1887

Abstract

The leader (L) proteins encoded by picornaviruses of the genus [Theiler's murine encephalomyelitis virus (TMEV) and (EMCV)] are small proteins thought to exert important functions in virus–host interactions. The L protein of persistent TMEV strains was shown to be dispensable for virus replication , but crucial for long-term persistence of the virus in the central nervous system of the mouse. The phenotype of chimeric viruses generated by exchanging the L-coding regions was analysed and it was shown that the L proteins of neurovirulent and persistent TMEV strains are functionally interchangeable and , despite the fact that L is the second most divergent protein encoded by these viruses after the L* protein. The L protein encoded by EMCV and Mengo virus (an EMCV strain) shares about 35 % amino acid identity with that of TMEV. It differs from the latter by lacking a serine/threonine-rich C-terminal domain and by carrying phosphorylated residues not conserved in the TMEV L protein. Our data show that, in spite of these differences, the L protein of Mengo virus shares, with that of TMEV, the ability to inhibit the transcription of type I interferon, cytokine and chemokine genes and to interfere with nucleocytoplasmic trafficking of host-cell proteins. Interestingly, analysis of viral RNA replication of the recombinant viruses raised the hypothesis that L proteins of TMEV and EMCV diverged during evolution to adapt to the different replication fitness of these viruses.

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2006-05-01
2019-10-20
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References

  1. Agol, V. I. ( 2002; ). Picornavirus genome: an overview. In Molecular Biology of Picornaviruses, pp. 127–148. Edited by B. L. Semler & E. Wimmer. Washington, DC: American Society for Microbiology.
  2. Badshah, C., Calenoff, M. A. & Rundell, K. ( 2000; ). The leader polypeptide of Theiler's murine encephalomyelitis virus is required for the assembly of virions in mouse L cells. J Virol 74, 875–882.[CrossRef]
    [Google Scholar]
  3. Brahic, M., Bureau, J.-F. & Michiels, T. ( 2005; ). The genetics of the persistent infection and demyelinating disease caused by Theiler's virus. Annu Rev Microbiol 59, 279–298.[CrossRef]
    [Google Scholar]
  4. Calenoff, M. A., Faaberg, K. S. & Lipton, H. L. ( 1990; ). Genomic regions of neurovirulence and attenuation in Theiler murine encephalomyelitis virus. Proc Natl Acad Sci U S A 87, 978–982.[CrossRef]
    [Google Scholar]
  5. Calenoff, M. A., Badshah, C. S., Dal Canto, M. C., Lipton, H. L. & Rundell, M. K. ( 1995; ). The leader polypeptide of Theiler's virus is essential for neurovirulence but not for virus growth in BHK cells. J Virol 69, 5544–5549.
    [Google Scholar]
  6. Chen, H.-H., Kong, W.-P. & Roos, R. P. ( 1995; ). The leader peptide of Theiler's murine encephalomyelitis virus is a zinc-binding protein. J Virol 69, 8076–8078.
    [Google Scholar]
  7. Chomczynski, P. & Sacchi, N. ( 1987; ). Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162, 156–159.
    [Google Scholar]
  8. Delhaye, S., van Pesch, V. & Michiels, T. ( 2004; ). The leader protein of Theiler's virus interferes with nucleocytoplasmic trafficking of cellular proteins. J Virol 78, 4357–4362.[CrossRef]
    [Google Scholar]
  9. Devaney, M. A., Vakharia, V. N., Lloyd, R. E., Ehrenfeld, E. & Grubman, M. J. ( 1988; ). Leader protein of foot-and-mouth disease virus is required for cleavage of the p220 component of the cap-binding protein complex. J Virol 62, 4407–4409.
    [Google Scholar]
  10. Duke, G. M., Osorio, J. E. & Palmenberg, A. C. ( 1990; ). Attenuation of Mengo virus through genetic engineering of the 5′ noncoding poly(C) tract. Nature 343, 474–476.[CrossRef]
    [Google Scholar]
  11. Duke, G. M., Hoffman, M. A. & Palmenberg, A. C. ( 1992; ). Sequence and structural elements that contribute to efficient encephalomyocarditis virus RNA translation. J Virol 66, 1602–1609.
