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研究生： 洪素珍
Hung, Su-Jhen
論文名稱： 流感病毒核蛋白基因變異對病毒複製特性的影響
Effect of genetic variations of influenza virus nucleoprotein on virus replication
指導教授： 王貞仁
Wang, Jen-Ren
學位類別： 碩士
Master
系所名稱： 醫學院 - 醫學檢驗生物技術學系
Department of Medical Laboratory Science and Biotechnology
論文出版年： 2014
畢業學年度： 102
語文別： 英文
論文頁數： 57
中文關鍵詞： A型流感病毒 、核蛋白 、基因變化 、聚合酶活性
外文關鍵詞： Influenza A virus, NP, genetic variation, polymerase activity
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    • A型流感病毒具有基因片段重配及快速突變的特性，不僅造成歷史上多次嚴重的大流行，更季節性地在全球傳播與流行。病毒RNA基因被病毒核蛋白及聚合酶包裹成RNP的結構，這個結構是做為病毒基因片段轉錄和複製的單元。核蛋白在病毒複製時扮演重要且多重的角色，它利用與聚合酶、RNA以及宿主細胞中的分子交互作用來進行調控。在本篇研究中，我們希望了解病毒不斷改變的過程中核蛋白基因序列的演化情形，並探討這樣的變化對於病毒複製特性是否有影響。我們收集了臨床上分離出的A型流感H3N2亞型病毒株，以定序方式得到核蛋白基因序列，再用演化分析法檢視基因的演變。在分析的時段中 (1999至2014年)，核蛋白基因已經延伸出至少六個演化分枝，且造成許多胺基酸的取代。接著，挑選自不同演化分枝的病毒株之核蛋白基因構築在質體上，利用微基因體實驗(mini-genome assay)去分析基因變化對聚合酶活性的影響。結果發現相較於其它來源，來自Taiwan/N1215/07病毒的核蛋白會顯著地有較高的活性；相對地，來自Taiwan/3446/02病毒的核蛋白則有顯著地較低的活性。進一步分析以定點突變法(site-directed mutagenesis)製造的位點突變，發現在攝氏33及37度的溫度條件下，S450G的取代會顯著地增加聚合酶活性，而K31R的取代會降低活性。另外，將它們突變成丙胺酸(alanine)後觀察到聚合酶活性與細胞中病毒生長速度皆亦有顯著地下降，更加確立這兩個位點對病毒複製的影響。綜合以上實驗結果，我們發現了核蛋白演化出的胺基酸變化確實影響了病毒的複製特性，並且證明31及450是可能的重要位點。我們認為持續性的監測核蛋白病毒基因演化對病毒複製特性的影響是非常重要的。

    Influenza A virus causes severe pandemics and annual epidemics through its RNA genome segment reassortment and frequent gene mutations. The RNA together with viral polymerase PB2, PB1, PA and nucleoprotein (NP) form the ribonucleoprotein (RNP) complexes, which are the functional units for viral genome transcription and replication. In RNP, NP plays an important role on polymerase activity by interaction with viral polymerase, vRNA and multiple host factors. Here, we aim to investigate the NP genetic evolution in human and characterize the effect of identified variations. NP genes of randomly selected H3N2 clinical isolates from 1999 to 2014 were sequenced and many genetic variations were identified. Phylogenetic analysis showed NP genes can be divided into 6 clades. Five NP genes from different clades were cloned into plasmid for the mini-genome assay to analyze the effect of NP genetic variations. The results showed that NP of Taiwan/N1215/07 virus had significantly higher polymerase activity than NP from other isolates; in contrast, NP of Taiwan/N3446/02 had significantly lower polymerase activity both at 33℃ and 37℃. By site-directed mutagenesis, we found that S450G of NP gene increased the polymerase activity but K31R decreased the activity. Furthermore, alanine substitutes of 31 and 450 residues significantly decreased the polymerase activity and virus growth in vitro. In conclusions, by analyzing the genetic variations identified from clinical isolates, we demonstrated that residues 31 and 450 of NP contribute to viral polymerase activity as well as virus replication, indicating the evolutionary genetic variations of NP play roles on functional change of influenza virus.

