Modulation of innate immune responses by the influenza a NS1 and PA-X proteins

Viruses

Volumn 10, Issue 12, 2018, Pages

  Nogales, Aitor ^a,b   Martinez Sobrido, Luis ^a   Topham, David J ^a   Dediego, Marta L ^a,c  

^a UNIVERSITY OF ROCHESTER MEDICAL CENTER   (United States)

^b Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria Consejo Superior de Investigaciones Científicas   (Spain)

^c CENTRO NACIONAL DE BIOTECNOLOGÍA   (Spain)

Author keywords

Cytokines; Host antiviral response; Host interactions; Influenza a virus; Innate immunity; Interferon; NS1; PA; PA X; Pathogenesis; Vaccine; Virus; Virus evolution

Indexed keywords

CYTOKINE; INFLAMMASOME; INFLUENZA VACCINE; INTERFERON; NUCLEOPROTEIN; PATTERN RECOGNITION RECEPTOR; VIRAL PROTEIN; VIRULENCE FACTOR; INS1 PROTEIN, INFLUENZA VIRUS; PA-X PROTEIN, INFLUENZA A VIRUS; REPRESSOR PROTEIN;

ANTIVIRAL ACTIVITY; DEFENSE MECHANISM; GENE EXPRESSION; IMMUNE RESPONSE; INFLUENZA; INNATE IMMUNITY; NONHUMAN; PROTEIN EXPRESSION; PROTEIN SYNTHESIS; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; UPREGULATION; VACCINATION; VIRUS INFECTION; VIRUS PATHOGENESIS; VIRUS REPLICATION; ANIMAL; HOST PATHOGEN INTERACTION; HUMAN; IMMUNE EVASION; IMMUNOLOGY; INFLUENZA A VIRUS; MOUSE; ORTHOMYXOVIRUS INFECTION; PATHOGENICITY; VIRULENCE;

ANIMALS; HOST-PATHOGEN INTERACTIONS; HUMANS; IMMUNE EVASION; IMMUNITY, INNATE; INFLUENZA A VIRUS; INFLUENZA, HUMAN; INTERFERONS; MICE; ORTHOMYXOVIRIDAE INFECTIONS; REPRESSOR PROTEINS; VIRAL NONSTRUCTURAL PROTEINS; VIRULENCE; VIRUS REPLICATION;

EID: 85058692793     PISSN: None     EISSN: 19994915     Source Type: Journal    
DOI: 10.3390/v10120708     Document Type: Review

References (177)

