2009). The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature 458(7240), 914-918.
  186. Smith, G. J., Vijaykrishna, D., Bahl, J., Lycett, S. J., Worobey, M., Pybus, O. G., Ma, S. K., Cheung, C. L., Raghwani, J., Bhatt, S., Peiris, J. S., Guan, Y., and Rambaut, A. (2009). Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature 459(7250), 1122-5.
  187. Ito, T., Couceiro, J. N., Kelm, S., Baum, L. G., Krauss, S., Castrucci, M. R., Donatelli, I., Kida, H., Paulson, J. C., Webster, R. G., and Kawaoka, Y. (1998). Molecular basis for the generation in pigs of influenza A viruses with pandemic potential. J Virol 72(9), 7367- 73.
  188. O'Neill, R. E., Talon, J., and Palese, P. (1998). The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins. EMBO J 17(1), 288-96.
  189. Nobusawa, E., and Sato, K. (2006). Comparison of the mutation rates of human influenza A and B viruses. J Virol 80(7), 3675-8.
  190. Bottcher, E., Matrosovich, T., Beyerle, M., Klenk, H. D., Garten, W., and Matrosovich, M. (2006). Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. J Virol 80(19), 9896-8.
  191. Hoffmann, E., Neumann, G., Kawaoka, Y., Hobom, G., and Webster, R. G. (2000a). A DNA transfection system for generation of influenza A virus from eight plasmids. Proc Natl Acad Sci U S A 97(11), 6108-13.
  192. Cheung, C. L., Vijaykrishna, D., Smith, G. J., Fan, X. H., Zhang, J. X., Bahl, J., Duan, L., Huang, K., Tai, H., Wang, J., Poon, L. L., Peiris, J. S., Chen, H., and Guan, Y. (2007). Establishment of influenza A virus (H6N1) in minor poultry species in southern China. J Virol 81(19), 10402-12.
  193. McAuley, J. L., Hornung, F., Boyd, K. L., Smith, A. M., McKeon, R., Bennink, J., Yewdell, J. W., and McCullers, J. A. (2007). Expression of the 1918 Influenza A Virus PB1-F2 Enhances the Pathogenesis of Viral and Secondary Bacterial Pneumonia. Cell Host & Microbe 2(4), 240-249.
  194. Subbarao, E. K., London, W., and Murphy, B. R. (1993). A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J Virol 67(4), 1761-4.
  195. Tarendeau, F., Crepin, T., Guilligay, D., Ruigrok, R. W., Cusack, S., and Hart, D. J. (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.
  196. Harrison, S. C. (2008). Viral membrane fusion. Nat Struct Mol Biol 15(7), 690-8.
  197. Bottcher-Friebertshauser, E., Freuer, C., Sielaff, F., Schmidt, S., Eickmann, M., Uhlendorff, J., Steinmetzer, T., Klenk, H. D., and Garten, W. (2010). Cleavage of influenza virus hemagglutinin by airway proteases TMPRSS2 and HAT differs in subcellular localization and susceptibility to protease inhibitors. J Virol 84(11), 5605-14.
  198. Hsu, M. T., Parvin, J. D., Gupta, S., Krystal, M., and Palese, P. (1987). Genomic RNAs of influenza viruses are held in a circular conformation in virions and in infected cells by a terminal panhandle. Proc Natl Acad Sci U S A 84(22), 8140-4.
  199. 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, G. G., Fodor, E., and Klenk, H.-D. (2011). Differential use of importin-α isoforms governs cell tropism and host adaptation of influenza virus. Nature Communications 2(1), 156.
  200. Fouchier, R. A., Schneeberger, P. M., Rozendaal, F. W., Broekman, J. M., Kemink, S. A., Munster, V., Kuiken, T., Rimmelzwaan, G. F., Schutten, M., Van Doornum, G. J., Koch, G., Bosman, A., Koopmans, M., and Osterhaus, A. D. (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), 1356-61.
  201. Matrosovich, M. N., Matrosovich, T. Y., Gray, T., Roberts, N. A., and Klenk, H. D. (2004). Human and avian influenza viruses target different cell types in cultures of human airway epithelium. Proc Natl Acad Sci U S A 101(13), 4620-4.
  202. Poch, O., Sauvaget, I., Delarue, M., and Tordo, N. (1989). Identification of four conserved motifs among the RNA-dependent polymerase encoding elements. EMBO J 8(12), 3867-74.
  203. Stieneke-Grober, A., Vey, M., Angliker, H., Shaw, E., Thomas, G., Roberts, C., Klenk, H. D., and Garten, W. (1992). Influenza virus hemagglutinin with multibasic cleavage site is activated by furin, a subtilisin-like endoprotease. EMBO J 11(7), 2407-14.
  204. Sanger, F., Nicklen, S., and Coulson, A. R. (1977). DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A 74(12), 5463-7.
  205. Klenk, H. D., Rott, R., Orlich, M., and Blodorn, J. (1975). Activation of influenza A viruses by trypsin treatment. Virology 68(2), 426-39.
  206. Ives, J. A., Carr, J. A., Mendel, D. B., Tai, C. Y., Lambkin, R., Kelly, L., Oxford, J. S., Hayden, F. G., and Roberts, N. A. (2002). The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo. Antiviral Res 55(2), 307-17.

* Das Dokument ist im Internet frei zugänglich - Hinweise zu den Nutzungsrechten
© UB Marburg 1997 - 2024 Universitätsbibliothek Marburg