    Chinese Abstract I Abstract II Acknowledgments III Table of contents IV List of tables VII List of figures VIII List of appendix figures IX Abbreviations X Chapter 1 Introduction 1 1.1 Introduction of influenza viruses 1 1.1.1 Classification and structure of influenza viruses 1 1.1.2 Significance and epidemiology of influenza A viruses 1 1.1.3 Evolution of influenza A viruses 2 1.2 Role of gene segments and translated proteins in influenza virus replication 3 1.2.1 Receptor recognition and endocytosis 3 1.2.2 Membrane fusion and RNA genome release 3 1.2.3 RNA transcription and replication 3 1.2.4 Assembly and viral particle budding 4 1.2.5 Resistance to host immune pressure 4 1.3 Significance of genetic changes in influenza A viruses 5 1.3.1 Surface proteins alteration 5 1.3.2 Internal gene evolution 5 1.4 Character of NP in influenza A viruses 6 1.4.1 Sequence, structure and functional domains of NP 6 1.4.2 Multi-functional roles of NP 6 1.5 Specific aims 7 Chapter 2 Materials and Methods 9 2.1 Materials 9 2.1.1Cell lines 9 2.1.2 Bacteria 9 2.1.3 Primers 9 2.1.3.1 For NP gene amplification 9 2.1.3.2 For NP expression plasmids construction 9 2.1.3.3 For site-directed mutagenesis 10 2.1.4 Plasmids 10 2.1.5 Enzymes 11 2.1.6 Chemicals and reagents 11 2.1.7 Buffers and solutions 12 2.1.8 Kits 13 2.1.9 Instruments 14 2.2 Methods 15 2.2.1 Cell lines and virus isolates 15 2.2.2 NP gene amplified and sequenced 15 2.2.3 Phylogenetic and amino acid substitution analysis 15 2.2.4 Construction of NP expression plasmids and site-directed mutagenesis 16 2.2.5 Mini-genome assay 16 2.2.6 Production of reverse genetics viruses 16 2.2.7 Immunofluorescence stain (IF stain) 17 2.2.8 Virus growth kinetics 17 2.2.9 Plaque assay 17 2.2.10 Analysis of sequences from database 18 2.2.11 Structural modeling of NP 18 Chapter 3 Results 19 3.1 Analyze the NP gene evolution of H3N2 virus isolates from NCKUH 19 3.1.1 Collection of NP gene sequences of H3N2 viruses 19 3.1.2 Analysis of NP gene evolution 19 3.1.3 Analysis of NP amino acid substitutions 19 3.2 Evaluate the effect of genetic variations on polymerase activity 20 3.2.1 Establishment of mini-genome assay 20 3.2.2 Investigation of the effect of NP genetic variations on polymerase activity 21 3.3 Identify determinant of NP on polymerase activity 21 3.3.1 Effect of K31R, S377G and S450G substitutions on NP function 21 3.3.2 Inspection of evolutional change on residue 31, 377 and 450 22 3.3.3 Investigation of the residue 31, 377 and 450 by alanine substitutions 22 3.4 Investigate the effect of substitutions on virus replication 23 3.4.1 Production of reverse genetics viruses with NP mutations 23 3.4.2 Comparison of virus replication 23 3.5 Examine the substitutions on functional domain and structure of NP 24 Chapter 4 Discussion and conclusions 25 References 29

    1. Aggarwal, S., S. Dewhurst, T. Takimoto, and B. Kim. 2011. Biochemical impact of the host adaptation-associated PB2 E627K mutation on the temperature-dependent RNA synthesis kinetics of influenza A virus polymerase complex. The Journal of biological chemistry 286:34504-34513.
    2. Ahn, I., and H. S. Son. 2012. Evolutionary analysis of human-origin influenza A virus (H3N2) genes associated with the codon usage patterns since 1993. Virus genes 44:198-206.