1. Palese, P.; Shaw, M.L. Orthomyxoviridae: The viruses and their replication. In Fields Virology; Knipe, D., Howley, P., Eds.; Lippincott Williams & Wilkins: Philadelphia, PA, USA, 2006; pp. 1648–1689.
2. Parrish, C.R.; Kawaoka, Y. The origins of new pandemic viruses: The acquisition of new host ranges by canine parvovirus and influenza A viruses. Annu. Rev. Microbiol. 2005, 59, 553–586. [CrossRef] [PubMed]
3. Steel, J.; Lowen, A.C.; Mubareka, S.; Palese, P. Transmission of influenza virus in a mammalian host is increased by PB2 amino acids 627K or 627E/701N. PLoS Pathog. 2009, 5, e1000252. [CrossRef] [PubMed]
4. Bailey, E.S.; Choi, J.Y.; Fieldhouse, J.K.; Borkenhagen, L.K.; Zemke, J.; Zhang, D.; Gray, G.C. The continual threat of influenza virus infections at the human-animal interface: What is new from a one health perspective? Evol. Med. Public Health 2018, 2018, 192–198. [CrossRef] [PubMed]
5. Gonzalez, G.; Marshall, J.F.; Morrell, J.; Robb, D.; McCauley, J.W.; Perez, D.R.; Parrish, C.R.; Murcia, P.R. Infection and pathogenesis of canine, equine, and human influenza viruses in canine tracheas. J. Virol. 2014, 88, 9208–9219. [CrossRef] [PubMed]
6. Thompson, W.W.; Shay, D.K.; Weintraub, E.; Brammer, L.; Cox, N.; Anderson, L.J.; Fukuda, K. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003, 289, 179–186. [CrossRef] [PubMed]
7. Taubenberger, J.K.; Morens, D.M. Influenza: The once and future pandemic. Public Health Rep. 2010, 125 (Suppl. 3), 16–26. [CrossRef] [PubMed]
8. Memorandum, W. A revision of the system of nomenclature for influenza viruses: A WHO memorandum. Bull. World Health Organ. 1980, 58, 585–591.
9. Medina, R.A.; Garcia-Sastre, A. Influenza A viruses: New research developments. Nat. Rev. Microbiol. 2011, 9, 590–603. [CrossRef] [PubMed]
10. Tong, S.; Zhu, X.; Li, Y.; Shi, M.; Zhang, J.; Bourgeois, M.; Yang, H.; Chen, X.; Recuenco, S.; Gomez, J.; et al. New world bats harbor diverse influenza A viruses. PLoS Pathog. 2013, 9, e1003657. [CrossRef]
11. Kuchipudi, S.V.; Nissly, R.H. Novel flu viruses in bats and cattle: “Pushing the Envelope” of Influenza Infection. Vet. Sci. 2018, 5, 71. [CrossRef]
12. Clark, A.M.; DeDiego, M.L.; Anderson, C.S.; Wang, J.; Yang, H.; Nogales, A.; Martinez-Sobrido, L.; Zand, M.S.; Sangster, M.Y.; Topham, D.J. Antigenicity of the 2015–2016 seasonal H1N1 human influenza virus HA and NA proteins. PLoS ONE 2017, 12, e0188267. [CrossRef] [PubMed]
13. Grohskopf, L.A.; Sokolow, L.Z.; Broder, K.R.; Walter, E.B.; Bresee, J.S.; Fry, A.M.; Jernigan, D.B. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices-United States, 2017-18 Influenza Season. Am. J. Transplant. 2017, 17, 2970–2982. [CrossRef] [PubMed]
14. Bui, C.M.; Chughtai, A.A.; Adam, D.C.; MacIntyre, C.R. An overview of the epidemiology and emergence of influenza A infection in humans over time. Arch. Public Health 2017, 75, 15. [CrossRef] [PubMed]
15. Garten, R.J.; Davis, C.T.; Russell, C.A.; Shu, B.; Lindstrom, S.; Balish, A.; Sessions, W.M.; Xu, X.; Skepner, E.; Deyde, V.; et al. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science 2009, 325, 197–201. [CrossRef] [PubMed]
16. Trifonov, V.; Khiabanian, H.; Rabadan, R. Geographic dependence, surveillance, and origins of the 2009 influenza A (H1N1) virus. N. Engl. J. Med. 2009, 361, 115–119. [CrossRef] [PubMed]
17. Su, Y.C.; Bahl, J.; Joseph, U.; Butt, K.M.; Peck, H.A.; Koay, E.S.; Oon, L.L.; Barr, I.G.; Vijaykrishna, D.; Smith, G.J. Phylodynamics of H1N1/2009 influenza reveals the transition from host adaptation to immune-driven selection. Nat. Commun. 2015, 6, 7952. [CrossRef] [PubMed]
18. Anderson, C.S.; Ortega, S.; Chaves, F.A.; Clark, A.M.; Yang, H.; Topham, D.J.; DeDiego, M.L. Natural and directed antigenic drift of the H1 influenza virus hemagglutinin stalk domain. Sci. Rep. 2017, 7, 14614. [CrossRef]
19. Girard, M.P.; Cherian, T.; Pervikov, Y.; Kieny, M.P. A review of vaccine research and development: Human acute respiratory infections. Vaccine 2005, 23, 5708–5724. [CrossRef]
20. Iwasaki, A.; Pillai, P.S. Innate immunity to influenza virus infection. Nat. Rev. Immunol. 2014, 14, 315–328. [CrossRef]
21. Goff, P.H.; Hayashi, T.; He, W.; Yao, S.; Cottam, H.B.; Tan, G.S.; Crain, B.; Krammer, F.; Messer, K.; Pu, M.; et al. Synthetic Toll-Like Receptor 4 (TLR4) and TLR7 Ligands Work Additively via MyD88 To Induce Protective Antiviral Immunity in Mice. J. Virol. 2017, 91, JVI-01050. [CrossRef]
22. Weber-Gerlach, M.; Weber, F. Standing on three legs: Antiviral activities of RIG-I against influenza viruses. Curr. Opin. Immunol. 2016, 42, 71–75. [CrossRef] [PubMed]
23. Pflug, A.; Guilligay, D.; Reich, S.; Cusack, S. Structure of influenza A polymerase bound to the viral RNA promoter. Nature 2014, 516, 355–360. [CrossRef] [PubMed]
24. Wolff, T.; Ludwig, S. Influenza viruses control the vertebrate type I interferon system: Factors, mechanisms, and consequences. J. Interferon Cytokine Res. 2009, 29, 549–557. [CrossRef] [PubMed]
25. Hermant, P.; Michiels, T. Interferon-lambda in the context of viral infections: Production, response and therapeutic implications. J. Innate Immun. 2014, 6, 563–574. [CrossRef] [PubMed]
26. Mogensen, T.H.; Paludan, S.R. Molecular pathways in virus-induced cytokine production. Microbiol. Mol. Biol. Rev. 2001, 65, 131–150. [CrossRef] [PubMed]
27. Crotta, S.; Davidson, S.; Mahlakoiv, T.; Desmet, C.J.; Buckwalter, M.R.; Albert, M.L.; Staeheli, P.; Wack, A. Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia. PLoS Pathog. 2013, 9, e1003773. [CrossRef] [PubMed]
28. Levy, D.E.; Marie, I.J.; Durbin, J.E. Induction and function of type I and III interferon in response to viral infection. Curr. Opin. Virol. 2011, 1, 476–486. [CrossRef]
