Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1992 Jul;66(7):4508–4517. doi: 10.1128/jvi.66.7.4508-4517.1992

Influence of Theiler's murine encephalomyelitis virus 5' untranslated region on translation and neurovirulence.

S B Stein 1, L Zhang 1, R P Roos 1
PMCID: PMC241260  PMID: 1602556

Abstract

The DA strain of Theiler's murine encephalomyelitis virus (TMEV), a picornavirus, causes a persistent, restricted infection and demyelinating disease in mice. In contrast, the GDVII strain causes an acute, fatal, neuronal disease and is highly neurovirulent. To investigate the role of the TMEV 5' untranslated region (UTR) in translational efficiency and the TMEV subgroup differences, we tested the translational efficiency of transcripts in vitro derived from plasmids containing DA, GDVII, or DA/GDVII chimeric 5' UTRs preceding a reporter gene or the rest of the TMEV genome. We demonstrated that GDVII RNA translates more efficiently in rabbit reticulocyte lysate than DA RNA and that this enhanced translation is mediated by multiple domains in the GDVII 5' UTR as well as a region of the genome outside of the 5' UTR. We also identified a region within DA nucleotides 14 to 395 which inhibits translation of DA RNA and could contribute to the persistent, restricted DA central nervous system infection; the predicted secondary structure of the 5' UTR demonstrates a remarkable stem-loop structure within this region that is relatively unique among picornaviruses. Data from experiments involving DA/GDVII chimeric 5' UTR full-length infectious cDNA clones suggested that sequences in the 5' UTR can affect the neurovirulence phenotype but that translational efficiency is necessary but not sufficient for neurovirulence. These studies emphasize the multigenic nature of neurovirulence and the importance of translation in the regulation of picornaviral gene expression.

