Letter | Published:

Characterization of the 1918 influenza virus polymerase genes

Naturevolume 437pages889893 (2005) | Download Citation

Subjects

Abstract

The influenza A viral heterotrimeric polymerase complex (PA, PB1, PB2) is known to be involved in many aspects of viral replication and to interact with host factors1, thereby having a role in host specificity2,3. The polymerase protein sequences from the 1918 human influenza virus differ from avian consensus sequences at only a small number of amino acids, consistent with the hypothesis that they were derived from an avian source shortly before the pandemic. However, when compared to avian sequences, the nucleotide sequences of the 1918 polymerase genes have more synonymous differences than expected, suggesting evolutionary distance from known avian strains. Here we present sequence and phylogenetic analyses of the complete genome of the 1918 influenza virus4,5,6,7,8, and propose that the 1918 virus was not a reassortant virus (like those of the 1957 and 1968 pandemics9,10), but more likely an entirely avian-like virus that adapted to humans. These data support prior phylogenetic studies suggesting that the 1918 virus was derived from an avian source11. A total of ten amino acid changes in the polymerase proteins consistently differentiate the 1918 and subsequent human influenza virus sequences from avian virus sequences. Notably, a number of the same changes have been found in recently circulating, highly pathogenic H5N1 viruses that have caused illness and death in humans and are feared to be the precursors of a new influenza pandemic. The sequence changes identified here may be important in the adaptation of influenza viruses to humans.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Fodor, E. & Brownlee, G. G. in Influenza (ed. Potter, C. W.) 1–29 (Elsevier, Amsterdam, 2002)

  2. 2

    Subbarao, E. K., London, W. & Murphy, B. R. A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J. Virol. 67, 1761–1764 (1993)

  3. 3

    Naffakh, N., Massin, P., Escriou, N., Crescenzo-Chaigne, B. & van der Werf, S. Genetic analysis of the compatibility between polymerase proteins from human and avian strains of influenza A viruses. J. Gen. Virol. 81, 1283–1291 (2000)

  4. 4

    Reid, A. H., Fanning, T. G., Hultin, J. V. & Taubenberger, J. K. Origin and evolution of the 1918 “Spanish” influenza virus hemagglutinin gene. Proc. Natl Acad. Sci. USA 96, 1651–1656 (1999)

  5. 5

    Reid, A. H., Fanning, T. G., Janczewski, T. A. & Taubenberger, J. K. Characterization of the 1918 “Spanish” influenza virus neuraminidase gene. Proc. Natl Acad. Sci. USA 97, 6785–6790 (2000)

  6. 6

    Basler, C. F. et al. Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes. Proc. Natl Acad. Sci. USA 98, 2746–2751 (2001)

  7. 7

    Reid, A. H., Fanning, T. G., Janczewski, T. A., McCall, S. & Taubenberger, J. K. Characterization of the 1918 “Spanish” influenza virus matrix gene segment. J. Virol. 76, 10717–10723 (2002)

  8. 8

    Reid, A. H., Fanning, T. G., Janczewski, T. A., Lourens, R. & Taubenberger, J. K. Novel origin of the 1918 pandemic influenza virus nucleoprotein gene segment. J. Virol. 78, 12462–12470 (2004)

  9. 9

    Kawaoka, Y., Krauss, S. & Webster, R. G. Avian-to-human transmission of the PB1 gene of influenza A viruses in the 1957 and 1968 pandemics. J. Virol. 63, 4603–4608 (1989)

  10. 10

    Scholtissek, C., Rohde, W., Von Hoyningen, V. & Rott, R. On the origin of the human influenza virus subtypes H2N2 and H3N2. Virology 87, 13–20 (1978)

  11. 11

    Reid, A. H., Taubenberger, J. K. & Fanning, T. G. Evidence of an absence: the genetic origins of the 1918 pandemic influenza virus. Nature Rev. Microbiol. 2, 909–914 (2004)

  12. 12

    Johnson, N. P. & Mueller, J. Updating the accounts: global mortality of the 1918–1920 “Spanish” influenza pandemic. Bull. Hist. Med. 76, 105–115 (2002)

  13. 13

    Geiss, G. K. et al. Cellular transcriptional profiling in influenza A virus-infected lung epithelial cells: the role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza. Proc. Natl Acad. Sci. USA 99, 10736–10741 (2002)

  14. 14

    Tumpey, T. M. et al. Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus. Proc. Natl Acad. Sci. USA 99, 13849–13854 (2002)

  15. 15

    Tumpey, T. M. et al. Pathogenicity and immunogenicity of influenza viruses with genes from the 1918 pandemic virus. Proc. Natl Acad. Sci. USA 101, 3166–3171 (2004)

  16. 16

    Kash, J. C. et al. The global host immune response: contribution of HA and NA genes from the 1918 Spanish influenza to viral pathogenesis. J. Virol. 78, 9499–9511 (2004)

  17. 17

    Kobasa, D. et al. Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus. Nature 431, 703–707 (2004)