29. Hoffmann, H.H.; Schneider, W.M.; Rice, C.M. Interferons and viruses: An evolutionary arms race of molecular interactions. Trends Immunol. 2015, 36, 124–138. [CrossRef]
30. Schindler, C.; Levy, D.E.; Decker, T. JAK-STAT signaling: From interferons to cytokines. J. Biol. Chem. 2007, 282, 20059–20063. [CrossRef]
31. Tenoever, B.R.; Ng, S.L.; Chua, M.A.; McWhirter, S.M.; Garcia-Sastre, A.; Maniatis, T. Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity. Science 2007, 315, 1274–1278. [CrossRef]
32. Ng, S.L.; Friedman, B.A.; Schmid, S.; Gertz, J.; Myers, R.M.; tenOever, B.R.; Maniatis, T. I kappa B kinase epsilon (IKK epsilon) regulates the balance between type I and type II interferon responses. Proc. Natl. Acad. Sci. USA 2011, 108, 21170–21175. [CrossRef] [PubMed]
33. Groslambert, M.; Py, B.F. Spotlight on the NLRP3 inflammasome pathway. J. Inflamm. Res. 2018, 11, 359–374. [CrossRef] [PubMed]
34. Guarda, G.; Zenger, M.; Yazdi, A.S.; Schroder, K.; Ferrero, I.; Menu, P.; Tardivel, A.; Mattmann, C.; Tschopp, J. Differential expression of NLRP3 among hematopoietic cells. J. Immunol. 2011, 186, 2529–2534. [CrossRef] [PubMed]
35. Pothlichet, J.; Meunier, I.; Davis, B.K.; Ting, J.P.; Skamene, E.; von Messling, V.; Vidal, S.M. Type I IFN triggers RIG-I/TLR3/NLRP3-dependent inflammasome activation in influenza A virus infected cells. PLoS Pathog. 2013, 9, e1003256. [CrossRef] [PubMed]
36. Ichinohe, T.; Pang, I.K.; Iwasaki, A. Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat. Immunol. 2010, 11, 404–410. [CrossRef] [PubMed]
37. McAuley, J.L.; Tate, M.D.; MacKenzie-Kludas, C.J.; Pinar, A.; Zeng, W.; Stutz, A.; Latz, E.; Brown, L.E.; Mansell, A. Activation of the NLRP3 inflammasome by IAV virulence protein PB1-F2 contributes to severe pathophysiology and disease. PLoS Pathog. 2013, 9, e1003392. [CrossRef] [PubMed]
38. Allen, I.C.; Scull, M.A.; Moore, C.B.; Holl, E.K.; McElvania-TeKippe, E.; Taxman, D.J.; Guthrie, E.H.; Pickles, R.J.; Ting, J.P. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity 2009, 30, 556–565. [CrossRef] [PubMed]
39. Schroder, K.; Tschopp, J. The inflammasomes. Cell 2010, 140, 821–832. [CrossRef]
40. Villalon-Letelier, F.; Brooks, A.G.; Saunders, P.M.; Londrigan, S.L.; Reading, P.C. Host cell restriction factors that limit influenza a infection. Viruses 2017, 9, 376. [CrossRef]
41. Staeheli, P.; Haller, O.; Boll, W.; Lindenmann, J.; Weissmann, C. Mx protein: Constitutive expression in 3T3 cells transformed with cloned Mx cDNA confers selective resistance to influenza virus. Cell 1986, 44, 147–158. [CrossRef]
42. Krug, R.M.; Shaw, M.; Broni, B.; Shapiro, G.; Haller, O. Inhibition of influenza viral mRNA synthesis in cells expressing the interferon-induced Mx gene product. J. Virol. 1985, 56, 201–206. [PubMed]
43. Haller, O.; Arnheiter, H.; Pavlovic, J.; Staeheli, P. The Discovery of the Antiviral Resistance Gene Mx: A Story of Great Ideas, Great Failures, and Some Success. Annu. Rev. Virol. 2018, 5, 33–51. [CrossRef] [PubMed]
44. Turan, K.; Mibayashi, M.; Sugiyama, K.; Saito, S.; Numajiri, A.; Nagata, K. Nuclear MxA proteins form a complex with influenza virus NP and inhibit the transcription of the engineered influenza virus genome. Nucleic Acids Res. 2004, 32, 643–652. [CrossRef] [PubMed]
45. Pavlovic, J.; Arzet, H.A.; Hefti, H.P.; Frese, M.; Rost, D.; Ernst, B.; Kolb, E.; Staeheli, P.; Haller, O. Enhanced virus resistance of transgenic mice expressing the human MxA protein. J. Virol. 1995, 69, 4506–4510. [PubMed]
46. Goujon, C.; Moncorge, O.; Bauby, H.; Doyle, T.; Ward, C.C.; Schaller, T.; Hue, S.; Barclay, W.S.; Schulz, R.; Malim, M.H. Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection. Nature 2013, 502, 559–562. [CrossRef] [PubMed]
47. Brass, A.L.; Huang, I.C.; Benita, Y.; John, S.P.; Krishnan, M.N.; Feeley, E.M.; Ryan, B.J.; Weyer, J.L.; van der Weyden, L.; Fikrig, E.; et al. The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell 2009, 139, 1243–1254. [CrossRef] [PubMed]
48. Bailey, C.C.; Zhong, G.; Huang, I.C.; Farzan, M. IFITM-Family Proteins: The Cell’s First Line of Antiviral Defense. Annu. Rev. Virol. 2014, 1, 261–283. [CrossRef] [PubMed]
49. Diamond, M.S.; Farzan, M. The broad-spectrum antiviral functions of IFIT and IFITM proteins. Nat. Rev. Immunol. 2013, 13, 46–57. [CrossRef] [PubMed]
50. ′ A: A novel oligonucleotide synthesized by interferon-treated L cell extracts. Cell 1978, 13, 565–572. [CrossRef]
51. Silverman, R.H.; Weiss, S.R. Viral phosphodiesterases that antagonize double-stranded RNA signaling to RNase L by degrading 2-5A. J. Interferon Cytokine Res. 2014, 34, 455–463. [CrossRef] [PubMed]
52. Malathi, K.; Dong, B.; Gale, M., Jr.; Silverman, R.H. Small self-RNA generated by RNase L amplifies antiviral innate immunity. Nature 2007, 448, 816–819. [CrossRef] [PubMed]
53. Drappier, M.; Michiels, T. Inhibition of the OAS/RNase L pathway by viruses. Curr. Opin. Virol. 2015, 15, 19–26. [CrossRef] [PubMed]
54. Patel, R.C.; Sen, G.C. PACT, a protein activator of the interferon-induced protein kinase, PKR. EMBO J. 1998, 17, 4379–4390. [CrossRef] [PubMed]
55. Kumar, A.; Haque, J.; Lacoste, J.; Hiscott, J.; Williams, B.R. Double-stranded RNA-dependent protein kinase activates transcription factor NF-kappa B by phosphorylating I kappa B. Proc. Natl. Acad. Sci. USA 1994, 91, 6288–6292. [CrossRef] [PubMed]
56. Schulz, O.; Pichlmair, A.; Rehwinkel, J.; Rogers, N.C.; Scheuner, D.; Kato, H.; Takeuchi, O.; Akira, S.; Kaufman, R.J.; Reis e Sousa, C. Protein kinase R contributes to immunity against specific viruses by regulating interferon mRNA integrity. Cell Host Microbe 2010, 7, 354–361. [CrossRef] [PubMed]
57. Balachandran, S.; Roberts, P.C.; Brown, L.E.; Truong, H.; Pattnaik, A.K.; Archer, D.R.; Barber, G.N. Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity 2000, 13, 129–141. [CrossRef]