    3. Arranz, R., R. Coloma, F. J. Chichon, J. J. Conesa, J. L. Carrascosa, J. M. Valpuesta, J. Ortin, and J. Martin-Benito. 2012. The structure of native influenza virion ribonucleoproteins. Science (New York, N.Y.) 338:1634-1637.
    4. Beigel, J. H., J. Farrar, A. M. Han, F. G. Hayden, R. Hyer, M. D. de Jong, S. Lochindarat, T. K. Nguyen, T. H. Nguyen, T. H. Tran, A. Nicoll, S. Touch, and K. Y. Yuen. 2005. Avian influenza A (H5N1) infection in humans. The New England journal of medicine 353:1374-1385.
    5. Biswas, S. K., P. L. Boutz, and D. P. Nayak. 1998. Influenza virus nucleoprotein interacts with influenza virus polymerase proteins. Journal of virology 72:5493-5501.
    6. Bloom, J. D., L. I. Gong, and D. Baltimore. 2010. Permissive secondary mutations enable the evolution of influenza oseltamivir resistance. Science (New York, N.Y.) 328:1272-1275.
    7. Brandenburg, B., W. Koudstaal, J. Goudsmit, V. Klaren, C. Tang, M. V. Bujny, H. J. Korse, T. Kwaks, J. J. Otterstrom, J. Juraszek, A. M. van Oijen, R. Vogels, and R. H. Friesen. 2013. Mechanisms of hemagglutinin targeted influenza virus neutralization. PloS one 8:e80034.
    8. Bullough, P. A., F. M. Hughson, J. J. Skehel, and D. C. Wiley. 1994. Structure of influenza haemagglutinin at the pH of membrane fusion. Nature 371:37-43.
    9. Chan, P. K. 2002. Outbreak of avian influenza A(H5N1) virus infection in Hong Kong in 1997. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 34 Suppl 2:S58-64.
    10. Deyde, V. M., X. Xu, R. A. Bright, M. Shaw, C. B. Smith, Y. Zhang, Y. Shu, L. V. Gubareva, N. J. Cox, and A. I. Klimov. 2007. Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. The Journal of infectious diseases 196:249-257.
    11. Eisfeld, A. J., E. Kawakami, T. Watanabe, G. Neumann, and Y. Kawaoka. 2011. RAB11A is essential for transport of the influenza virus genome to the plasma membrane. Journal of virology 85:6117-6126.
    12. Elton, D., E. Medcalf, K. Bishop, and P. Digard. 1999. Oligomerization of the influenza virus nucleoprotein: identification of positive and negative sequence elements. Virology 260:190-200.
    13. Elton, D., L. Medcalf, K. Bishop, D. Harrison, and P. Digard. 1999. Identification of amino acid residues of influenza virus nucleoprotein essential for RNA binding. Journal of virology 73:7357-7367.
    14. Ferguson, N. M., A. P. Galvani, and R. M. Bush. 2003. Ecological and immunological determinants of influenza evolution. Nature 422:428-433.
    15. Fukuda, M., S. Asano, T. Nakamura, M. Adachi, M. Yoshida, M. Yanagida, and E. Nishida. 1997. CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature 390:308-311.
    16. Gabriel, G., A. Herwig, and H. D. Klenk. 2008. Interaction of polymerase subunit PB2 and NP with importin alpha1 is a determinant of host range of influenza A virus. PLoS pathogens 4:e11.
    17. Galiano, M., B. F. Johnson, R. Myers, J. Ellis, R. Daniels, and M. Zambon. 2012. Fatal cases of influenza A(H3N2) in children: insights from whole genome sequence analysis. PloS one 7:e33166.
