1887

Abstract

Proteolytic cleavage of the fusion protein (F) is an important control mechanism of the biological activity of paramyxoviruses. The sequence R-R-H-K-R(112) at the cleavage site of the F protein of measles virus (MV) was altered by site-directed mutagenesis to R-N-H-N-R(112), which is not recognized by the ubiquitous cellular protease furin. When transiently expressed in cell cultures standard F protein was cleaved, whereas the mutant remained in the uncleaved form. Syncytium formation by the mutant that was analysed after coexpression with haemagglutinin protein depended on the presence of trypsin. Recombinant MV containing the mutation required trypsin activation for fusion and infectivity in cell culture. Intranasal infection of transgenic mice susceptible to MV infection (Ifnar-CD46Ge) resulted in a moderately productive infection and inflammation of the lung. In contrast to parental virus, intracerebral inoculation did not induce neural disease. The possible effects of the change in cleavage activation on tissue tropism and pathogenicity are discussed.

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2000-02-01
2019-10-19
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References

  1. Alkathib, G., Roder, J., Richardson, C., Briedis, D., Weinberg, R., Smith, D., Taylor, J., Paoletti, E. & Shen, S.-H. ( 1994; ). Characterization of a cleavage mutant of measles virus fusion protein defective in syncytium formation. Journal of Virology 68, 6770-6774.
    [Google Scholar]
  2. Bolt, G. & Pedersen, I. R. ( 1998; ). The role of subtilisin-like proconvertases for cleavage of the measles virus fusion glycoprotein in different cell types. Virology 252, 387-398.[CrossRef]
    [Google Scholar]
  3. Borrow, P. & Oldstone, M. B. A. ( 1995; ). Measles virus–mononuclear cell interactions. Current Topics of Microbiology and Immunology 191, 85-100.
    [Google Scholar]
  4. Cathomen, T., Buchholz, C. J., Spielhofer, P. & Cattaneo, R. ( 1995; ). Preferential initiation at the second AUG of the measles virus F mRNA: a role for the long untranslated region. Virology 214, 628-632.[CrossRef]
    [Google Scholar]
  5. Cathomen, T., Naim, H. Y. & Cattaneo, R. ( 1998; ). Measles virus with altered envelope protein cytoplasmic tails gain cell fusion competence. Journal of Virology 72, 1224-1234.
    [Google Scholar]
  6. Dörig, R. E., Marcil, A., Chopra, A. & Richardson, C. D. ( 1993; ). The human CD46 molecule is a receptor for measles virus (Edmonston strain). Cell 75, 295-305.[CrossRef]
    [Google Scholar]
  7. Fujinami, R. S. & Oldstone, M. B. A. ( 1981; ). Failure to cleave measles virus fusion protein in lymphoid cells. Journal of Experimental Medicine 154, 1489-1499.[CrossRef]
    [Google Scholar]
  8. Kido, H., Yokogoshi, Y., Sakai, K., Tashiro, M., Kishino, Y., Fukutomi, A. & Katunuma, N. ( 1992; ). Isolation and characterization of a novel trypsin-like protease found in rat bronchial epithelial Clara cells. A possible activator of the viral fusion glycoprotein. Journal of Biological Chemistry 267, 13573-13579.
    [Google Scholar]
  9. Klenk, H.-D. & Garten, W. ( 1994; ). Activation cleavage of viral spike proteins by host proteases. In Cellular Receptors for Animal Viruses, pp. 241-280. Edited by E. Wimmer. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory.
  10. Maisner, A., Klenk, H.-D. & Herrler, G. ( 1998; ). Polarized budding of measles virus is not determined by viral glycoproteins. Journal of Virology 72, 5276-5278.
    [Google Scholar]
