1887

Abstract

Influenza virus causes seasonal epidemics and sporadic pandemics resulting in morbidity, mortality, and economic losses worldwide. Understanding how to regulate influenza virus replication is important for developing vaccine and therapeutic strategies. Identifying microRNAs (miRs) that affect host genes used by influenza virus for replication can support an antiviral strategy. In this study, G-protein coupled receptor (GPCR) and ion channel (IC) host genes in human alveolar epithelial (A549) cells used by influenza virus for replication (Orr-Burks , 2021) were examined as miR target genes following A/CA/04/09- or B/Yamagata/16/1988 replication. Thirty-three miRs were predicted to target GPCR or IC genes and their miR mimics were evaluated for their ability to decrease influenza virus replication. Paired miR inhibitors were used as an ancillary measure to confirm or not the antiviral effects of a miR mimic. Fifteen miRs lowered influenza virus replication and four miRs were found to reduce replication irrespective of virus strain and type differences. These findings provide evidence for novel miR disease intervention strategies for influenza viruses.

Keyword(s): GPCR , influenza , ion channel and microRNA
Funding
This study was supported by the:
  • National Institute of Allergy and Infectious Diseases (NIAID) Centers of Excellence for Influenza Research and Surveillance (CEIRS) (Award HSN2662007000006C)
    • Principle Award Recipient: RalphA. Tripp
  • National Institute of Allergy and Infectious Diseases (NIAID) Centers of Excellence for Influenza Research and Surveillance (CEIRS) (Award HHSN2722014000004C)
    • Principle Award Recipient: RalphA. Tripp
  • This is an open-access article distributed under the terms of the Creative Commons Attribution NonCommercial License.
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2021-11-17
2024-03-29
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References

  1. Jagger BW, Wise HM, Kash JC, Walters K-. A, Wills NM. An overlapping protein-coding region in influenza A virus segment 3 modulates the host response. Science 2012; 337:199–204 [View Article] [PubMed]
    [Google Scholar]
  2. Shi M, Jagger BW, Wise HM, Digard P, Holmes EC et al. Evolutionary conservation of the PA-X open reading frame in segment 3 of influenza A virus. J Virol 2012; 86:12411–12413 [View Article] [PubMed]
    [Google Scholar]
  3. Wise HM, Barbezange C, Jagger BW, Dalton RM, Gog JR et al. Overlapping signals for translational regulation and packaging of influenza A virus segment 2. Nucleic Acids Res 2011; 39:7775–7790 [View Article] [PubMed]
    [Google Scholar]
  4. Wise HM, Foeglein A, Sun J, Dalton RM, Patel S et al. A complicated message: Identification of a novel PB1-related protein translated from influenza A virus segment 2 mRNA. J Virol 2009; 83:8021–8031 [View Article] [PubMed]
    [Google Scholar]
  5. Yamayoshi S, Watanabe M, Goto H, Kawaoka Y. Identification of a novel viral protein expressed from the PB2 segment of influenza A virus. J Virol 2016; 90:444–456 [View Article] [PubMed]
    [Google Scholar]
  6. Yang C-W, Chen M-F, Stambas J. Uncovering the potential pan proteomes encoded by genomic strand RNAs of influenza A viruses. PLoS One 2016; 11:e0146936 [View Article]
    [Google Scholar]
  7. Sandbulte MR, Westgeest KB, Gao J, Xu X, Klimov AI et al. Discordant antigenic drift of neuraminidase and hemagglutinin in H1N1 and H3N2 influenza viruses. Proc Natl Acad Sci U S A 2011; 108:20748–20753 [View Article] [PubMed]
    [Google Scholar]
  8. Carrat F, Flahault A. fluenza vaccine: the challenge of antigenic drift. Vaccine 2007; 25:6852–6862 [View Article] [PubMed]
    [Google Scholar]
  9. Shrestha SS, Swerdlow DL, Borse RH, Prabhu VS, Finelli L. Estimating the burden of 2009 pandemic influenza A (H1N1) in the United States (April 2009-April 2010). Clin Infect Dis 2010; 52:S75–S82 [View Article]
    [Google Scholar]
  10. Zimmerman RK, Nowalk MP, Chung J, Jackson ML, Jackson LA et al. 2014-2015 influenza vaccine effectiveness in the United States by vaccine type. Clin Infect Dis 2016; 63:1564–1573 [View Article] [PubMed]