    18. Gao, R., B. Cao, Y. Hu, Z. Feng, D. Wang, W. Hu, J. Chen, Z. Jie, H. Qiu, K. Xu, X. Xu, H. Lu, W. Zhu, Z. Gao, N. Xiang, Y. Shen, Z. He, Y. Gu, Z. Zhang, Y. Yang, X. Zhao, L. Zhou, X. Li, S. Zou, Y. Zhang, X. Li, L. Yang, J. Guo, J. Dong, Q. Li, L. Dong, Y. Zhu, T. Bai, S. Wang, P. Hao, W. Yang, Y. Zhang, J. Han, H. Yu, D. Li, G. F. Gao, G. Wu, Y. Wang, Z. Yuan, and Y. Shu. 2013. Human infection with a novel avian-origin influenza A (H7N9) virus. The New England journal of medicine 368:1888-1897.
    19. Gubareva, L. V. 2004. Molecular mechanisms of influenza virus resistance to neuraminidase inhibitors. Virus research 103:199-203.
    20. Gubareva, L. V., R. Bethell, G. J. Hart, K. G. Murti, C. R. Penn, and R. G. Webster. 1996. Characterization of mutants of influenza A virus selected with the neuraminidase inhibitor 4-guanidino-Neu5Ac2en. Journal of virology 70:1818-1827.
    21. Hale, B. G., R. E. Randall, J. Ortin, and D. Jackson. 2008. The multifunctional NS1 protein of influenza A viruses. The Journal of general virology 89:2359-2376.
    22. Harrison, S. C. 2008. Viral membrane fusion. Nature structural & molecular biology 15:690-698.
    23. Huang, S. S., D. Banner, Y. Fang, D. C. Ng, T. Kanagasabai, D. J. Kelvin, and A. A. Kelvin. 2011. Comparative analyses of pandemic H1N1 and seasonal H1N1, H3N2, and influenza B infections depict distinct clinical pictures in ferrets. PloS one 6:e27512.
    24. Isoda, N., Y. Tsuda, S. Asakura, M. Okamatsu, Y. Sakoda, and H. Kida. 2012. The nucleoprotein is responsible for intracerebral pathogenicity of A/duck/Mongolia/47/2001 (H7N1) in chicks. Archives of virology 157:2257-2264.
    25. Jackson, D., M. J. Hossain, D. Hickman, D. R. Perez, and R. A. Lamb. 2008. A new influenza virus virulence determinant: the NS1 protein four C-terminal residues modulate pathogenicity. Proceedings of the National Academy of Sciences of the United States of America 105:4381-4386.
    26. Jagger, B. W., M. J. Memoli, Z. M. Sheng, L. Qi, R. J. Hrabal, G. L. Allen, V. G. Dugan, R. Wang, P. Digard, J. C. Kash, and J. K. Taubenberger. 2010. The PB2-E627K mutation attenuates viruses containing the 2009 H1N1 influenza pandemic polymerase. mBio 1.
    27. Johnson, B. F., L. E. Wilson, J. Ellis, A. J. Elliot, W. S. Barclay, R. G. Pebody, J. McMenamin, D. M. Fleming, and M. C. Zambon. 2009. Fatal cases of influenza a in childhood. PloS one 4:e7671.
    28. Koel, B. F., D. F. Burke, T. M. Bestebroer, S. van der Vliet, G. C. Zondag, G. Vervaet, E. Skepner, N. S. Lewis, M. I. Spronken, C. A. Russell, M. Y. Eropkin, A. C. Hurt, I. G. Barr, J. C. de Jong, G. F. Rimmelzwaan, A. D. Osterhaus, R. A. Fouchier, and D. J. Smith. 2013. Substitutions near the receptor binding site determine major antigenic change during influenza virus evolution. Science (New York, N.Y.) 342:976-979.
    29. Li, Q., L. Zhou, M. Zhou, Z. Chen, F. Li, H. Wu, N. Xiang, E. Chen, F. Tang, D. Wang, L. Meng, Z. Hong, W. Tu, Y. Cao, L. Li, F. Ding, B. Liu, M. Wang, R. Xie, R. Gao, X. Li, T. Bai, S. Zou, J. He, J. Hu, Y. Xu, C. Chai, S. Wang, Y. Gao, L. Jin, Y. Zhang, H. Luo, H. Yu, J. He, Q. Li, X. Wang, L. Gao, X. Pang, G. Liu, Y. Yan, H. Yuan, Y. Shu, W. Yang, Y. Wang, F. Wu, T. M. Uyeki, and Z. Feng. 2014. Epidemiology of human infections with avian influenza A(H7N9) virus in China. The New England journal of medicine 370:520-532.