58. Lamb, R.A.; Lai, C.J. Sequence of interrupted and uninterrupted mRNAs and cloned DNA coding for the two overlapping nonstructural proteins of influenza virus. Cell 1980, 21, 475–485. [CrossRef]
59. Robb, N.C.; Jackson, D.; Vreede, F.T.; Fodor, E. Splicing of influenza A virus NS1 mRNA is independent of the viral NS1 protein. J. Gen. Virol. 2010, 91, 2331–2340. [CrossRef] [PubMed]
60. Marc, D. Influenza virus non-structural protein NS1: Interferon antagonism and beyond. J. Gen. Virol. 2014, 95, 2594–2611. [CrossRef]
61. Lohrmann, F.; Dijkman, R.; Stertz, S.; Thiel, V.; Haller, O.; Staeheli, P.; Kochs, G. Emergence of a C-terminal seven-amino-acid elongation of NS1 in around 1950 conferred a minor growth advantage to former seasonal influenza A viruses. J. Virol. 2013, 87, 11300–11303. [CrossRef]
62. Chauche, C.; Nogales, A.; Zhu, H.; Goldfarb, D.; Ahmad Shanizza, A.I.; Gu, Q.; Parrish, C.R.; Martinez-Sobrido, L.; Marshall, J.F.; Murcia, P.R. Mammalian adaptation of an avian influenza A virus involves stepwise changes in NS1. J. Virol. 2018, 92, JVI-01875. [CrossRef] [PubMed]
63. Chien, C.Y.; Tejero, R.; Huang, Y.; Zimmerman, D.E.; Rios, C.B.; Krug, R.M.; Montelione, G.T. A novel RNA-binding motif in influenza A virus non-structural protein 1. Nat. Struct. Biol. 1997, 4, 891–895. [CrossRef] [PubMed]
64. Liu, J.; Lynch, P.A.; Chien, C.Y.; Montelione, G.T.; Krug, R.M.; Berman, H.M. Crystal structure of the unique RNA-binding domain of the influenza virus NS1 protein. Nat. Struct. Biol. 1997, 4, 896–899. [CrossRef]
65. Wang, W.; Riedel, K.; Lynch, P.; Chien, C.Y.; Montelione, G.T.; Krug, R.M. RNA binding by the novel helical domain of the influenza virus NS1 protein requires its dimer structure and a small number of specific basic amino acids. RNA 1999, 5, 195–205. [CrossRef] [PubMed]
66. Donelan, N.R.; Basler, C.F.; Garcia-Sastre, A. A recombinant influenza A virus expressing an RNA-binding-defective NS1 protein induces high levels of beta interferon and is attenuated in mice. J. Virol. 2003, 77, 13257–13266. [CrossRef] [PubMed]
67. Greenspan, D.; Palese, P.; Krystal, M. Two nuclear location signals in the influenza virus NS1 nonstructural protein. J. Virol. 1988, 62, 3020–3026. [PubMed]
68. Melen, K.; Kinnunen, L.; Fagerlund, R.; Ikonen, N.; Twu, K.Y.; Krug, R.M.; Julkunen, I. Nuclear and nucleolar targeting of influenza A virus NS1 protein: Striking differences between different virus subtypes. J. Virol. 2007, 81, 5995–6006. [CrossRef]
69. Li, Y.; Yamakita, Y.; Krug, R.M. Regulation of a nuclear export signal by an adjacent inhibitory sequence: The effector domain of the influenza virus NS1 protein. Proc. Natl. Acad. Sci. USA 1998, 95, 4864–4869. [CrossRef]
70. Hale, B.G.; Randall, R.E.; Ortin, J.; Jackson, D. The multifunctional NS1 protein of influenza A viruses. J. Gen. Virol. 2008, 89, 2359–2376. [CrossRef]
71. Nogales, A.; Martinez-Sobrido, L.; Chiem, K.; Topham, D.J.; DeDiego, M.L. Functional Evolution of the 2009 Pandemic H1N1 Influenza NS1 and PA in Humans. J. Virol. 2018, 92, e01206-18. [CrossRef]
72. Nogales, A.; Chauche, C.; DeDiego, M.L.; Topham, D.J.; Parrish, C.R.; Murcia, P.R.; Martinez-Sobrido, L. The K186E Amino Acid Substitution in the Canine Influenza Virus H3N8 NS1 Protein Restores Its Ability to Inhibit Host Gene Expression. J. Virol. 2017, 91, JVI-00877. [CrossRef] [PubMed]
73. Steidle, S.; Martinez-Sobrido, L.; Mordstein, M.; Lienenklaus, S.; Garcia-Sastre, A.; Staheli, P.; Kochs, G. Glycine 184 in nonstructural protein NS1 determines the virulence of influenza A virus strain PR8 without affecting the host interferon response. J. Virol. 2010, 84, 12761–12770. [CrossRef] [PubMed]
74. Kochs, G.; Garcia-Sastre, A.; Martinez-Sobrido, L. Multiple anti-interferon actions of the influenza A virus NS1 protein. J. Virol. 2007, 81, 7011–7021. [CrossRef] [PubMed]
75. Hale, B.G. Conformational plasticity of the influenza A virus NS1 protein. J. Gen. Virol. 2014, 95, 2099–2105. [CrossRef] [PubMed]
76. Jackson, D.; Hossain, M.J.; Hickman, D.; Perez, D.R.; Lamb, R.A. A new influenza virus virulence determinant: The NS1 protein four C-terminal residues modulate pathogenicity. Proc. Natl. Acad. Sci. USA 2008, 105, 4381–4386. [CrossRef] [PubMed]
77. Klemm, C.; Boergeling, Y.; Ludwig, S.; Ehrhardt, C. Immunomodulatory nonstructural proteins of influenza a Viruses. Trends Microbiol. 2018, 26, 624–636. [CrossRef]
78. Garcia-Sastre, A.; Egorov, A.; Matassov, D.; Brandt, S.; Levy, D.E.; Durbin, J.E.; Palese, P.; Muster, T. Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology 1998, 252, 324–330. [CrossRef]
79. Kochs, G.; Koerner, I.; Thiel, L.; Kothlow, S.; Kaspers, B.; Ruggli, N.; Summerfield, A.; Pavlovic, J.; Stech, J.; Staeheli, P. Properties of H7N7 influenza A virus strain SC35M lacking interferon antagonist NS1 in mice and chickens. J. Gen. Virol. 2007, 88, 1403–1409. [CrossRef]
80. Nogales, A.; Huang, K.; Chauche, C.; DeDiego, M.L.; Murcia, P.R.; Parrish, C.R.; Martinez-Sobrido, L. Canine influenza viruses with modified NS1 proteins for the development of live-attenuated vaccines. Virology 2017, 500, 1–10. [CrossRef]
81. Talon, J.; Salvatore, M.; O’Neill, R.E.; Nakaya, Y.; Zheng, H.; Muster, T.; Garcia-Sastre, A.; Palese, P. Influenza A and B viruses expressing altered NS1 proteins: A vaccine approach. Proc. Natl. Acad. Sci. USA 2000, 97, 4309–4314. [CrossRef]
82. Nogales, A.; Baker, S.F.; Ortiz-Riano, E.; Dewhurst, S.; Topham, D.J.; Martinez-Sobrido, L. Influenza A virus attenuation by codon deoptimization of the NS gene for vaccine development. J. Virol. 2014, 88, 10525–10540. [CrossRef]