    [Google Scholar]
  12. Dvorak, C. M. T., Hall, D. J., Hill, M., Riddle, M., Pranter, A., Dillman, J., Deibel, M. & Palmenberg, A. C. ( 2001; ). Leader protein of encephalomyocarditis virus binds zinc, is phosphorylated during viral infection, and affects the efficiency of genome translation. Virology 290, 261–271.[CrossRef]
    [Google Scholar]
  13. Fu, J., Stein, S., Rosenstein, L., Bodwell, T., Routbort, M., Semler, B. L. & Roos, R. P. ( 1990; ). Neurovirulence determinants of genetically engineered Theiler viruses. Proc Natl Acad Sci U S A 87, 4125–4129.[CrossRef]
    [Google Scholar]
  14. Ghadge, G. D., Ma, L., Sato, S., Kim, J. & Roos, R. P. ( 1998; ). A protein critical for a Theiler's virus-induced immune system-mediated demyelinating disease has a cell type-specific antiapoptotic effect and a key role in virus persistence. J Virol 72, 8605–8612.
    [Google Scholar]
  15. Hoffman, M. A. & Palmenberg, A. C. ( 1996; ). Revertant analysis of J-K mutations in the encephalomyocarditis virus internal ribosomal entry site detects an altered leader protein. J Virol 70, 6425–6430.
    [Google Scholar]
  16. Imai, Y., Matsushima, Y., Sugimura, T. & Terada, M. ( 1991; ). A simple and rapid method for generating a deletion by PCR. Nucleic Acids Res 19, 2785.[CrossRef]
    [Google Scholar]
  17. Jnaoui, K. & Michiels, T. ( 1998; ). Adaptation of Theiler's virus to L929 cells: mutations in the putative receptor binding site on the capsid map to neutralization sites and modulate viral persistence. Virology 244, 397–404.[CrossRef]
    [Google Scholar]
  18. Kaminski, A., Hunt, S. L., Patton, J. G. & Jackson, R. J. ( 1995; ). Direct evidence that polypyrimidine tract binding protein (PTB) is essential for internal initiation of translation of encephalomyocarditis virus RNA. RNA 1, 924–938.
    [Google Scholar]
  19. Kong, W.-P. & Roos, R. P. ( 1991; ). Alternative translation initiation site in the DA strain of Theiler's murine encephalomyelitis virus. J Virol 65, 3395–3399.
    [Google Scholar]
  20. Kong, W.-P., Ghadge, G. D. & Roos, R. P. ( 1994; ). Involvement of cardiovirus leader in host cell-restricted virus expression. Proc Natl Acad Sci U S A 91, 1796–1800.[CrossRef]
    [Google Scholar]
  21. Kunkel, T. A. ( 1985; ). Rapid and efficient site-specific mutagenesis without phenotypic selection. Proc Natl Acad Sci U S A 82, 488–492.[CrossRef]
    [Google Scholar]
  22. Lipton, H. L. ( 1975; ). Theiler's virus infection in mice: an unusual biphasic disease process leading to demyelination. Infect Immun 11, 1147–1155.
    [Google Scholar]
  23. McAllister, A., Tangy, F., Aubert, C. & Brahic, M. ( 1989; ). Molecular cloning of the complete genome of Theiler's virus, strain DA, and production of infectious transcripts. Microb Pathog 7, 381–388.[CrossRef]
    [Google Scholar]
  24. McAllister, A., Tangy, F., Aubert, C. & Brahic, M. ( 1990; ). Genetic mapping of the ability of Theiler's virus to persist and demyelinate. J Virol 64, 4252–4257.
    [Google Scholar]
  25. Mena, I., Roussarie, J.-P. & Brahic, M. ( 2004; ). Infection of macrophage primary cultures by persistent and nonpersistent strains of Theiler's virus: role of capsid and noncapsid viral determinants. J Virol 78, 13356–13361.[CrossRef]
    [Google Scholar]
  26. Michiels, T., Jarousse, N. & Brahic, M. ( 1995; ). Analysis of the leader and capsid coding regions of persistent and neurovirulent strains of Theiler's virus. Virology 214, 550–558.[CrossRef]
    [Google Scholar]
  27. Michiels, T., Dejong, V., Rodrigus, R. & Shaw-Jackson, C. ( 1997; ). Protein 2A is not required for Theiler's virus replication. J Virol 71, 9549–9556.
    [Google Scholar]
  28. Ohara, Y., Stein, S., Fu, J., Stillman, L., Klaman, L. & Roos, R. P. ( 1988; ). Molecular cloning and sequence determination of DA strain of Theiler's murine encephalomyelitis viruses. Virology 164, 245–255.[CrossRef]
    [Google Scholar]
  29. Ohsawa, K., Watanabe, Y., Miyata, H. & Sato, H. ( 2003; ). Genetic analysis of a Theiler-like virus isolated from rats. Comp Med 53, 191–196.