    30. Li, Z., T. Watanabe, M. Hatta, S. Watanabe, A. Nanbo, M. Ozawa, S. Kakugawa, M. Shimojima, S. Yamada, G. Neumann, and Y. Kawaoka. 2009. Mutational analysis of conserved amino acids in the influenza A virus nucleoprotein. Journal of virology 83:4153-4162.
    31. Lin, J. H., S. C. Chiu, J. C. Cheng, H. W. Chang, K. L. Hsiao, Y. C. Lin, H. S. Wu, M. Salemi, and H. F. Liu. 2011. Phylodynamics and molecular evolution of influenza A virus nucleoprotein genes in Taiwan between 1979 and 2009. PloS one 6:e23454.
    32. Lin, J. H., S. C. Chiu, Y. C. Lin, J. C. Cheng, H. S. Wu, M. Salemi, and H. F. Liu. 2013. Exploring the molecular epidemiology and evolutionary dynamics of influenza A virus in Taiwan. PloS one 8:e61957.
    33. Ma, W., R. E. Kahn, and J. A. Richt. 2008. The pig as a mixing vessel for influenza viruses: Human and veterinary implications. Journal of molecular and genetic medicine : an international journal of biomedical research 3:158-166.
    34. Manz, B., M. Schwemmle, and L. Brunotte. 2013. Adaptation of avian influenza A virus polymerase in mammals to overcome the host species barrier. Journal of virology 87:7200-7209.
    35. Matrosovich, M., A. Tuzikov, N. Bovin, A. Gambaryan, A. Klimov, M. R. Castrucci, I. Donatelli, and Y. Kawaoka. 2000. Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals. Journal of virology 74:8502-8512.
    36. Moeller, A., R. N. Kirchdoerfer, C. S. Potter, B. Carragher, and I. A. Wilson. 2012. Organization of the influenza virus replication machinery. Science (New York, N.Y.) 338:1631-1634.
    37. Ng, A. K., J. H. Wang, and P. C. Shaw. 2009. Structure and sequence analysis of influenza A virus nucleoprotein. Science in China. Series C, Life sciences / Chinese Academy of Sciences 52:439-449.
    38. Ng, A. K., H. Zhang, K. Tan, Z. Li, J. H. Liu, P. K. Chan, S. M. Li, W. Y. Chan, S. W. Au, A. Joachimiak, T. Walz, J. H. Wang, and P. C. Shaw. 2008. Structure of the influenza virus A H5N1 nucleoprotein: implications for RNA binding, oligomerization, and vaccine design. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22:3638-3647.
    39. Ohkura, T., F. Momose, R. Ichikawa, K. Takeuchi, and Y. Morikawa. 2014. Influenza A virus hemagglutinin and neuraminidase mutually accelerate their apical targeting through clustering of lipid rafts. Journal of virology.
    40. Ozawa, M., K. Fujii, Y. Muramoto, S. Yamada, S. Yamayoshi, A. Takada, H. Goto, T. Horimoto, and Y. Kawaoka. 2007. Contributions of two nuclear localization signals of influenza A virus nucleoprotein to viral replication. Journal of virology 81:30-41.
    41. Pinto, L. H., and R. A. Lamb. 2006. The M2 proton channels of influenza A and B viruses. The Journal of biological chemistry 281:8997-9000.
    42. Rambaut, A., O. G. Pybus, M. I. Nelson, C. Viboud, J. K. Taubenberger, and E. C. Holmes. 2008. The genomic and epidemiological dynamics of human influenza A virus. Nature 453:615-619.
