Advertisement

Proteolytic Activation of Influenza Viruses: Substrates and Proteases

  • Hans-Dieter Klenk
  • Masanobu Ohuchi
  • Reiko Ohuchi
  • Andrea Stieneke-Gröber
  • Martin Vey
  • Wolfgang Garten
Chapter
Part of the Federation of European Microbiological Societies Symposium Series book series (FEMS, volume 61)

Abstract

Like many other viral glycoproteins, the hemagglutinin (HA) of influenza viruses is activated by proteolytic cleavage. Cleavage which is necessary for the fusion activity of the hemagglutinin and thus for the infectivity of the virus is exerted by host cell proteases, and the presence of an appropriate enzyme determines whether infectious virus is made in a given cell. Proteolytic activation is therefore indispensable for effective virus spread in the infected host and has been found to be a prime determinant for virus pathogenicity. This concept has been derived mainly from studies on avian influenza viruses. The pathogenic strains of these viruses are activated by ubiquitous proteases and cause therefore systemic infection mostly leading to rapid death of the animal, whereas activation of the apathogenic strains occurs only in epithelial cells of the respiratory or the enteric tract resulting in local infection of these organs. The mammalian influenza viruses, including the human ones, resemble the apathogenic avian strains in possessing also hemagglutinins of restricted cleavability and in causing usually local infection of the respiratory tract.1