  11. Mrkic, B., Pavlovic, J., Rülicke, T., Volpe, P., Buchholz, C., Hourcade, D., Atkinson, J. P., Aguzzi, A. & Cattaneo, R. ( 1998; ). Measles virus spread and pathogenesis in genetically modified mice. Journal of Virology 72, 7420-7427.
    [Google Scholar]
  12. Naniche, D., Varior-Krishnan, G., Cervoni, F., Wild, T. F., Rossi, B., Rabourdin-Combe, C. & Gerlier, D. ( 1993; ). Human membrane cofactor protein (CD46) acts as cellular receptor for measles virus. Journal of Virology 67, 4831-4841.
    [Google Scholar]
  13. Paterson, R. G., Shaughnessy, M. A. & Lamb, R. A. ( 1989; ). Analysis of the relationship between cleavability of a paramyxovirus fusion protein and length of the connecting peptide. Journal of Virology 63, 1293-1301.
    [Google Scholar]
  14. Prill, V., Lehmann, L., von-Figura, K. & Peters, C. ( 1993; ). The cytoplasmic tail of lysosomal acid phosphatase contains overlapping but distinct signals for basolateral sorting and rapid internalization in polarized MDCK cells. EMBO Journal 12, 2181-2193.
    [Google Scholar]
  15. Radecke, F., Spielhofer, P., Schneider, H., Kaelin, K., Huber, M., Dötsch, C., Christiansen, G. & Billeter, M. A. ( 1995; ). Rescue of measles viruses from cloned DNA. EMBO Journal 14, 5773-5784.
    [Google Scholar]
  16. Schlender, J., Schnorr, J., Spielhofer, P., Cathomen, T., Cattaneo, R., Billeter, M. A., ter Meulen, V. & Schneider-Schaulies, S. ( 1996; ). Interaction of measles virus glycoproteins with the surface of uninfected peripheral blood lymphocytes induces immunosuppression in vitro. Proceedings of the National Academy of Sciences, USA 93, 13194-13199.[CrossRef]
    [Google Scholar]
  17. Schneider-Schaulies, J., Dunster, L. M., Schwartz-Albiez, R., Krohne, G. & ter Meulen, V. ( 1995; ). Physical association of moesin and CD46 as a receptor complex for measles virus. Journal of Virology 69, 2248-2256.
    [Google Scholar]
  18. Singh, M., Cattaneo, R. & Billeter, M. A. ( 1999; ). A recombinant measles virus expressing hepatitis B virus surface antigen induces humoral immune responses in genetically modified mice. Journal of Virology 73, 4823-4828.
    [Google Scholar]
  19. Tashiro, M., Yamakawa, M., Tobita, K., Klenk, H.-D., Seto, J. T. & Rott, R. ( 1992a; ). Significance of basolateral domain of polarized MDCK cells for Sendai virus-induced cell fusion. Archives of Virology 125, 129-139.[CrossRef]
    [Google Scholar]
  20. Tashiro, M., Yokogishi, Y., Tobita, K., Seto, J. T., Rott, R. & Kido, H. ( 1992b; ). Tryptase Clara, an activating protease for Sendai virus in rat lungs, is involved in pneumopathogenicity. Journal of Virology 66, 7211-7216.
    [Google Scholar]
  21. Vey, M., Orlich, M., Adler, S., Klenk, H.-D., Rott, R. & Garten, W. ( 1992; ). Hemagglutinin activation of pathogenic influenza viruses of serotype H7 requires the protease recognition motif R-X-K/R-R. Virology 188, 408-413.[CrossRef]
    [Google Scholar]
  22. Ward, C. D., Paterson, R. G. & Lamb, R. A. ( 1995; ). Mutants of the paramyxovirus SV5 fusion protein: regulated and extensive syncytium formation. Virology 209, 242-249.[CrossRef]
    [Google Scholar]
  23. Watanabe, M., Hirano, A., Stenglein, S., Nelson, J., Thomas, G. & Wong, T. C. ( 1995; ). Engineered serine protease inhibitor prevents furin-catalyzed activation of fusion glycoprotein and production of infectious measles virus. Journal of Virology 69, 3216-3220.
    [Google Scholar]
  24. Wild, T. F., Malvoisin, E. & Buckland, R. ( 1991; ). Measles virus: both the haemagglutinin and fusion glycoproteins are required for fusion. Journal of General Virology 72, 439-442.[CrossRef]
    [Google Scholar]
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