1887

Abstract

A multibasic cleavage site (MBCS) in the haemagglutinin (HA) protein of influenza A virus is a key determinant of pathogenicity in chickens, and distinguishes highly pathogenic avian influenza (HPAI) viruses from low pathogenic avian influenza viruses (LPAI). An MBCS has only been detected in viruses of the H5 and H7 subtypes. Here we investigated the phenotype of a human H3N2 virus with an MBCS in HA. Insertion of an MBCS in the H3N2 virus resulted in cleavage of HA and efficient replication in Madin–Darby canine kidney cells in the absence of exogenous trypsin , similar to HPAI H5N1 virus. However, studies in ferrets demonstrated that insertion of the MBCS into HA did not result in increased virus shedding, cellular host range, systemic replication or pathogenicity, as compared with wild-type virus. This study indicates that acquisition of an MBCS alone is insufficient to increase pathogenicity of a prototypical seasonal human H3N2 virus.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.030379-0
2011-06-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jgv/92/6/1410.html?itemId=/content/journal/jgv/10.1099/vir.0.030379-0&mimeType=html&fmt=ahah

References

  1. Belser J. A., Lu X., Maines T. R., Smith C., Li Y., Donis R. O., Katz J. M., Tumpey T. M. 2007; Pathogenesis of avian influenza (H7) virus infection in mice and ferrets: enhanced virulence of Eurasian H7N7 viruses isolated from humans. J Virol 81:11139–11147 [View Article][PubMed]
    [Google Scholar]
  2. Bertram S., Glowacka I., Steffen I., Kühl A., Pöhlmann S. 2010; Novel insights into proteolytic cleavage of influenza virus hemagglutinin. Rev Med Virol 20:298–310 [View Article][PubMed]
    [Google Scholar]
  3. Bodewes R., Rimmelzwaan G. F., Osterhaus A. D. 2010; Animal models for the preclinical evaluation of candidate influenza vaccines. Expert Rev Vaccines 9:59–72 [View Article][PubMed]
    [Google Scholar]
  4. Bogs J., Veits J., Gohrbandt S., Hundt J., Stech O., Breithaupt A., Teifke J. P., Mettenleiter T. C., Stech J. 2010; Highly pathogenic H5N1 influenza viruses carry virulence determinants beyond the polybasic hemagglutinin cleavage site. PLoS ONE 5:e11826 [View Article][PubMed]
    [Google Scholar]
  5. Chen J., Lee K. H., Steinhauer D. A., Stevens D. J., Skehel J. J., Wiley D. C. 1998; Structure of the hemagglutinin precursor cleavage site, a determinant of influenza pathogenicity and the origin of the labile conformation. Cell 95:409–417 [View Article][PubMed]
    [Google Scholar]
  6. de Jong J. C., Claas E. C., Osterhaus A. D., Webster R. G., Lim W. L. 1997; A pandemic warning?. Nature 389:554 [View Article][PubMed]
    [Google Scholar]
  7. de Wit E., Spronken M. I., Bestebroer T. M., Rimmelzwaan G. F., Osterhaus A. D., Fouchier R. A. 2004; Efficient generation and growth of influenza virus A/PR/8/34 from eight cDNA fragments. Virus Res 103:155–161 [View Article][PubMed]
    [Google Scholar]
  8. Fouchier R. A., Schneeberger P. M., Rozendaal F. W., Broekman J. M., Kemink S. A., Munster V., Kuiken T., Rimmelzwaan G. F., Schutten M. et al. 2004; Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc Natl Acad Sci U S A 101:1356–1361 [View Article][PubMed]
    [Google Scholar]
  9. Fouchier R. A., Munster V., Wallensten A., Bestebroer T. M., Herfst S., Smith D., Rimmelzwaan G. F., Olsen B., Osterhaus A. D. 2005; Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls. J Virol 79:2814–2822 [View Article][PubMed]
    [Google Scholar]
  10. Gabriel G., Dauber B., Wolff T., Planz O., Klenk H. D., Stech J. 2005; The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host. Proc Natl Acad Sci U S A 102:18590–18595 [View Article][PubMed]
    [Google Scholar]