Keywords

Influenza Virus Cleavage Site MDCK Cell Avian Influenza Virus H5N2 Influenza Virus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    H.-D. Klenk and R. Rott, The molecular biology of influenza virus pathogenicity, Adv. Virus Res. 34:247 (1988).PubMedCrossRefGoogle Scholar
  2. 2.
    F.X. Bosch, W. Garten, H.-D. Klenk, and R. Rott, Proteolytic cleavage of influenza virus hemagglutinins, Primary structure of the connecting peptide between HA1 and HA2 determines proteolytic cleavability and pathogenicity of influenza viruses, Virology 113:725 (1981).PubMedCrossRefGoogle Scholar
  3. 3.
    W. Garten, F.X. Bosch, D. Linder, R. Rott, and H.-D. Klenk, Proteolytic activation of the influenza hemagglutinin: The structure of the cleavage site and the enzymes involved in cleavage, Virology 115:361 (1981).PubMedCrossRefGoogle Scholar
  4. 4.
    Y. Kawaoka and R.G. Webster, Sequence requirements for cleavage activation of influenza virus hemagglutinin expressed in mammalian cells, Proc. Natl. Acad. Sci. USA 85:321 (1988).CrossRefGoogle Scholar
  5. 5.
    S. Li, M. Orlich, and R. Rott, Generation of seal influenza virus variants pathogenic for chickens because of hemagglutinin cleavage site changes. J. Virol. 64:3297 (1990).PubMedGoogle Scholar
  6. 6.
    Y. Kawaoka and R.G. Webster, Interplay between carbohydrate in the stalk and the length of the connecting peptide determines the cleavability of influenza virus hemagglutinin, J. Virol. 63:3296 (1989).PubMedGoogle Scholar
  7. 7.
    M.-J. Gething, J. Henneberry, and J. Sambrook, Fusion activity of the hemagglutinin of influenza virus, Curr. Top. Membr. Trans. 13:339 (1989).Google Scholar
  8. 8.
    D. Katchikian, M. Orlich, and R.Rott, Increased viral pathogenicity after insertion of a 28S ribosomal RNA sequence into the haemagglutinin gene of an influenza virus, Nature 340:156 (1989).CrossRefGoogle Scholar
  9. 9.
    M. Orlich, D. Khatchikian, A. Teigler, and R. Rott, Structural variation occurring in the hemagglutinin of influenza virus A/Turkey/Oregon/71 during adaptation to different cell types, Virology 176:531 (1990).PubMedCrossRefGoogle Scholar
  10. 10.
    R. Rott, M. Orlich, H.-D. Klenk, M.L. Wang, J.J. Skehel, and D.C. Wiley, Studies on the adaptation of influenza viruses to MDCK cells, EMBO J. 3:3328 (1984).Google Scholar
  11. 11.
    K.L. Deshpande, V.A. Fried, M. Ando, and R.G. Webster, Glycosylation affects cleavage of an H5N2 influenza virus hemagglutinin and regulates virulence, Proc. Natl. Acad. Sci. USA 84:34 (1987).CrossRefGoogle Scholar
  12. 12.
    Y. Kawaoka, C.W. Naeve, and R.G. Webster, Is virulence of H5N2 influenza viruses in chickens associated with loss of carbohydrate from the hemagglutinin? Virology 139:303 (1984).PubMedCrossRefGoogle Scholar
  13. 13.
    M. Ohuchi, M. Orlich, R. Ohuchi, B.E. Simpson, W. Garten, H.-D. Klenk, and R. Rott, Mutations at the cleavage site of the hemagglutinin alter the pathogenicity of influenza virus A/chick/Penn/83 (H5N2), Virolology 168:274 (1989).CrossRefGoogle Scholar
  14. 14.
    M. Enami, W. Luytjes, M. Krystal, and P. Palese, Introduction of site-specific mutations into the genome of influenza virus, Proc. Natl. Acad. Sci. USA 87:3802 (1990).PubMedCrossRefGoogle Scholar
  15. 15.
    D. Gotoh, T. Ogasawara, T. Toyoda, N.M. Inocencio, M. Hamaguchi, and Y. Nagai, An endoprotease homologous to the blood clotting factor X as a determinant of viral tropism in chick embryo, EMBO J. 9:4189 (1990).PubMedGoogle Scholar
  16. 16.
    R. Ohuchi, M. Ohuchi, W. Garten, and H.-D. Klenk, Human influenza virus hemagglutinin with high sensitivity to proteolytic activation, J. Virol. 65:3530 (1991).PubMedGoogle Scholar
  17. 17.
    H.-D. Klenk, W. Garten, and R. Rott, Inhibition of proteolytic cleavage of the hemagglutinin of influenza virus by calcium-specific ionophore A23187, EMBO J. 3:2911 (1984).PubMedGoogle Scholar
  18. 18.
    H.-D. Klenk, W. Wöllert, R. Rott, and C. Scholtissek, Association of influenza virus proteins with cytoplasmatic fractions, Virology 57:28 (1974).PubMedCrossRefGoogle Scholar
  19. 19.
    I. de Curtis and K. Simons, Isolation of exocytotic carrier vesicles from BHK cells, Cell 58:719 (1989).PubMedCrossRefGoogle Scholar
  20. 20.
    K. Kuroda, A. Gröner, K. Frese, D. Drenckhahn, C. Hauser, R. Rott, W. Doerfler, and H.-D. Klenk, Synthesis of biologically active influenza virus hemagglutinin in insect larvae, J. Virol. 63:1677 (1989).PubMedGoogle Scholar
  21. 21.
    R.S. Fuller, R.E. Sterne, and J. Thomer, Enzymes required for yeast prohormone processing, Ann. Rev. Physiol. 50:345 (1988).CrossRefGoogle Scholar
  22. 22.
    R.S. Fuller, C. Brenner, P. Gluschaukof, and C.A. Wilcox, The yeast prohormone-processing Kex2 protease, an enzyme with specificity for paired basic residues, in: “Advances in Life Sciences,” (1991), in press.Google Scholar
  23. 23.
    P.A. Bresnahan, R. Ladne, L. Thomas, I. Thorner, H.L. Gibson, A.J. Brake, P.J. Barr, and G. Thomas, Human fur gene encodes a yeast Kex2-like endoprotein that cleaves pro-ß-NGF in vivo, Cell. Biol. 111:2851 (1990).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1992

Authors and Affiliations

  • Hans-Dieter Klenk
    • 1
  • Masanobu Ohuchi
    • 1
  • Reiko Ohuchi
    • 1
  • Andrea Stieneke-Gröber
    • 1
  • Martin Vey
    • 1
  • Wolfgang Garten
    • 1
  1. 1.Institut für VirologiePhilipps-UniversitätMarburgGermany

Personalised recommendations