1887

Abstract

Influenza B virus (FLUBV) is an important pathogen that infects humans and causes seasonal influenza epidemics. To date, little is known about defective genomes of FLUBV and their roles in viral replication. In this study, by using a next-generation sequencing approach, we analyzed total mRNAs extracted from A549 cells infected with B/Brisbane/60/2008 virus (Victoria lineage), and identified four defective FLUBV genomes with two (PB1∆A and PB1∆B) from the polymerase basic subunit 1 (PB1) segment and the other two (M∆A and M∆B) from the matrix (M) protein-encoding segment. These defective genomes contained significant deletions in the central regions with each having the potential for encoding a novel polypeptide. Significantly, each of the discovered defective RNAs can potently inhibit the replication of B/Yamanashi/166/98 (Yamagata lineage). Furthermore, PB1∆A was able to interfere modestly with influenza A virus (FLUAV) replication. In summary, our study provides important initial insights into FLUBV defective-interfering genomes, which can be further explored to achieve better understanding of the replication, pathogenesis and evolution of FLUBV.

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2018-04-01
2024-03-29
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References

  1. Palese P, Shaw M. Orthomyxoviridae: the viruses and their replication. In Fields BN, Knipe DM, Howley PM. (editors) Fields Virology Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2007 pp. 1647–1689
    [Google Scholar]
  2. Hause BM, Collin EA, Liu R, Huang B, Sheng Z et al. Characterization of a novel influenza virus in cattle and Swine: proposal for a new genus in the Orthomyxoviridae family. mBio 2014; 5:e00031-14 [View Article][PubMed]
    [Google Scholar]
  3. Hause BM, Ducatez M, Collin EA, Ran Z, Liu R et al. Isolation of a novel swine influenza virus from Oklahoma in 2011 which is distantly related to human influenza C viruses. PLoS Pathog 2013; 9:e1003176 [View Article][PubMed]
    [Google Scholar]
  4. Cox NJ, Subbarao K. Global epidemiology of influenza: past and present. Annu Rev Med 2000; 51:407–421 [View Article][PubMed]
    [Google Scholar]
  5. McCullers JA, Facchini S, Chesney PJ, Webster RG. Influenza B virus encephalitis. Clin Infect Dis 1999; 28:898–900 [View Article][PubMed]
    [Google Scholar]
  6. McCullers JA, Saito T, Iverson AR. Multiple genotypes of influenza B virus circulated between 1979 and 2003. J Virol 2004; 78:12817–12828 [View Article][PubMed]
    [Google Scholar]
  7. Monto AS. Epidemiology of influenza. Vaccine 2008; 26:D45–D48 [View Article][PubMed]
    [Google Scholar]
  8. Paul Glezen W, Schmier JK, Kuehn CM, Ryan KJ, Oxford J. The burden of influenza B: a structured literature review. Am J Public Health 2013; 103:e43e51 [View Article][PubMed]
    [Google Scholar]
  9. Gutiérrez-Pizarraya A, Pérez-Romero P, Alvarez R, Aydillo TA, Osorio-Gómez G et al. Unexpected severity of cases of influenza B infection in patients that required hospitalization during the first postpandemic wave. J Infect 2012; 65:423–430 [View Article][PubMed]
    [Google Scholar]
  10. Wu P, Goldstein E, Ho LM, Yang L, Nishiura H et al. Excess mortality associated with influenza A and B virus in Hong Kong, 1998-2009. J Infect Dis 2012; 206:1862–1871 [View Article][PubMed]
    [Google Scholar]
  11. McCullers JA, Hayden FG. Fatal influenza B infections: time to reexamine influenza research priorities. J Infect Dis 2012; 205:870–872 [View Article][PubMed]
    [Google Scholar]