    [Google Scholar]
  11. McKimm-Breschkin JL. fluenza neuraminidase inhibitors: antiviral action and mechanisms of resistance. Influenza Other Respir Viruses 2013; 7 Suppl 1:25–36 [View Article] [PubMed]
    [Google Scholar]
  12. Hussain M, Galvin HD, Haw TY, Nutsford AN, Husain M. Drug resistance in influenza A virus: the epidemiology and management. Infect Drug Resist 2017; 10:121–134 [View Article] [PubMed]
    [Google Scholar]
  13. Samson M, Pizzorno A, Abed Y, Boivin G. fluenza virus resistance to neuraminidase inhibitors. Antiviral Res 2013; 98:174–185 [View Article] [PubMed]
    [Google Scholar]
  14. Sheu TG, Deyde VM, Okomo-Adhiambo M, Garten RJ, Xu X et al. Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide from 2004 to 2008. Antimicrob Agents Chemother 2008; 52:3284–3292 [View Article] [PubMed]
    [Google Scholar]
  15. Omoto S, Speranzini V, Hashimoto T, Noshi T, Yamaguchi H et al. Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Sci Rep 2018; 8:9633 [View Article] [PubMed]
    [Google Scholar]
  16. Yang T. Baloxavir marboxil: the first cap-dependent endonuclease inhibitor for the treatment of influenza. Ann Pharmacother 2019; 53:754–759 [View Article] [PubMed]
    [Google Scholar]
  17. Deyde VM, Xu X, Bright RA, Shaw M, Smith CB et al. Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. J Infect Dis 2007; 196:249–257 [View Article] [PubMed]
    [Google Scholar]
  18. Shapira SD, Gat-Viks I, Shum BOV, Dricot A, de Grace MM et al. A physical and regulatory map of host-influenza interactions reveals pathways in H1N1 infection. Cell 2009; 139:1255–1267 [View Article] [PubMed]
    [Google Scholar]
  19. Fujioka Y, Tsuda M, Hattori T, Sasaki J, Sasaki T et al. The Ras-PI3K signaling pathway is involved in clathrin-independent endocytosis and the internalization of influenza viruses. PLoS One 2011; 6:e16324 [View Article] [PubMed]
    [Google Scholar]
  20. Ehrhardt C, Marjuki H, Wolff T, Nürnberg B, Planz O et al. Bivalent role of the phosphatidylinositol-3-kinase (PI3K) during influenza virus infection and host cell defence. Cell Microbiol 2006; 8:1336–1348 [View Article] [PubMed]
    [Google Scholar]
  21. Planz O. Development of cellular signaling pathway inhibitors as new antivirals against influenza. Antiviral Res 2013; 98:457–468 [View Article] [PubMed]
    [Google Scholar]
  22. Bakre A, Andersen LE, Meliopoulos V, Coleman K, Yan X et al. Identification of host kinase genes required for influenza virus replication and the regulatory role of MicroRNAs. PLoS One 2013; 8:e66796 [View Article] [PubMed]
    [Google Scholar]
  23. Meliopoulos VA, Andersen LE, Birrer KF, Simpson KJ, Lowenthal JW et al. Host gene targets for novel influenza therapies elucidated by high‐throughput RNA interference screens. FASEB J 2012; 26:1372–1386 [View Article]
    [Google Scholar]
  24. Meliopoulos VA, Andersen LE, Brooks P, Yan X, Bakre A et al. MicroRNA regulation of human protease genes essential for influenza virus replication. PLoS One 2012; 7:e37169 [View Article] [PubMed]
    [Google Scholar]
  25. Perwitasari O, Johnson S, Yan X, Howerth E, Shacham S et al. Verdinexor, a novel selective inhibitor of nuclear export, reduces influenza a virus replication in vitro and in vivo. J Virol 2014; 88:10228–10243 [View Article] [PubMed]
    [Google Scholar]
  26. Zhang W, Tripp RA. RNA interference inhibits respiratory syncytial virus replication and disease pathogenesis without inhibiting priming of the memory immune response. J Virol 2008; 82:12221–12231 [View Article] [PubMed]
    [Google Scholar]
  27. Karlas A, Machuy N, Shin Y, Pleissner K-P, Artarini A. Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication. Nature 2010; 463:818–822 [View Article] [PubMed]
    [Google Scholar]
  28. Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?. Nat Rev Genet 2008; 9:102–114 [View Article] [PubMed]
    [Google Scholar]
  29. Lee Y, Kim M, Han J, Yeom K-H, Lee S et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J 2004; 23:4051–4060 [View Article] [PubMed]
    [Google Scholar]
  30. Alles J, Fehlmann T, Fischer U, Backes C, Galata V. An estimate of the total number of true human miRNAs. Nucleic Acids Res 2019; 47:3353–3364 [View Article] [PubMed]