    [Google Scholar]
  30. Palmenberg, A. C. & Sgro, J.-Y. ( 2002; ). Alignments and comparative profiles of picornavirus genera. In Molecular Biology of Picornaviruses, pp. 149–155. Edited by B. L. Semler & E. Wimmer. Washington, DC: American Society for Microbiology.
  31. Petro, T. M. ( 2005; ). ERK-MAP-kinases differentially regulate expression of IL-23 p19 compared with p40 and IFN-β in Theiler's virus-infected RAW264.7 cells. Immunol Lett 97, 47–53.[CrossRef]
    [Google Scholar]
  32. Pevear, D. C., Calenoff, M., Rozhon, E. & Lipton, H. L. ( 1987; ). Analysis of the complete nucleotide sequence of the picornavirus Theiler's murine encephalomyelitis virus indicates that it is closely related to cardioviruses. J Virol 61, 1507–1516.
    [Google Scholar]
  33. Pevear, D. C., Borkowski, J., Calenoff, M., Oh, C. K., Ostrowski, B. & Lipton, H. L. ( 1988; ). Insights into Theiler's virus neurovirulence based on a genomic comparison of the neurovirulent GDVII and less virulent BeAn strains. Virology 165, 1–12.[CrossRef]
    [Google Scholar]
  34. Pritchard, A. E., Strom, T. & Lipton, H. L. ( 1992; ). Nucleotide sequence identifies Vilyuisk virus as a divergent Theiler's virus. Virology 191, 469–472.[CrossRef]
    [Google Scholar]
  35. Roos, R. P., Kong, W.-P. & Semler, B. L. ( 1989; ). Polyprotein processing of Theiler's murine encephalomyelitis virus. J Virol 63, 5344–5353.
    [Google Scholar]
  36. Shaw-Jackson, C. & Michiels, T. ( 1999; ). Absence of internal ribosome entry site-mediated tissue specificity in the translation of a bicistronic transgene. J Virol 73, 2729–2738.
    [Google Scholar]
  37. Takata, H., Obuchi, M., Yamamoto, J., Odagiri, T., Roos, R. P., Iizuka, H. & Ohara, Y. ( 1998; ). L* protein of the DA strain of Theiler's murine encephalomyelitis virus is important for virus growth in a murine macrophage-like cell line. J Virol 72, 4950–4955.
    [Google Scholar]
  38. Tangy, F., McAllister, A. & Brahic, M. ( 1989; ). Molecular cloning of the complete genome of strain GDVII of Theiler's virus and production of infectious transcripts. J Virol 63, 1101–1106.
    [Google Scholar]
  39. Theiler, M. & Gard, S. ( 1940; ). Encephalomyelitis of mice. I. Characteristics and pathogenesis of the virus. J Exp Med 72, 49–67.[CrossRef]
    [Google Scholar]
  40. van Eyll, O. & Michiels, T. ( 2000; ). Influence of the Theiler's virus L* protein on macrophage infection, viral persistence, and neurovirulence. J Virol 74, 9071–9077.[CrossRef]
    [Google Scholar]
  41. van Eyll, O. & Michiels, T. ( 2002; ). Non-AUG-initiated internal translation of the L* protein of Theiler's virus and importance of this protein for viral persistence. J Virol 76, 10665–10673.[CrossRef]
    [Google Scholar]
  42. van Pesch, V., van Eyll, O. & Michiels, T. ( 2001; ). The leader protein of Theiler's virus inhibits immediate-early alpha/beta interferon production. J Virol 75, 7811–7817.[CrossRef]
    [Google Scholar]
  43. Yoneyama, M., Suhara, W., Fukuhara, Y., Fukuda, M., Nishida, E. & Fujita, T. ( 1998; ). Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300. EMBO J 17, 1087–1095.[CrossRef]
    [Google Scholar]
  44. Zoll, J., Galama, J. M. D., van Kuppeveld, F. J. M. & Melchers, W. J. G. ( 1996; ). Mengovirus leader is involved in the inhibition of host cell protein synthesis. J Virol 70, 4948–4952.
    [Google Scholar]
  45. Zoll, J., Melchers, W. J. G., Galama, J. M. D. & van Kuppeveld, F. J. M. ( 2002; ). The mengovirus leader protein suppresses alpha/beta interferon production by inhibition of the iron/ferritin-mediated activation of NF-κB. J Virol 76, 9664–9672.[CrossRef]
    [Google Scholar]
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