  12. Paddock CD, Liu L, Denison AM, Bartlett JH, Holman RC et al. Myocardial injury and bacterial pneumonia contribute to the pathogenesis of fatal influenza B virus infection. J Infect Dis 2012; 205:895–905 [View Article][PubMed]
    [Google Scholar]
  13. Osterhaus AD, Rimmelzwaan GF, Martina BE, Bestebroer TM, Fouchier RA. Influenza B virus in seals. Science 2000; 288:1051–1053 [View Article][PubMed]
    [Google Scholar]
  14. Ran Z, Shen H, Lang Y, Kolb EA, Turan N et al. Domestic pigs are susceptible to infection with influenza B viruses. J Virol 2015; 89:4818–4826 [View Article][PubMed]
    [Google Scholar]
  15. Nakagawa N, Higashi N, Nakagawa T. Cocirculation of antigenic variants and the vaccine-type virus during the 2004-2005 influenza B virus epidemics in Japan. J Clin Microbiol 2009; 47:352–357 [View Article][PubMed]
    [Google Scholar]
  16. Nerome R, Hiromoto Y, Sugita S, Tanabe N, Ishida M et al. Evolutionary characteristics of influenza B virus since its first isolation in 1940: dynamic circulation of deletion and insertion mechanism. Arch Virol 1998; 143:1569–1583 [View Article][PubMed]
    [Google Scholar]
  17. Shen J, Kirk BD, Ma J, Wang Q. Diversifying selective pressure on influenza B virus hemagglutinin. J Med Virol 2009; 81:114–124 [View Article][PubMed]
    [Google Scholar]
  18. Lin JH, Chiu SC, Shaw MW, Lin YC, Lee CH et al. Characterization of the epidemic influenza B viruses isolated during 2004-2005 season in Taiwan. Virus Res 2007; 124:204–211 [View Article][PubMed]
    [Google Scholar]
  19. McCullers JA, Wang GC, He S, Webster RG. Reassortment and insertion-deletion are strategies for the evolution of influenza B viruses in nature. J Virol 1999; 73:7343–7348[PubMed]
    [Google Scholar]
  20. Glezen WP. Editorial commentary: Changing epidemiology of influenza B virus. Clin Infect Dis 2014; 59:1525–1526 [View Article][PubMed]
    [Google Scholar]
  21. Vijaykrishna D, Holmes EC, Joseph U, Fourment M, Su YC et al. The contrasting phylodynamics of human influenza B viruses. elife 2015; 4:e05055 [View Article][PubMed]
    [Google Scholar]
  22. Hai R, Schmolke M, Varga ZT, Manicassamy B, Wang TT et al. PB1-F2 expression by the 2009 pandemic H1N1 influenza virus has minimal impact on virulence in animal models. J Virol 2010; 84:4442–4450 [View Article][PubMed]
    [Google Scholar]
  23. 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]
  24. Lamb RA, Lai CJ, Choppin PW. Sequences of mRNAs derived from genome RNA segment 7 of influenza virus: colinear and interrupted mRNAs code for overlapping proteins. Proc Natl Acad Sci USA 1981; 78:4170–4174 [View Article][PubMed]
    [Google Scholar]
  25. Horvath CM, Williams MA, Lamb RA. Eukaryotic coupled translation of tandem cistrons: identification of the influenza B virus BM2 polypeptide. EMBO J 1990; 9:2639–2647[PubMed]
    [Google Scholar]
  26. Robb NC, Fodor E. The accumulation of influenza A virus segment 7 spliced mRNAs is regulated by the NS1 protein. J Gen Virol 2012; 93:113–118 [View Article][PubMed]
    [Google Scholar]
  27. Dubois J, Terrier O, Rosa-Calatrava M. Influenza viruses and mRNA splicing: doing more with less. mBio 2014; 5:e00070-14 [View Article][PubMed]
    [Google Scholar]
  28. Davis AR, Hiti AL, Nayak DP. Influenza defective interfering viral RNA is formed by internal deletion of genomic RNA. Proc Natl Acad Sci USA 1980; 77:215–219 [View Article][PubMed]
    [Google Scholar]
  29. Davis AR, Nayak DP. Sequence relationships among defective interfering influenza viral RNAs. Proc Natl Acad Sci USA 1979; 76:3092–3096 [View Article][PubMed]