83. DeDiego, M.L.; Nogales, A.; Lambert-Emo, K.; Martinez-Sobrido, L.; Topham, D.J. NS1 Protein Mutation I64T Affects Interferon Responses and Virulence of Circulating H3N2 Human Influenza A Viruses. J. Virol. 2016, 90, 9693–9711. [CrossRef]
84. Nogales, A.; Martinez-Sobrido, L.; Topham, D.J.; DeDiego, M.L. NS1 Protein Amino Acid Changes D189N and V194I Affect Interferon Responses, Thermosensitivity, and Virulence of Circulating H3N2 Human Influenza A Viruses. J. Virol. 2017, 91, e01930-16. [CrossRef]
85. Trapp, S.; Soubieux, D.; Lidove, A.; Esnault, E.; Lion, A.; Guillory, V.; Wacquiez, A.; Kut, E.; Quere, P.; Larcher, T.; et al. Major contribution of the RNA-binding domain of NS1 in the pathogenicity and replication potential of an avian H7N1 influenza virus in chickens. Virol. J. 2018, 15, 55. [CrossRef]
86. Newby, C.M.; Sabin, L.; Pekosz, A. The RNA binding domain of influenza A virus NS1 protein affects secretion of tumor necrosis factor alpha, interleukin-6, and interferon in primary murine tracheal epithelial cells. J. Virol. 2007, 81, 9469–9480. [CrossRef]
87. Min, J.Y.; Krug, R.M. The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: Inhibiting the 2’-5’ oligo (A) synthetase/RNase L pathway. Proc. Natl. Acad. Sci. USA 2006, 103, 7100–7105. [CrossRef]
88. Mibayashi, M.; Martinez-Sobrido, L.; Loo, Y.M.; Cardenas, W.B.; Gale, M., Jr.; Garcia-Sastre, A. Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. J. Virol. 2007, 81, 514–524. [CrossRef]
89. Guo, Z.; Chen, L.M.; Zeng, H.; Gomez, J.A.; Plowden, J.; Fujita, T.; Katz, J.M.; Donis, R.O.; Sambhara, S. NS1 protein of influenza A virus inhibits the function of intracytoplasmic pathogen sensor, RIG-I. Am. J. Respir. Cell Mol. Biol. 2007, 36, 263–269. [CrossRef]
90. Opitz, B.; Rejaibi, A.; Dauber, B.; Eckhard, J.; Vinzing, M.; Schmeck, B.; Hippenstiel, S.; Suttorp, N.; Wolff, T. IFNbeta induction by influenza A virus is mediated by RIG-I which is regulated by the viral NS1 protein. Cell. Microbiol. 2007, 9, 930–938. [CrossRef]
91. Gack, M.U.; Albrecht, R.A.; Urano, T.; Inn, K.S.; Huang, I.C.; Carnero, E.; Farzan, M.; Inoue, S.; Jung, J.U.; Garcia-Sastre, A. Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe 2009, 5, 439–449. [CrossRef]
92. Rajsbaum, R.; Albrecht, R.A.; Wang, M.K.; Maharaj, N.P.; Versteeg, G.A.; Nistal-Villan, E.; Garcia-Sastre, A.; Gack, M.U. Species-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein. PLoS Pathog. 2012, 8, e1003059. [CrossRef]
93. Koliopoulos, M.G.; Lethier, M.; van der Veen, A.G.; Haubrich, K.; Hennig, J.; Kowalinski, E.; Stevens, R.V.; Martin, S.R.; Reis e Sousa, C.; Cusack, S.; et al. Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition. Nat. Commun. 2018, 9, 1820. [CrossRef]
94. Feng, W.; Sun, X.; Shi, N.; Zhang, M.; Guan, Z.; Duan, M. Influenza a virus NS1 protein induced A20 contributes to viral replication by suppressing interferon-induced antiviral response. Biochem. Biophys. Res. Commun. 2017, 482, 1107–1113. [CrossRef]
95. Maelfait, J.; Roose, K.; Vereecke, L.; Mc Guire, C.; Sze, M.; Schuijs, M.J.; Willart, M.; Ibanez, L.I.; Hammad, H.; Lambrecht, B.N.; et al. A20 Deficiency in Lung Epithelial Cells Protects against Influenza A Virus Infection. PLoS Pathog. 2016, 12, e1005410. [CrossRef]
96. ′ -phosphates. Science 2006, 314, 997–1001. [CrossRef]
97. Marazzi, I.; Ho, J.S.; Kim, J.; Manicassamy, B.; Dewell, S.; Albrecht, R.A.; Seibert, C.W.; Schaefer, U.; Jeffrey, K.L.; Prinjha, R.K.; et al. Suppression of the antiviral response by an influenza histone mimic. Nature 2012, 483, 428–433. [CrossRef]
98. Gao, S.; Song, L.; Li, J.; Zhang, Z.; Peng, H.; Jiang, W.; Wang, Q.; Kang, T.; Chen, S.; Huang, W. Influenza A virus-encoded NS1 virulence factor protein inhibits innate immune response by targeting IKK. Cell. Microbiol. 2012, 14, 1849–1866. [CrossRef]
99. Talon, J.; Horvath, C.M.; Polley, R.; Basler, C.F.; Muster, T.; Palese, P.; Garcia-Sastre, A. Activation of interferon regulatory factor 3 is inhibited by the influenza A virus NS1 protein. J. Virol. 2000, 74, 7989–7996. [CrossRef]
100. Ludwig, S.; Wang, X.; Ehrhardt, C.; Zheng, H.; Donelan, N.; Planz, O.; Pleschka, S.; Garcia-Sastre, A.; Heins, G.; Wolff, T. The influenza A virus NS1 protein inhibits activation of Jun N-terminal kinase and AP-1 transcription factors. J. Virol. 2002, 76, 11166–11171. [CrossRef]
101. Li, S.; Min, J.Y.; Krug, R.M.; Sen, G.C. Binding of the influenza A virus NS1 protein to PKR mediates the inhibition of its activation by either PACT or double-stranded RNA. Virology 2006, 349, 13–21. [CrossRef]
102. Min, J.Y.; Li, S.; Sen, G.C.; Krug, R.M. A site on the influenza A virus NS1 protein mediates both inhibition of PKR activation and temporal regulation of viral RNA synthesis. Virology 2007, 363, 236–243. [CrossRef]
103. Schierhorn, K.L.; Jolmes, F.; Bespalowa, J.; Saenger, S.; Peteranderl, C.; Dzieciolowski, J.; Mielke, M.; Budt, M.; Pleschka, S.; Herrmann, A.; et al. Influenza A Virus Virulence Depends on Two Amino Acids in the N-Terminal Domain of Its NS1 Protein To Facilitate Inhibition of the RNA-Dependent Protein Kinase PKR. J. Virol. 2017, 91, e00198-17. [CrossRef]
104. Tawaratsumida, K.; Phan, V.; Hrincius, E.R.; High, A.A.; Webby, R.; Redecke, V.; Hacker, H. Quantitative proteomic analysis of the influenza A virus nonstructural proteins NS1 and NS2 during natural cell infection identifies PACT as an NS1 target protein and antiviral host factor. J. Virol. 2014, 88, 9038–9048. [CrossRef]
105. Cheong, W.C.; Kang, H.R.; Yoon, H.; Kang, S.J.; Ting, J.P.; Song, M.J. Influenza A Virus NS1 Protein Inhibits the NLRP3 Inflammasome. PLoS ONE 2015, 10, e0126456. [CrossRef]