  18. 18

    Chen, W. et al. A novel influenza A virus mitochondrial protein that induces cell death. Nature Med. 7, 1306–1312 (2001)

  19. 19

    Shinya, K. et al. PB2 amino acid at position 627 affects replicative efficiency, but not cell tropism, of Hong Kong H5N1 influenza A viruses in mice. Virology 320, 258–266 (2004)

  20. 20

    Fouchier, R. A. et al. Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc. Natl Acad. Sci. USA 101, 1356–1361 (2004)

  21. 21

    Chen, H. et al. Avian flu: H5N1 virus outbreak in migratory waterfowl. Nature 436, 191–192 (2005)

  22. 22

    Li, K. S. et al. Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature 430, 209–213 (2004)

  23. 23

    Puthavathana, P. et al. Molecular characterization of the complete genome of human influenza H5N1 virus isolates from Thailand. J. Gen. Virol. 86, 423–433 (2005)

  24. 24

    Toyoda, T., Adyshev, D. M., Kobayashi, M., Iwata, A. & Ishihama, A. Molecular assembly of the influenza virus RNA polymerase: determination of the subunit–subunit contact sites. J. Gen. Virol. 77, 2149–2157 (1996)

  25. 25

    Masunaga, K., Mizumoto, K., Kato, H., Ishihama, A. & Toyoda, T. Molecular mapping of influenza virus RNA polymerase by site-specific antibodies. Virology 256, 130–141 (1999)

  26. 26

    Ohtsu, Y., Honda, Y., Sakata, Y., Kato, H. & Toyoda, T. Fine mapping of the subunit binding sites of influenza virus RNA polymerase. Microbiol. Immunol. 46, 167–175 (2002)

  27. 27

    Biswas, S. K. & Nayak, D. P. Mutational analysis of the conserved motifs of influenza A virus polymerase basic protein 1. J. Virol. 68, 1819–1826 (1994)

  28. 28

    Gonzalez, S. & Ortin, J. Distinct regions of influenza virus PB1 polymerase subunit recognize vRNA and cRNA templates. EMBO J. 18, 3767–3775 (1999)

  29. 29

    Guo, Y. J. et al. Characterization of the pathogenicity of members of the newly established H9N2 influenza virus lineages in Asia. Virology 267, 279–288 (2000)

  30. 30

    Holmes, E. C. et al. Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment among recent H3N2 viruses. PLoS Biol. 3, e300 (2005)

Download references

Acknowledgements

The research described in this report was done using stringent safety precautions to protect the laboratory workers, the environment and the public from this virus. The intention of this research is to provide the basis for understanding how influenza pandemic strains form and to help ascertain the risk of future influenza pandemics. This study was partially supported by a grant to J.K.T. from the National Institutes of Health, and by intramural funds from the Armed Forces Institute of Pathology. The opinions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Department of the Army or the US Department of Defense.Author Contributions J.K.T. planned the project, and A.H.R., R.M.L., R.W. and G.J. generated the sequence data. J.K.T., A.H.R. and T.G.F. performed data analysis. J.K.T. wrote the manuscript.

Author information

Author notes

    • Ann H. Reid

    Present address: Board on Life Sciences, The National Academies, 6th Floor, 500 Fifth Street N.W., Washington, DC, 20001, USA

    • Raina M. Lourens

    Present address: University of Iowa, Roy J. and Lucille A. Carver College of Medicine, 200 CMAB, Iowa City, Iowa, 52242, USA

Affiliations

  1. Department of Molecular Pathology, Armed Forces Institute of Pathology, Maryland, 20850, Rockville, USA

    • Jeffery K. Taubenberger
    • , Ann H. Reid
    • , Raina M. Lourens
    • , Ruixue Wang
    • , Guozhong Jin
    •  & Thomas G. Fanning

Authors

  1. Search for Jeffery K. Taubenberger in:

  2. Search for Ann H. Reid in:

  3. Search for Raina M. Lourens in:

  4. Search for Ruixue Wang in:

  5. Search for Guozhong Jin in:

  6. Search for Thomas G. Fanning in:

Competing interests

Coding sequences of the PB2, PB1 and PA genes have been deposited in GenBank under accession numbers DQ208309, DQ208310 and DQ208311, respectively. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Corresponding author

Correspondence to Jeffery K. Taubenberger.

Supplementary information

  1. Supplementary Table

    Influenza sequences used in the analysis (DOC 454 kb)

  2. Supplementary Figure 1

    Complete coding sequence of the 1918 influenza virus PB2 gene segment (DOC 67 kb)

  3. Supplementary Figure 2

    Theoretical translation of the 1918 influenza virus PB1 open reading frame (a) and the PB1-F2 open reading frame (b) as aligned to representative PB1 proteins from other human and animal influenza A viruses. (PPT 46 kb)

  4. Supplementary Figure Legends

    Text to accompany the above Supplementary Figures. (DOC 23 kb)

About this article

Publication history

Received

Accepted

Issue Date

DOI

https://doi.org/10.1038/nature04230

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.