    [Google Scholar]
  30. Janda JM, Davis AR, Nayak DP, De BK. Diversity and generation of defective interfering influenza virus particles. Virology 1979; 95:48–58 [View Article][PubMed]
    [Google Scholar]
  31. Nayak DP, Sivasubramanian N, Davis AR, Cortini R, Sung J. Complete sequence analyses show that two defective interfering influenza viral RNAs contain a single internal deletion of a polymerase gene. Proc Natl Acad Sci USA 1982; 79:2216–2220 [View Article][PubMed]
    [Google Scholar]
  32. Noble S, Dimmock NJ. Characterization of putative defective interfering (DI) A/WSN RNAs isolated from the lungs of mice protected from an otherwise lethal respiratory infection with influenza virus A/WSN (H1N1): a subset of the inoculum DI RNAs. Virology 1995; 210:9–19 [View Article][PubMed]
    [Google Scholar]
  33. Odagiri T, Tashiro M. Segment-specific noncoding sequences of the influenza virus genome RNA are involved in the specific competition between defective interfering RNA and its progenitor RNA segment at the virion assembly step. J Virol 1997; 71:2138–2145[PubMed]
    [Google Scholar]
  34. Dimmock NJ, Easton AJ. Defective interfering influenza virus RNAs: time to reevaluate their clinical potential as broad-spectrum antivirals?. J Virol 2014; 88:5217–5227 [View Article][PubMed]
    [Google Scholar]
  35. Dimmock NJ, Easton AJ. Cloned defective interfering influenza RNA and a possible pan-specific treatment of respiratory virus diseases. Viruses 2015; 7:3768–3788 [View Article][PubMed]
    [Google Scholar]
  36. Baum A, Sachidanandam R, García-Sastre A. Preference of RIG-I for short viral RNA molecules in infected cells revealed by next-generation sequencing. Proc Natl Acad Sci USA 2010; 107:16303–16308 [View Article][PubMed]
    [Google Scholar]
  37. Frensing T, Pflugmacher A, Bachmann M, Peschel B, Reichl U. Impact of defective interfering particles on virus replication and antiviral host response in cell culture-based influenza vaccine production. Appl Microbiol Biotechnol 2014; 98:8999–9008 [View Article][PubMed]
    [Google Scholar]
  38. Pérez-Cidoncha M, Killip MJ, Oliveros JC, Asensio VJ, Fernández Y et al. An unbiased genetic screen reveals the polygenic nature of the influenza virus anti-interferon response. J Virol 2014; 88:4632–4646 [View Article][PubMed]
    [Google Scholar]
  39. Ngunjiri JM, Buchek GM, Mohni KN, Sekellick MJ, Marcus PI. Influenza virus subpopulations: exchange of lethal H5N1 virus NS for H1N1 virus NS triggers de novo generation of defective-interfering particles and enhances interferon-inducing particle efficiency. J Interferon Cytokine Res 2013; 33:99–107 [View Article][PubMed]
    [Google Scholar]
  40. Dimmock NJ, Rainsford EW, Scott PD, Marriott AC. Influenza virus protecting RNA: an effective prophylactic and therapeutic antiviral. J Virol 2008; 82:8570–8578 [View Article][PubMed]
    [Google Scholar]
  41. Easton AJ, Scott PD, Edworthy NL, Meng B, Marriott AC et al. A novel broad-spectrum treatment for respiratory virus infections: influenza-based defective interfering virus provides protection against pneumovirus infection in vivo . Vaccine 2011; 29:2777–2784 [View Article][PubMed]
    [Google Scholar]
  42. Scott PD, Meng B, Marriott AC, Easton AJ, Dimmock NJ. Defective interfering influenza A virus protects in vivo against disease caused by a heterologous influenza B virus. J Gen Virol 2011; 92:2122–2132 [View Article][PubMed]
    [Google Scholar]