106. Park, H.S.; Liu, G.; Thulasi Raman, S.N.; Landreth, S.L.; Liu, Q.; Zhou, Y. NS1 Protein of 2009 Pandemic Influenza A Virus Inhibits Porcine NLRP3 Inflammasome-Mediated Interleukin-1 Beta Production by Suppressing ASC Ubiquitination. J. Virol. 2018, 92, JVI-00022. [CrossRef]
107. Moriyama, M.; Chen, I.Y.; Kawaguchi, A.; Koshiba, T.; Nagata, K.; Takeyama, H.; Hasegawa, H.; Ichinohe, T. The RNA-and TRIM25-Binding Domains of Influenza Virus NS1 Protein Are Essential for Suppression of NLRP3 Inflammasome-Mediated Interleukin-1beta Secretion. J. Virol. 2016, 90, 4105–4114. [CrossRef]
108. Das, K.; Ma, L.C.; Xiao, R.; Radvansky, B.; Aramini, J.; Zhao, L.; Marklund, J.; Kuo, R.L.; Twu, K.Y.; Arnold, E.; et al. Structural basis for suppression of a host antiviral response by influenza A virus. Proc. Natl. Acad. Sci. USA 2008, 105, 13093–13098. [CrossRef]
109. ′ end processing of cellular pre-mRNAS. Virology 2003, 307, 386–395. [CrossRef]
110. Nemeroff, M.E.; Barabino, S.M.; Li, Y.; Keller, W.; Krug, R.M. Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3’end formation of cellular pre-mRNAs. Mol. Cell 1998, 1, 991–1000. [CrossRef]
111. Chen, Z.; Li, Y.; Krug, R.M. Influenza A virus NS1 protein targets poly(A)-binding protein II of the cellular 3’-end processing machinery. EMBO J. 1999, 18, 2273–2283. [CrossRef]
112. Tu, J.; Guo, J.; Zhang, A.; Zhang, W.; Zhao, Z.; Zhou, H.; Liu, C.; Chen, H.; Jin, M. Effects of the C-terminal truncation in NS1 protein of the 2009 pandemic H1N1 influenza virus on host gene expression. PLoS ONE 2011, 6, e26175. [CrossRef]
113. Aragon, T.; de la Luna, S.; Novoa, I.; Carrasco, L.; Ortin, J.; Nieto, A. Eukaryotic translation initiation factor 4GI is a cellular target for NS1 protein, a translational activator of influenza virus. Mol. Cell. Biol. 2000, 20, 6259–6268. [CrossRef]
114. Hale, B.G.; Jackson, D.; Chen, Y.H.; Lamb, R.A.; Randall, R.E. Influenza A virus NS1 protein binds p85beta and activates phosphatidylinositol-3-kinase signaling. Proc. Natl. Acad. Sci. USA 2006, 103, 14194–14199. [CrossRef]
115. Li, Y.; Anderson, D.H.; Liu, Q.; Zhou, Y. Mechanism of influenza A virus NS1 protein interaction with the p85beta, but not the p85alpha, subunit of phosphatidylinositol 3-kinase (PI3K) and up-regulation of PI3K activity. J. Biol. Chem. 2008, 283, 23397–23409. [CrossRef]
116. Satterly, N.; Tsai, P.L.; van Deursen, J.; Nussenzveig, D.R.; Wang, Y.; Faria, P.A.; Levay, A.; Levy, D.E.; Fontoura, B.M. Influenza virus targets the mRNA export machinery and the nuclear pore complex. Proc. Natl. Acad. Sci. USA 2007, 104, 1853–1858. [CrossRef]
117. Wang, X.; Li, M.; Zheng, H.; Muster, T.; Palese, P.; Beg, A.A.; Garcia-Sastre, A. Influenza A virus NS1 protein prevents activation of NF-kappaB and induction of alpha/beta interferon. J. Virol. 2000, 74, 11566–11573. [CrossRef]
118. Stasakova, J.; Ferko, B.; Kittel, C.; Sereinig, S.; Romanova, J.; Katinger, H.; Egorov, A. 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. 2005, 86, 185–195. [CrossRef]
119. Ehrhardt, C.; Wolff, T.; Pleschka, S.; Planz, O.; Beermann, W.; Bode, J.G.; Schmolke, M.; Ludwig, S. Influenza A virus NS1 protein activates the PI3K/Akt pathway to mediate antiapoptotic signaling responses. J. Virol. 2007, 81, 3058–3067. [CrossRef]
120. Hrincius, E.R.; Dierkes, R.; Anhlan, D.; Wixler, V.; Ludwig, S.; Ehrhardt, C. Phosphatidylinositol-3-kinase (PI3K) is activated by influenza virus vRNA via the pathogen pattern receptor Rig-I to promote efficient type I interferon production. Cell. Microbiol. 2011, 13, 1907–1919. [CrossRef]
121. Lu, X.; Masic, A.; Liu, Q.; Zhou, Y. Regulation of influenza A virus induced CXCL-10 gene expression requires PI3K/Akt pathway and IRF3 transcription factor. Mol. Immunol. 2011, 48, 1417–1423. [CrossRef]
122. Shin, Y.K.; Li, Y.; Liu, Q.; Anderson, D.H.; Babiuk, L.A.; Zhou, Y. SH3 binding motif 1 in influenza A virus NS1 protein is essential for PI3K/Akt signaling pathway activation. J. Virol. 2007, 81, 12730–12739. [CrossRef]
123. ′ -end processing complex assembly and function. Wiley Interdiscip. Rev. RNA 2011, 2, 321–335. [CrossRef]
124. Levene, R.E.; Gaglia, M.M. Host Shutoff in Influenza A Virus: Many Means to an End. Viruses 2018, 10, 475. [CrossRef]
125. Hale, B.G.; Steel, J.; Medina, R.A.; Manicassamy, B.; Ye, J.; Hickman, D.; Hai, R.; Schmolke, M.; Lowen, A.C.; Perez, D.R.; et al. Inefficient control of host gene expression by the 2009 pandemic H1N1 influenza A virus NS1 protein. J. Virol. 2010, 84, 6909–6922. [CrossRef]
126. Clark, A.M.; Nogales, A.; Martinez-Sobrido, L.; Topham, D.J.; DeDiego, M.L. Functional Evolution of Influenza Virus NS1 Protein in Currently Circulating Human 2009 Pandemic H1N1 Viruses. J. Virol. 2017, 91, JVI-00721. [CrossRef]
127. Hale, B.G.; Steel, J.; Manicassamy, B.; Medina, R.A.; Ye, J.; Hickman, D.; Lowen, A.C.; Perez, D.R.; Garcia-Sastre, A. Mutations in the NS1 C-terminal tail do not enhance replication or virulence of the 2009 pandemic H1N1 influenza A virus. J. Gen. Virol. 2010, 91, 1737–1742. [CrossRef]
128. Anastasina, M.; Le May, N.; Bugai, A.; Fu, Y.; Soderholm, S.; Gaelings, L.; Ohman, T.; Tynell, J.; Kyttanen, S.; Barboric, M.; et al. Influenza virus NS1 protein binds cellular DNA to block transcription of antiviral genes. Biochim. Biophys. Acta 2016, 1859, 1440–1448. [CrossRef]
129. Pica, N.; Langlois, R.A.; Krammer, F.; Margine, I.; Palese, P. NS1-truncated live attenuated virus vaccine provides robust protection to aged mice from viral challenge. J. Virol. 2012, 86, 10293–10301. [CrossRef]
130. Kochs, G.; Martinez-Sobrido, L.; Lienenklaus, S.; Weiss, S.; Garcia-Sastre, A.; Staeheli, P. Strong interferon-inducing capacity of a highly virulent variant of influenza A virus strain PR8 with deletions in the NS1 gene. J. Gen. Virol. 2009, 90, 2990–2994. [CrossRef]