    43. Rossman, J. S., and R. A. Lamb. 2011. Influenza virus assembly and budding. Virology 411:229-236.
    44. Sakabe, S., M. Ozawa, R. Takano, K. Iwastuki-Horimoto, and Y. Kawaoka. 2011. Mutations in PA, NP, and HA of a pandemic (H1N1) 2009 influenza virus contribute to its adaptation to mice. Virus research 158:124-129.
    45. Samson, M., A. Pizzorno, Y. Abed, and G. Boivin. 2013. Influenza virus resistance to neuraminidase inhibitors. Antiviral research 98:174-185.
    46. Schmidtke, M., R. Zell, K. Bauer, A. Krumbholz, C. Schrader, J. Suess, and P. Wutzler. 2006. Amantadine resistance among porcine H1N1, H1N2, and H3N2 influenza A viruses isolated in Germany between 1981 and 2001. Intervirology 49:286-293.
    47. Schrauwen, E. J. A., and R. A. M. Fouchier. 2014. Host adaptation and transmission of influenza A viruses in mammals. Emerging Microbes & Infections 3:e9.
    48. Seo, S. H., E. Hoffmann, and R. G. Webster. 2002. Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nature medicine 8:950-954.
    49. Shen, Y. F., Y. H. Chen, S. Y. Chu, M. I. Lin, H. T. Hsu, P. Y. Wu, C. J. Wu, H. W. Liu, F. Y. Lin, G. Lin, P. H. Hsu, A. S. Yang, Y. S. Cheng, Y. T. Wu, C. H. Wong, and M. D. Tsai. 2011. E339...R416 salt bridge of nucleoprotein as a feasible target for influenza virus inhibitors. Proceedings of the National Academy of Sciences of the United States of America 108:16515-16520.
    50. Smith, D. J., A. S. Lapedes, J. C. de Jong, T. M. Bestebroer, G. F. Rimmelzwaan, A. D. Osterhaus, and R. A. Fouchier. 2004. Mapping the antigenic and genetic evolution of influenza virus. Science (New York, N.Y.) 305:371-376.
    51. Solorzano, A., R. J. Webby, K. M. Lager, B. H. Janke, A. Garcia-Sastre, and J. A. Richt. 2005. Mutations in the NS1 protein of swine influenza virus impair anti-interferon activity and confer attenuation in pigs. Journal of virology 79:7535-7543.
    52. Steel, J., A. C. Lowen, S. Mubareka, and P. Palese. 2009. Transmission of influenza virus in a mammalian host is increased by PB2 amino acids 627K or 627E/701N. PLoS pathogens 5:e1000252.
    53. Tada, T., K. Suzuki, Y. Sakurai, M. Kubo, H. Okada, T. Itoh, and K. Tsukamoto. 2011. Emergence of avian influenza viruses with enhanced transcription activity by a single amino acid substitution in the nucleoprotein during replication in chicken brains. Journal of virology 85:10354-10363.
    54. Tada, T., K. Suzuki, Y. Sakurai, M. Kubo, H. Okada, T. Itoh, and K. Tsukamoto. 2011. NP body domain and PB2 contribute to increased virulence of H5N1 highly pathogenic avian influenza viruses in chickens. Journal of virology 85:1834-1846.
    55. Thompson, W. W., D. K. Shay, E. Weintraub, L. Brammer, N. Cox, L. J. Anderson, and K. Fukuda. 2003. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA : the journal of the American Medical Association 289:179-186.
    56. Thongratsakul, S., Y. Suzuki, H. Hiramatsu, T. Sakpuaram, T. Sirinarumitr, C. Poolkhet, P. Moonjit, R. Yodsheewan, and T. Songserm. 2010. Avian and human influenza A virus receptors in trachea and lung of animals. Asian Pacific journal of allergy and immunology / launched by the Allergy and Immunology Society of Thailand 28:294-301.