    [Google Scholar]
  31. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120:15–20 [View Article] [PubMed]
    [Google Scholar]
  32. Kehl T, Backes C, Kern F, Fehlmann T, Ludwig N et al. About miRNAs, miRNA seeds, target genes and target pathways. Oncotarget 2017; 8:107167–107175 [View Article] [PubMed]
    [Google Scholar]
  33. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009; 136:215–233 [View Article] [PubMed]
    [Google Scholar]
  34. Loveday E-K, Svinti V, Diederich S, Pasick J, Jean F. Temporal- and strain-specific host microRNA molecular signatures associated with swine-origin H1N1 and avian-origin H7N7 influenza A virus infection. J Virol 2012; 86:6109–6122 [View Article] [PubMed]
    [Google Scholar]
  35. Moheimani F, Koops J, Williams T, Reid AT, Hansbro PM et al. fluenza A virus infection dysregulates the expression of microRNA-22 and its targets; CD147 and HDAC4, in epithelium of asthmatics. Respir Res 2018; 19:145 [View Article] [PubMed]
    [Google Scholar]
  36. Makkoch J, Poomipak W, Saengchoowong S, Khongnomnan K, Praianantathavorn K et al. Human microRNAs profiling in response to influenza A viruses (subtypes pH1N1, H3N2, and H5N1). Exp Biol Med (Maywood) 2015; 241:409–420 [View Article]
    [Google Scholar]
  37. Bao Y, Gao Y, Jin Y, Cong W, Pan X et al. MicroRNA expression profiles and networks in mouse lung infected with H1N1 influenza virus. Mol Genet Genomics 2015; 290:1885–1897 [View Article] [PubMed]
    [Google Scholar]
  38. Skalsky RL, Cullen BR. Viruses, microRNAs, and host interactions. Annu Rev Microbiol 2010; 64:123–141 [View Article] [PubMed]
    [Google Scholar]
  39. Umbach JL, Cullen BR. The role of RNAi and microRNAs in animal virus replication and antiviral immunity. Genes Dev 2009; 23:1151–1164 [View Article] [PubMed]
    [Google Scholar]
  40. Nejad C, Stunden HJ, Gantier MP. A guide to miRNAs in inflammation and innate immune responses. FEBS J 2018; 285:3695–3716 [View Article] [PubMed]
    [Google Scholar]
  41. Cullen BR. MicroRNAs as mediators of viral evasion of the immune system. Nat Immunol 2013; 14:205–210 [View Article] [PubMed]
    [Google Scholar]
  42. Orr-Burks NL, Shim B-S, Wu W, Bakre AA, Karpilow J et al. MicroRNA screening identifies miR-134 as a regulator of poliovirus and enterovirus 71 infection. Sci Data 2017; 4:170023 [View Article] [PubMed]
    [Google Scholar]
  43. Orr-Burks N, Murray J, Todd KV, Bakre A, Tripp RA. G-Protein-coupled receptor and ion channel genes used by influenza virus for replication. J Virol 2021; 95:e02410-20 [View Article]
    [Google Scholar]
  44. Christopher AF, Kaur RP, Kaur G, Kaur A, Gupta V et al. MicroRNA therapeutics: Discovering novel targets and developing specific therapy. Perspect Clin Res 2016; 7:68–74 [View Article] [PubMed]
    [Google Scholar]
  45. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 2017; 16:203–222 [View Article] [PubMed]
    [Google Scholar]
  46. Sun X, Tse LV, Ferguson AD, Whittaker GR. Modifications to the hemagglutinin cleavage site control the virulence of a neurotropic H1N1 influenza virus. J Virol 2010; 84:8683–8690 [View Article] [PubMed]
    [Google Scholar]
  47. Woolcock PR. Avian influenza virus isolation and propagation in chicken eggs. Spackman E. eds In Methods in Molecular Biology Vol 436 Humana Press; 2008 pp 35–46 [View Article]
    [Google Scholar]
  48. Reed LJ, Muench H. A simple method of estimating fifty per cent endpoints12. Am J Hyg 1938; 27:493–497 [View Article]
    [Google Scholar]
  49. Klimov A, Balish A, Veguilla V, Sun H, Schiffer J et al. Influenza virus titration, antigenic characterization, and serological methods for antibody detection. Methods Mol Biol 2012; 865:25–51 [View Article] [PubMed]
    [Google Scholar]
  50. Appleyard G, Maber HB. Plaque formation by influenza viruses in the presence of trypsin. J Gen Virol 1974; 25:351–357 [View Article] [PubMed]
    [Google Scholar]
  51. Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 2006; 34:D140–4 [View Article] [PubMed]
    [Google Scholar]