131. Steel, J.; Lowen, A.C.; Pena, L.; Angel, M.; Solorzano, A.; Albrecht, R.; Perez, D.R.; Garcia-Sastre, A.; Palese, P. Live attenuated influenza viruses containing NS1 truncations as vaccine candidates against H5N1 highly pathogenic avian influenza. J. Virol. 2009, 83, 1742–1753. [CrossRef]
132. Baskin, C.R.; Bielefeldt-Ohmann, H.; Garcia-Sastre, A.; Tumpey, T.M.; Van Hoeven, N.; Carter, V.S.; Thomas, M.J.; Proll, S.; Solorzano, A.; Billharz, R.; et al. Functional genomic and serological analysis of the protective immune response resulting from vaccination of macaques with an NS1-truncated influenza virus. J. Virol. 2007, 81, 11817–11827. [CrossRef]
133. Chambers, T.M.; Quinlivan, M.; Sturgill, T.; Cullinane, A.; Horohov, D.W.; Zamarin, D.; Arkins, S.; Garcia-Sastre, A.; Palese, P. Influenza A viruses with truncated NS1 as modified live virus vaccines: Pilot studies of safety and efficacy in horses. Equine Vet. J. 2009, 41, 87–92. [CrossRef]
134. Quinlivan, M.; Zamarin, D.; Garcia-Sastre, A.; Cullinane, A.; Chambers, T.; Palese, P. Attenuation of equine influenza viruses through truncations of the NS1 protein. J. Virol. 2005, 79, 8431–8439. [CrossRef]
135. Ayllon, J.; Domingues, P.; Rajsbaum, R.; Miorin, L.; Schmolke, M.; Hale, B.G.; Garcia-Sastre, A. A single amino acid substitution in the novel H7N9 influenza A virus NS1 protein increases CPSF30 binding and virulence. J. Virol. 2014, 88, 12146–12151. [CrossRef]
136. Spesock, A.; Malur, M.; Hossain, M.J.; Chen, L.M.; Njaa, B.L.; Davis, C.T.; Lipatov, A.S.; York, I.A.; Krug, R.M.; Donis, R.O. The virulence of 1997 H5N1 influenza viruses in the mouse model is increased by correcting a defect in their NS1 proteins. J. Virol. 2011, 85, 7048–7058. [CrossRef]
137. Kuo, R.L.; Zhao, C.; Malur, M.; Krug, R.M. Influenza A virus strains that circulate in humans differ in the ability of their NS1 proteins to block the activation of IRF3 and interferon-beta transcription. Virology 2010, 408, 146–158. [CrossRef]
138. Twu, K.Y.; Kuo, R.L.; Marklund, J.; Krug, R.M. The H5N1 influenza virus NS genes selected after 1998 enhance virus replication in mammalian cells. J. Virol. 2007, 81, 8112–8121. [CrossRef]
139. Kaewborisuth, C.; Kaplan, B.; Zanin, M.; Finkelstein, D.; Webby, R.J.; Lekcharoensuk, P. G45R on nonstructural protein 1 of influenza A virus contributes to virulence by increasing the expression of proinflammatory cytokines in mice. Arch. Virol. 2017, 162, 45–55. [CrossRef]
140. Seo, S.H.; Hoffmann, E.; Webster, R.G. Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nat. Med. 2002, 8, 950–954. [CrossRef]
141. Lipatov, A.S.; Andreansky, S.; Webby, R.J.; Hulse, D.J.; Rehg, J.E.; Krauss, S.; Perez, D.R.; Doherty, P.C.; Webster, R.G.; Sangster, M.Y. Pathogenesis of Hong Kong H5N1 influenza virus NS gene reassortants in mice: The role of cytokines and B-and T-cell responses. J. Gen. Virol. 2005, 86, 1121–1130. [CrossRef]
142. Ramos, I.; Fernandez-Sesma, A. Modulating the Innate Immune Response to Influenza A Virus: Potential Therapeutic Use of Anti-Inflammatory Drugs. Front. Immunol. 2015, 6, 361. [CrossRef]
143. Nogales, A.; Martinez-Sobrido, L. Reverse genetics approaches for the development of influenza vaccines. Int. J. Mol. Sci. 2016, 18, 20. [CrossRef]
144. Belongia, E.A.; Kieke, B.A.; Donahue, J.G.; Greenlee, R.T.; Balish, A.; Foust, A.; Lindstrom, S.; Shay, D.K. Effectiveness of inactivated influenza vaccines varied substantially with antigenic match from the 2004–2005 season to the 2006–2007 season. J. Infect Dis. 2009, 199, 159–167. [CrossRef]
145. Osterholm, M.T.; Kelley, N.S.; Sommer, A.; Belongia, E.A. Efficacy and effectiveness of influenza vaccines: A systematic review and meta-analysis. Lancet Infect. Dis. 2012, 12, 36–44. [CrossRef]
146. Kim, H.; Webster, R.G.; Webby, R.J. Influenza Virus: Dealing with a Drifting and Shifting Pathogen. Viral Immunol. 2018, 31, 174–183. [CrossRef]
147. DeDiego, M.L.; Anderson, C.S.; Yang, H.; Holden-Wiltse, J.; Fitzgerald, T.; Treanor, J.J.; Topham, D.J. Directed selection of influenza virus produces antigenic variants that match circulating human virus isolates and escape from vaccine-mediated immune protection. Immunology 2016, 148, 160–173. [CrossRef]
148. Wong, S.S.; Webby, R.J. Traditional and new influenza vaccines. Clin. Microbiol. Rev. 2013, 26, 476–492. [CrossRef]
149. Belshe, R.B.; Edwards, K.M.; Vesikari, T.; Black, S.V.; Walker, R.E.; Hultquist, M.; Kemble, G.; Connor, E.M.; Group, C.-T.C.E.S. Live attenuated versus inactivated influenza vaccine in infants and young children. N. Engl. J. Med. 2007, 356, 685–696. [CrossRef]
150. Cox, M.M.; Patriarca, P.A.; Treanor, J. FluBlok, a recombinant hemagglutinin influenza vaccine. Influenza Other Respir Viruses 2008, 2, 211–219. [CrossRef]
151. Chan, W.; Zhou, H.; Kemble, G.; Jin, H. The cold adapted and temperature sensitive influenza A/Ann Arbor/6/60 virus, the master donor virus for live attenuated influenza vaccines, has multiple defects in replication at the restrictive temperature. Virology 2008, 380, 304–311. [CrossRef]
152. Zhou, B.; Li, Y.; Belser, J.A.; Pearce, M.B.; Schmolke, M.; Subba, A.X.; Shi, Z.; Zaki, S.R.; Blau, D.M.; Garcia-Sastre, A.; et al. NS-based live attenuated H1N1 pandemic vaccines protect mice and ferrets. Vaccine 2010, 28, 8015–8025. [CrossRef] [PubMed]
153. Mossler, C.; Groiss, F.; Wolzt, M.; Wolschek, M.; Seipelt, J.; Muster, T. Phase I/II trial of a replication-deficient trivalent influenza virus vaccine lacking NS1. Vaccine 2013, 31, 6194–6200. [CrossRef]
154. Du, Y.; Xin, L.; Shi, Y.; Zhang, T.H.; Wu, N.C.; Dai, L.; Gong, D.; Brar, G.; Shu, S.; Luo, J.; et al. Genome-wide identification of interferon-sensitive mutations enables influenza vaccine design. Science 2018, 359, 290–296. [CrossRef] [PubMed]