  11. Gohrbandt S., Veits J., Hundt J., Bogs J., Breithaupt A., Teifke J. P., Weber S., Mettenleiter T. C., Stech J. 2011; Amino acids adjacent to the haemagglutinin cleavage site are relevant for virulence of avian influenza viruses of subtype H5. J Gen Virol 92:51–59 [View Article][PubMed]
    [Google Scholar]
  12. Govorkova E. A., Rehg J. E., Krauss S., Yen H. L., Guan Y., Peiris M., Nguyen T. D., Hanh T. H., Puthavathana P. et al. 2005; Lethality to ferrets of H5N1 influenza viruses isolated from humans and poultry in 2004. J Virol 79:2191–2198 [View Article][PubMed]
    [Google Scholar]
  13. Hatta M., Gao P., Halfmann P., Kawaoka Y. 2001; Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293:1840–1842 [View Article][PubMed]
    [Google Scholar]
  14. Hoffmann E., Neumann G., Kawaoka Y., Hobom G., Webster R. G. 2000; A DNA transfection system for generation of influenza A virus from eight plasmids. Proc Natl Acad Sci U S A 97:6108–6113 [View Article][PubMed]
    [Google Scholar]
  15. Horimoto T., Kawaoka Y. 1994; Reverse genetics provides direct evidence for a correlation of hemagglutinin cleavability and virulence of an avian influenza A virus. J Virol 68:3120–3128[PubMed]
    [Google Scholar]
  16. Imai H., Shinya K., Takano R., Kiso M., Muramoto Y., Sakabe S., Murakami S., Ito M., Yamada S. et al. 2010; The HA and NS genes of human H5N1 influenza A virus contribute to high virulence in ferrets. PLoS Pathog 6:e1001106 [View Article][PubMed]
    [Google Scholar]
  17. Jackson S., Van Hoeven N., Chen L. M., Maines T. R., Cox N. J., Katz J. M., Donis R. O. 2009; Reassortment between avian H5N1 and human H3N2 influenza viruses in ferrets: a public health risk assessment. J Virol 83:8131–8140 [View Article][PubMed]
    [Google Scholar]
  18. Kawaoka Y. 1991; Structural features influencing hemagglutinin cleavability in a human influenza A virus. J Virol 65:1195–1201[PubMed]
    [Google Scholar]
  19. Klenk H. D., Garten W. 1994; Host cell proteases controlling virus pathogenicity. Trends Microbiol 2:39–43 [View Article][PubMed]
    [Google Scholar]
  20. Korteweg C., Gu J. 2008; Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. Am J Pathol 172:1155–1170 [View Article][PubMed]
    [Google Scholar]
  21. Kuiken T., van den Brand J., van Riel D., Pantin-Jackwood M., Swayne D. E. 2010; Comparative pathology of select agent influenza A virus infections. Vet Pathol 47:893–914 [View Article][PubMed]
    [Google Scholar]
  22. Maher J. A., DeStefano J. 2004; The ferret: an animal model to study influenza virus. Lab Anim (NY) 33:50–53 [View Article][PubMed]
    [Google Scholar]
  23. Maines T. R., Lu X. H., Erb S. M., Edwards L., Guarner J., Greer P. W., Nguyen D. C., Szretter K. J., Chen L. M. et al. 2005; Avian influenza (H5N1) viruses isolated from humans in Asia in 2004 exhibit increased virulence in mammals. J Virol 79:11788–11800 [View Article][PubMed]
    [Google Scholar]
  24. Munster V. J., Schrauwen E. J., de Wit E., van den Brand J. M., Bestebroer T. M., Herfst S., Rimmelzwaan G. F., Osterhaus A. D., Fouchier R. A. 2010; Insertion of a multibasic cleavage motif into the hemagglutinin of a low-pathogenic avian influenza H6N1 virus induces a highly pathogenic phenotype. J Virol 84:7953–7960 [View Article][PubMed]
    [Google Scholar]
  25. Nicholson K. G., Wood J. M., Zambon M. 2003; Influenza. Lancet 362:1733–1745 [View Article][PubMed]
    [Google Scholar]
  26. Ohuchi R., Ohuchi M., Garten W., Klenk H. D. 1991; Human influenza virus hemagglutinin with high sensitivity to proteolytic activation. J Virol 65:3530–3537[PubMed]
    [Google Scholar]
  27. Parks C. L., Latham T., Cahill A., O’neill R. E., Passarotti C. J., Buonagurio D. A., Bechert T. M., D’Arco G. A., Neumann G. et al. 2007; Phenotypic properties resulting from directed gene segment reassortment between wild-type A/Sydney/5/97 influenza virus and the live attenuated vaccine strain. Virology 367:275–287 [View Article][PubMed]