  43. Bean WJ, Kawaoka Y, Wood JM, Pearson JE, Webster RG. Characterization of virulent and avirulent A/chicken/Pennsylvania/83 influenza A viruses: potential role of defective interfering RNAs in nature. J Virol 1985; 54:151–160[PubMed]
    [Google Scholar]
  44. Chambers TM, Webster RG. Defective interfering virus associated with A/Chicken/Pennsylvania/83 influenza virus. J Virol 1987; 61:1517–1523[PubMed]
    [Google Scholar]
  45. Saira K, Lin X, DePasse JV, Halpin R, Twaddle A et al. Sequence analysis of in vivo defective interfering-like RNA of influenza A H1N1 pandemic virus. J Virol 2013; 87:8064–8074 [View Article][PubMed]
    [Google Scholar]
  46. von Magnus P. Incomplete forms of influenza virus. Adv Virus Res 1954; 2:59–79[PubMed] [Crossref]
    [Google Scholar]
  47. Tobita K, Odagiri T, Tanaka T. Isolation of a novel type of interfering influenza B virus defective in the function of M gene. Arch Virol 1986; 90:223–236 [View Article][PubMed]
    [Google Scholar]
  48. Briedis DJ, Lamb RA. Influenza B virus genome: sequences and structural organization of RNA segment 8 and the mRNAs coding for the NS1 and NS2 proteins. J Virol 1982; 42:186–193[PubMed]
    [Google Scholar]
  49. Sheth N, Roca X, Hastings ML, Roeder T, Krainer AR et al. Comprehensive splice-site analysis using comparative genomics. Nucleic Acids Res 2006; 34:3955–3967 [View Article][PubMed]
    [Google Scholar]
  50. Kawakami E, Watanabe T, Fujii K, Goto H, Watanabe S et al. Strand-specific real-time RT-PCR for distinguishing influenza vRNA, cRNA, and mRNA. J Virol Methods 2011; 173:1–6 [View Article][PubMed]
    [Google Scholar]
  51. Boergeling Y, Rozhdestvensky TS, Schmolke M, Resa-Infante P, Robeck T et al. Evidence for a novel mechanism of influenza virus-induced type I interferon expression by a defective RNA-encoded protein. PLoS Pathog 2015; 11:e1004924 [View Article][PubMed]
    [Google Scholar]
  52. Neumann G, Watanabe T, Ito H, Watanabe S, Goto H et al. Generation of influenza A viruses entirely from cloned cDNAs. Proc Natl Acad Sci USA 1999; 96:9345–9350 [View Article][PubMed]
    [Google Scholar]
  53. Matsuda T, Cepko CL. Electroporation and RNA interference in the rodent retina in vivo and in vitro . Proc Natl Acad Sci USA 2004; 101:16–22 [View Article][PubMed]
    [Google Scholar]
  54. Hoffmann E, Mahmood K, Yang CF, Webster RG, Greenberg HB et al. Rescue of influenza B virus from eight plasmids. Proc Natl Acad Sci USA 2002; 99:11411–11416 [View Article][PubMed]
    [Google Scholar]
  55. Gould PS, Easton AJ, Dimmock NJ. Live attenuated influenza vaccine contains substantial and unexpected amounts of defective viral genomic RNA. Viruses 2017; 9:269 [View Article][PubMed]
    [Google Scholar]
  56. Hsu MT, Parvin JD, Gupta S, Krystal M, Palese P. 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 USA 1987; 84:8140–8144 [View Article][PubMed]
    [Google Scholar]
  57. Jennings PA, Finch JT, Winter G, Robertson JS. Does the higher order structure of the influenza virus ribonucleoprotein guide sequence rearrangements in influenza viral RNA?. Cell 1983; 34:619–627 [View Article][PubMed]
    [Google Scholar]
  58. Wu TD, Nacu S. Fast and SNP-tolerant detection of complex variants and splicing in short reads. Bioinformatics 2010; 26:873–881 [View Article][PubMed]
    [Google Scholar]
  59. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 2009; 25:2078–2079 [View Article][PubMed]
    [Google Scholar]
  60. Anders S, Pyl PT, Huber W. HTSeq–a Python framework to work with high-throughput sequencing data. Bioinformatics 2015; 31:166–169 [View Article][PubMed]
    [Google Scholar]
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