155. Jagger, B.W.; Wise, H.M.; Kash, J.C.; Walters, K.A.; Wills, N.M.; Xiao, Y.L.; Dunfee, R.L.; Schwartzman, L.M.; Ozinsky, A.; Bell, G.L.; et al. An Overlapping Protein-Coding Region in Influenza A Virus Segment 3 Modulates the Host Response. Science 2012, 337, 199–204. [CrossRef] [PubMed]
156. Resa-Infante, P.; Jorba, N.; Coloma, R.; Ortin, J. The influenza virus RNA synthesis machine: Advances in its structure and function. RNA Biol. 2011, 8, 207–215. [CrossRef]
157. Firth, A.E.; Jagger, B.W.; Wise, H.M.; Nelson, C.C.; Parsawar, K.; Wills, N.M.; Napthine, S.; Taubenberger, J.K.; Digard, P.; Atkins, J.F. Ribosomal frameshifting used in influenza A virus expression occurs within the sequence UCC_UUU_CGU and is in the +1 direction. Open Biol. 2012, 2, 120109. [CrossRef]
158. Shi, M.; Jagger, B.W.; Wise, H.M.; Digard, P.; Holmes, E.C.; Taubenberger, J.K. Evolutionary conservation of the PA-X open reading frame in segment 3 of influenza A virus. J. Virol. 2012, 86, 12411–12413. [CrossRef]
159. Hayashi, T.; MacDonald, L.A.; Takimoto, T. Influenza A Virus Protein PA-X Contributes to Viral Growth and Suppression of the Host Antiviral and Immune Responses. J. Virol. 2015, 89, 6442–6452. [CrossRef]
160. Khaperskyy, D.A.; McCormick, C. Timing Is Everything: Coordinated Control of Host Shutoff by Influenza A Virus NS1 and PA-X Proteins. J. Virol. 2015, 89, 6528–6531. [CrossRef]
161. Khaperskyy, D.A.; Schmaling, S.; Larkins-Ford, J.; McCormick, C.; Gaglia, M.M. Selective Degradation of Host RNA Polymerase II Transcripts by Influenza A Virus PA-X Host Shutoff Protein. PLoS Pathog. 2016, 12, e1005427. [CrossRef]
162. Hu, J.; Ma, C.; Liu, X. PA-X: A key regulator of influenza A virus pathogenicity and host immune responses. Med. Microbiol. Immunol. 2018, 207, 1–15. [CrossRef]
163. Hu, J.; Mo, Y.Q.; Wang, X.Q.; Gu, M.; Hu, Z.L.; Zhong, L.; Wu, Q.W.; Hao, X.L.; Hu, S.L.; Liu, W.B.; et al. PA-X Decreases the Pathogenicity of Highly Pathogenic H5N1 Influenza A Virus in Avian Species by Inhibiting Virus Replication and Host Response. J. Virol. 2015, 89, 4126–4142. [CrossRef] [PubMed]
164. Bavagnoli, L.; Cucuzza, S.; Campanini, G.; Rovida, F.; Paolucci, S.; Baldanti, F.; Maga, G. The novel influenza A virus protein PA-X and its naturally deleted variant show different enzymatic properties in comparison to the viral endonuclease PA. Nucleic Acids Res. 2015, 43, 9405–9417. [CrossRef]
165. Gao, H.J.; Xu, G.L.; Sun, Y.P.; Qi, L.; Wang, J.L.; Kong, W.L.; Sun, H.L.; Pu, J.; Chang, K.C.; Liu, J.H. PA-X is a virulence factor in avian H9N2 influenza virus. J. Gen. Virol. 2015, 96, 2587–2594. [CrossRef] [PubMed]
166. Lee, J.; Yu, H.; Li, Y.; Ma, J.; Lang, Y.; Duff, M.; Henningson, J.; Liu, Q.; Li, Y.; Nagy, A.; et al. Impacts of different expressions of PA-X protein on 2009 pandemic H1N1 virus replication, pathogenicity and host immune responses. Virology 2017, 504, 25–35. [CrossRef]
167. Hayashi, T.; Chaimayo, C.; McGuinness, J.; Takimoto, T. Critical Role of the PA-X C-Terminal Domain of Influenza A Virus in Its Subcellular Localization and Shutoff Activity. J. Virol. 2016, 90, 7131–7141. [CrossRef]
168. Desmet, E.A.; Bussey, K.A.; Stone, R.; Takimoto, T. Identification of the N-terminal domain of the influenza virus PA responsible for the suppression of host protein synthesis. J. Virol. 2013, 87, 3108–3118. [CrossRef]
169. Oishi, K.; Yamayoshi, S.; Kawaoka, Y. Mapping of a Region of the PA-X Protein of Influenza A Virus That Is Important for Its Shutoff Activity. J. Virol. 2015, 89, 8661–8665. [CrossRef] [PubMed]
170. Gao, H.; Sun, H.; Hu, J.; Qi, L.; Wang, J.; Xiong, X.; Wang, Y.; He, Q.; Lin, Y.; Kong, W.; et al. Twenty amino acids at the C-terminus of PA-X are associated with increased influenza A virus replication and pathogenicity. J. Gen. Virol. 2015, 96, 2036–2049. [CrossRef]
171. Oishi, K.; Yamayoshi, S.; Kawaoka, Y. Identification of novel amino acid residues of influenza virus PA-X that are important for PA-X shutoff activity by using yeast. Virology 2018, 516, 71–75. [CrossRef]
172. Gao, H.; Sun, Y.; Hu, J.; Qi, L.; Wang, J.; Xiong, X.; Wang, Y.; He, Q.; Lin, Y.; Kong, W.; et al. The contribution of PA-X to the virulence of pandemic 2009 H1N1 and highly pathogenic H5N1 avian influenza viruses. Sci. Rep. 2015, 5, 8262. [CrossRef] [PubMed]
173. Hu, J.; Mo, Y.; Gao, Z.; Wang, X.; Gu, M.; Liang, Y.; Cheng, X.; Hu, S.; Liu, W.; Liu, H.; et al. PA-X-associated early alleviation of the acute lung injury contributes to the attenuation of a highly pathogenic H5N1 avian influenza virus in mice. Med. Microbiol. Immunol. 2016, 205, 381–395. [CrossRef] [PubMed]
174. Nogales, A.; Rodriguez, L.; DeDiego, M.L.; Topham, D.J.; Martinez-Sobrido, L. Interplay of PA-X and NS1 Proteins in Replication and Pathogenesis of a Temperature-Sensitive 2009 Pandemic H1N1 Influenza A Virus. J. Virol. 2017, 91, JVI-00720. [CrossRef] [PubMed]
175. Aydillo, T.; Ayllon, J.; Pavlisin, A.; Martinez-Romero, C.; Tripathi, S.; Mena, I.; Moreira-Soto, A.; Vicente-Santos, A.; Corrales-Aguilar, E.; Schwemmle, M.; et al. Specific Mutations in the PB2 Protein of Influenza A Virus Compensate for the Lack of Efficient Interferon Antagonism of the NS1 Protein of Bat Influenza A-Like Viruses. J. Virol. 2018, 92, JVI-02021. [CrossRef] [PubMed]
176. Toback, S.L.; Levin, M.J.; Block, S.L.; Belshe, R.B.; Ambrose, C.S.; Falloon, J. Quadrivalent Ann Arbor strain live-attenuated influenza vaccine. Expert Rev. Vaccines 2012, 11, 1293–1303. [CrossRef]
177. Caspard, H.; Mallory, R.M.; Yu, J.; Ambrose, C.S. Live-attenuated influenza vaccine effectiveness in children from 2009 to 2015–2016: A systematic review and meta-analysis. Open Forum Infect. Dis. 2017, 4, ofx111. [CrossRef] [PubMed]