  52. Griffiths-Jones S, Saini HK, Dongen’s VAN, Enright AJ. miRBase: tools for microRNA genomics. Nucleic Acids Res 2008; 36:8 [View Article]
    [Google Scholar]
  53. Pleschka S, Wolff T, Ehrhardt C, Hobom G, Planz O et al. fluenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade. Nat Cell Biol 2001; 3:301–305 [View Article] [PubMed]
    [Google Scholar]
  54. Ludwig S, Wolff T, Ehrhardt C, Wurzer WJ, Reinhardt J et al. MEK inhibition impairs influenza B virus propagation without emergence of resistant variants. FEBS Lett 2004; 561:37–43 [View Article] [PubMed]
    [Google Scholar]
  55. Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 2009; 55:611–622 [View Article] [PubMed]
    [Google Scholar]
  56. Tobita K. Permanent canine kidney (MDCK) cells for isolation and plaque assay of influenza B viruses. Med Microbiol Immunol 1975; 162:23–27 [View Article] [PubMed]
    [Google Scholar]
  57. Tobita K, Sugiura A, Enomote C, Furuyama M. Plaque assay and primary isolation of influenza a viruses in an established line of canine kidney cells (MDCK) in the presence of trypsin. Med Microbiol Immunol 1975; 162:9–14 [View Article] [PubMed]
    [Google Scholar]
  58. Hirst GK. The quantitative determination of influenza virus and antibodies by means of red cell agglutination. J Exp Med 1942; 75:49–64 [View Article] [PubMed]
    [Google Scholar]
  59. Thomson DW, Bracken CP, Szubert JM, Goodall GJ, Stoecklin G. On measuring miRNAs after transient transfection of mimics or antisense inhibitors. PLoS One 2013; 8:e55214 [View Article]
    [Google Scholar]
  60. Wang Z. The Guideline of the Design and Validation of MiRNA Mimics. MicroRNA and Cancer. Methods in Molecular Biology Totowa, NJ: Humana Press; 2011
    [Google Scholar]
  61. Robertson B, Dalby AB, Karpilow J, Khvorova A, Leake D et al. Specificity and functionality of microRNA inhibitors. Silence 2010; 1:1–9 [View Article]
    [Google Scholar]
  62. Wu W, Orr-Burks N, Karpilow J, Tripp RA. Development of improved vaccine cell lines against rotavirus. Sci Data 2017; 4:170021 [View Article] [PubMed]
    [Google Scholar]
  63. Jorquera PA, Mathew C, Pickens J, Williams C, Luczo JM et al. Verdinexor (KPT-335), a selective inhibitor of nuclear export, reduces respiratory syncytial virus replication in vitro. J Virol 2019; 93:e01684-18 [View Article] [PubMed]
    [Google Scholar]
  64. Brooke CB. Biological activities of “Noninfectious” influenza A virus particles. Future Virol 2014; 9:41–51 [View Article] [PubMed]
    [Google Scholar]
  65. Robertson B, Dalby AB, Karpilow J, Khvorova A, Leake D et al. Specificity and functionality of microRNA inhibitors. Silence 2010; 1:10 [View Article] [PubMed]
    [Google Scholar]
  66. Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell 2009; 136:642–655 [View Article] [PubMed]
    [Google Scholar]
  67. Djuranovic S, Nahvi A, Green R. A parsimonious model for gene regulation by miRNAs. Science 2011; 331:550–553 [View Article] [PubMed]
    [Google Scholar]
  68. Davidson BL, McCray PB Jr. Current prospects for RNA interference-based therapies. Nat Rev Genet 2011; 12:329–340 [View Article] [PubMed]
    [Google Scholar]
  69. Carmon KS, Gong X, Lin Q, Thomas A, Liu Q. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proc Natl Acad Sci U S A 2011; 108:11452–11457 [View Article] [PubMed]
    [Google Scholar]
  70. Okinaga S, Slattery D, Humbles A, Zsengeller Z, Morteau O et al. C5L2, a Nonsignaling C5A Binding Protein. Biochemistry 2003; 42:9406–9415 [View Article] [PubMed]
    [Google Scholar]
  71. Van Lith LHC, Oosterom J, Van Elsas A, Zaman GJR. C5a-stimulated recruitment of beta-arrestin2 to the nonsignaling 7-transmembrane decoy receptor C5L2. J Biomol Screen 2009; 14:1067–1075 [View Article] [PubMed]
    [Google Scholar]
  72. Gasparo DE, Catt K, Inagami T, Wright J, Unger T. International union of pharmacology. XXIII The Angiotensin II Receptors. Pharmacological Reviews 2000; 52:415–472
    [Google Scholar]
  73. He W, Miao FJ-P, Lin DC-H, Schwandner RT, Wang Z et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 2004; 429:188–193 [View Article] [PubMed]
    [Google Scholar]
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