    [Google Scholar]
  28. Rimmelzwaan G. F., Kuiken T., van Amerongen G., Bestebroer T. M., Fouchier R. A., Osterhaus A. D. 2001; Pathogenesis of influenza A (H5N1) virus infection in a primate model. J Virol 75:6687–6691 [View Article][PubMed]
    [Google Scholar]
  29. Röhm C., Zhou N., Süss J., Mackenzie J., Webster R. G. 1996; Characterization of a novel influenza hemagglutinin, H15: criteria for determination of influenza A subtypes. Virology 217:508–516 [View Article][PubMed]
    [Google Scholar]
  30. Stech O., Veits J., Weber S., Deckers D., Schröer D., Vahlenkamp T. W., Breithaupt A., Teifke J., Mettenleiter T. C., Stech J. 2009; Acquisition of a polybasic hemagglutinin cleavage site by a low-pathogenic avian influenza virus is not sufficient for immediate transformation into a highly pathogenic strain. J Virol 83:5864–5868 [View Article][PubMed]
    [Google Scholar]
  31. Steinhauer D. A. 1999; Role of hemagglutinin cleavage for the pathogenicity of influenza virus. Virology 258:1–20 [View Article][PubMed]
    [Google Scholar]
  32. Stieneke-Gröber A., Vey M., Angliker H., Shaw E., Thomas G., Roberts C., Klenk H. D., Garten W. 1992; Influenza virus hemagglutinin with multibasic cleavage site is activated by furin, a subtilisin-like endoprotease. EMBO J 11:2407–2414[PubMed]
    [Google Scholar]
  33. Svitek N., Rudd P. A., Obojes K., Pillet S., von Messling V. 2008; Severe seasonal influenza in ferrets correlates with reduced interferon and increased IL-6 induction. Virology 376:53–59 [View Article][PubMed]
    [Google Scholar]
  34. Tweed S. A., Skowronski D. M., David S. T., Larder A., Petric M., Lees W., Li Y., Katz J., Krajden M. et al. 2004; Human illness from avian influenza H7N3, British Columbia. Emerg Infect Dis 10:2196–2199[PubMed] [CrossRef]
    [Google Scholar]
  35. van den Brand J. M., Stittelaar K. J., van Amerongen G., Rimmelzwaan G. F., Simon J., de Wit E., Munster V., Bestebroer T., Fouchier R. A. et al. 2010; Severity of pneumonia due to new H1N1 influenza virus in ferrets is intermediate between that due to seasonal H1N1 virus and highly pathogenic avian influenza H5N1 virus. J Infect Dis 201:993–999 [View Article][PubMed]
    [Google Scholar]
  36. van Riel D., Rimmelzwaan G. F., van Amerongen G., Osterhaus A. D., Kuiken T. 2010; Highly pathogenic avian influenza virus H7N7 isolated from a fatal human case causes respiratory disease in cats but does not spread systemically. Am J Pathol 177:2185–2190 [View Article][PubMed]
    [Google Scholar]
  37. Webby R. J., Perez D. R., Coleman J. S., Guan Y., Knight J. H., Govorkova E. A., McClain-Moss L. R., Peiris J. S., Rehg J. E., Tuomanen E. 2004; Responsiveness to a pandemic alert: use of reverse genetics for rapid development of influenza vaccines. Lancet 363:1099–1103 [View Article][PubMed]
    [Google Scholar]
  38. Webster R. G., Rott R. 1987; Influenza virus A pathogenicity: the pivotal role of hemagglutinin. Cell 50:665–666 [View Article][PubMed]
    [Google Scholar]
  39. Webster R. G., Geraci J., Petursson G., Skirnisson K. 1981; Conjunctivitis in human beings caused by influenza A virus of seals. N Engl J Med 304:911 [View Article][PubMed]
    [Google Scholar]
  40. WHO (2010 Confirmed human cases of avian influenza A(H5N1) http://www.who.int/csr/disease/avian_influenza/country/en/index.html
  41. Zitzow L. A., Rowe T., Morken T., Shieh W. J., Zaki S., Katz J. M. 2002; Pathogenesis of avian influenza A (H5N1) viruses in ferrets. J Virol 76:4420–4429 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.030379-0
Loading
/content/journal/jgv/10.1099/vir.0.030379-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error