    57. Tong, S., X. Zhu, Y. Li, M. Shi, J. Zhang, M. Bourgeois, H. Yang, X. Chen, S. Recuenco, J. Gomez, L. M. Chen, A. Johnson, Y. Tao, C. Dreyfus, W. Yu, R. McBride, P. J. Carney, A. T. Gilbert, J. Chang, Z. Guo, C. T. Davis, J. C. Paulson, J. Stevens, C. E. Rupprecht, E. C. Holmes, I. A. Wilson, and R. O. Donis. 2013. New world bats harbor diverse influenza A viruses. PLoS pathogens 9:e1003657.
    58. Tripathi, S., J. Batra, W. Cao, K. Sharma, J. R. Patel, P. Ranjan, A. Kumar, J. M. Katz, N. J. Cox, R. B. Lal, S. Sambhara, and S. K. Lal. 2013. Influenza A virus nucleoprotein induces apoptosis in human airway epithelial cells: implications of a novel interaction between nucleoprotein and host protein Clusterin. Cell death & disease 4:e562.
    59. Tumpey, T. M., T. R. Maines, N. Van Hoeven, L. Glaser, A. Solorzano, C. Pappas, N. J. Cox, D. E. Swayne, P. Palese, J. M. Katz, and A. Garcia-Sastre. 2007. A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission. Science (New York, N.Y.) 315:655-659.
    60. Turrell, L., J. W. Lyall, L. S. Tiley, E. Fodor, and F. T. Vreede. 2013. The role and assembly mechanism of nucleoprotein in influenza A virus ribonucleoprotein complexes. Nature communications 4:1591.
    61. van den Brand, J. M., K. J. Stittelaar, G. van Amerongen, L. Reperant, L. de Waal, A. D. Osterhaus, and T. Kuiken. 2012. Comparison of temporal and spatial dynamics of seasonal H3N2, pandemic H1N1 and highly pathogenic avian influenza H5N1 virus infections in ferrets. PloS one 7:e42343.
    62. Wasilenko, J. L., L. Sarmento, and M. J. Pantin-Jackwood. 2009. A single substitution in amino acid 184 of the NP protein alters the replication and pathogenicity of H5N1 avian influenza viruses in chickens. Archives of virology 154:969-979.
    63. Westgeest, K. B., C. A. Russell, X. Lin, M. I. Spronken, T. M. Bestebroer, J. Bahl, R. van Beek, E. Skepner, R. A. Halpin, J. C. de Jong, G. F. Rimmelzwaan, A. D. Osterhaus, D. J. Smith, D. E. Wentworth, R. A. Fouchier, and M. de Graaf. 2014. Genomewide analysis of reassortment and evolution of human influenza A(H3N2) viruses circulating between 1968 and 2011. Journal of virology 88:2844-2857.
    64. Wu, Y., Y. Wu, B. Tefsen, Y. Shi, and G. F. Gao. 2014. Bat-derived influenza-like viruses H17N10 and H18N11. Trends in microbiology 22:183-191.
    65. Xu, J., M. C. Christman, R. O. Donis, and G. Lu. 2011. Evolutionary dynamics of influenza A nucleoprotein (NP) lineages revealed by large-scale sequence analyses. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 11:2125-2132.
    66. Ye, J., E. M. Sorrell, Y. Cai, H. Shao, K. Xu, L. Pena, D. Hickman, H. Song, M. Angel, R. A. Medina, B. Manicassamy, A. Garcia-Sastre, and D. R. Perez. 2010. Variations in the hemagglutinin of the 2009 H1N1 pandemic virus: potential for strains with altered virulence phenotype? PLoS pathogens 6:e1001145.
    67. Ye, Q., R. M. Krug, and Y. J. Tao. 2006. The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA. Nature 444:1078-1082.
    68. Zhang, J., A. Pekosz, and R. A. Lamb. 2000. Influenza virus assembly and lipid raft microdomains: a role for the cytoplasmic tails of the spike glycoproteins. Journal of virology 74:4634-4644.
    69. Zheng, W., and Y. J. Tao. 2013. Structure and assembly of the influenza A virus ribonucleoprotein complex. FEBS letters 587:1206-1214.

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