Full text

PDF
4508

Images in this article

4510Image
on p.4510
4511Image
on p.4511
4512Image
on p.4512

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andino R., Rieckhof G. E., Baltimore D. A functional ribonucleoprotein complex forms around the 5' end of poliovirus RNA. Cell. 1990 Oct 19;63(2):369–380. doi: 10.1016/0092-8674(90)90170-j. [DOI] [PubMed] [Google Scholar]
  2. Aubert C., Chamorro M., Brahic M. Identification of Theiler's virus infected cells in the central nervous system of the mouse during demyelinating disease. Microb Pathog. 1987 Nov;3(5):319–326. doi: 10.1016/0882-4010(87)90002-7. [DOI] [PubMed] [Google Scholar]
  3. Bienkowska-Szewczyk K., Ehrenfeld E. An internal 5'-noncoding region required for translation of poliovirus RNA in vitro. J Virol. 1988 Aug;62(8):3068–3072. doi: 10.1128/jvi.62.8.3068-3072.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cash E., Chamorro M., Brahic M. Theiler's virus RNA and protein synthesis in the central nervous system of demyelinating mice. Virology. 1985 Jul 15;144(1):290–294. doi: 10.1016/0042-6822(85)90327-7. [DOI] [PubMed] [Google Scholar]
  5. Clarke B. E., Sangar D. V., Burroughs J. N., Newton S. E., Carroll A. R., Rowlands D. J. Two initiation sites for foot-and-mouth disease virus polyprotein in vivo. J Gen Virol. 1985 Dec;66(Pt 12):2615–2626. doi: 10.1099/0022-1317-66-12-2615. [DOI] [PubMed] [Google Scholar]
  6. Dorner A. J., Semler B. L., Jackson R. J., Hanecak R., Duprey E., Wimmer E. In vitro translation of poliovirus RNA: utilization of internal initiation sites in reticulocyte lysate. J Virol. 1984 May;50(2):507–514. doi: 10.1128/jvi.50.2.507-514.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Duke G. M., Hoffman M. A., Palmenberg A. C. Sequence and structural elements that contribute to efficient encephalomyocarditis virus RNA translation. J Virol. 1992 Mar;66(3):1602–1609. doi: 10.1128/jvi.66.3.1602-1609.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Duke G. M., Osorio J. E., Palmenberg A. C. Attenuation of Mengo virus through genetic engineering of the 5' noncoding poly(C) tract. Nature. 1990 Feb 1;343(6257):474–476. doi: 10.1038/343474a0. [DOI] [PubMed] [Google Scholar]
  9. Evans D. M., Dunn G., Minor P. D., Schild G. C., Cann A. J., Stanway G., Almond J. W., Currey K., Maizel J. V., Jr Increased neurovirulence associated with a single nucleotide change in a noncoding region of the Sabin type 3 poliovaccine genome. Nature. 1985 Apr 11;314(6011):548–550. doi: 10.1038/314548a0. [DOI] [PubMed] [Google Scholar]
  10. Fu J. L., Stein S., Rosenstein L., Bodwell T., Routbort M., Semler B. L., Roos R. P. Neurovirulence determinants of genetically engineered Theiler viruses. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4125–4129. doi: 10.1073/pnas.87.11.4125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fu J., Rodriguez M., Roos R. P. Strains from both Theiler's virus subgroups encode a determinant for demyelination. J Virol. 1990 Dec;64(12):6345–6348. doi: 10.1128/jvi.64.12.6345-6348.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hambidge S. J., Sarnow P. Terminal 7-methyl-guanosine cap structure on the normally uncapped 5' noncoding region of poliovirus mRNA inhibits its translation in mammalian cells. J Virol. 1991 Nov;65(11):6312–6315. doi: 10.1128/jvi.65.11.6312-6315.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jang S. K., Davies M. V., Kaufman R. J., Wimmer E. Initiation of protein synthesis by internal entry of ribosomes into the 5' nontranslated region of encephalomyocarditis virus RNA in vivo. J Virol. 1989 Apr;63(4):1651–1660. doi: 10.1128/jvi.63.4.1651-1660.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jang S. K., Wimmer E. Cap-independent translation of encephalomyocarditis virus RNA: structural elements of the internal ribosomal entry site and involvement of a cellular 57-kD RNA-binding protein. Genes Dev. 1990 Sep;4(9):1560–1572. doi: 10.1101/gad.4.9.1560. [DOI] [PubMed] [Google Scholar]
  16. Kaminski A., Howell M. T., Jackson R. J. Initiation of encephalomyocarditis virus RNA translation: the authentic initiation site is not selected by a scanning mechanism. EMBO J. 1990 Nov;9(11):3753–3759. doi: 10.1002/j.1460-2075.1990.tb07588.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kong W. P., Roos R. P. Alternative translation initiation site in the DA strain of Theiler's murine encephalomyelitis virus. J Virol. 1991 Jun;65(6):3395–3399. doi: 10.1128/jvi.65.6.3395-3399.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kozak M. The scanning model for translation: an update. J Cell Biol. 1989 Feb;108(2):229–241. doi: 10.1083/jcb.108.2.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kuge S., Nomoto A. Construction of viable deletion and insertion mutants of the Sabin strain of type 1 poliovirus: function of the 5' noncoding sequence in viral replication. J Virol. 1987 May;61(5):1478–1487. doi: 10.1128/jvi.61.5.1478-1487.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Najita L., Sarnow P. Oxidation-reduction sensitive interaction of a cellular 50-kDa protein with an RNA hairpin in the 5' noncoding region of the poliovirus genome. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5846–5850. doi: 10.1073/pnas.87.15.5846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Nitayaphan S., Omilianowski D., Toth M. M., Parks G. D., Rueckert R. R., Palmenberg A. C., Roos R. P. Relationship of Theiler's murine encephalomyelitis viruses to the cardiovirus genus of picornaviruses. Intervirology. 1986;26(3):140–148. doi: 10.1159/000149693. [DOI] [PubMed] [Google Scholar]
  22. Ohara Y., Stein S., Fu J. L., Stillman L., Klaman L., Roos R. P. Molecular cloning and sequence determination of DA strain of Theiler's murine encephalomyelitis viruses. Virology. 1988 May;164(1):245–255. doi: 10.1016/0042-6822(88)90642-3. [DOI] [PubMed] [Google Scholar]
  23. Oldstone M. B. Viruses can cause disease in the absence of morphological evidence of cell injury: implication for uncovering new diseases in the future. J Infect Dis. 1989 Mar;159(3):384–389. doi: 10.1093/infdis/159.3.384. [DOI] [PubMed] [Google Scholar]
  24. Pelletier J., Kaplan G., Racaniello V. R., Sonenberg N. Cap-independent translation of poliovirus mRNA is conferred by sequence elements within the 5' noncoding region. Mol Cell Biol. 1988 Mar;8(3):1103–1112. doi: 10.1128/mcb.8.3.1103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pelletier J., Kaplan G., Racaniello V. R., Sonenberg N. Translational efficiency of poliovirus mRNA: mapping inhibitory cis-acting elements within the 5' noncoding region. J Virol. 1988 Jul;62(7):2219–2227. doi: 10.1128/jvi.62.7.2219-2227.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pelletier J., Sonenberg N. Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature. 1988 Jul 28;334(6180):320–325. doi: 10.1038/334320a0. [DOI] [PubMed] [Google Scholar]
  27. Pevear D. C., Calenoff M., Rozhon E., Lipton H. L. Analysis of the complete nucleotide sequence of the picornavirus Theiler's murine encephalomyelitis virus indicates that it is closely related to cardioviruses. J Virol. 1987 May;61(5):1507–1516. doi: 10.1128/jvi.61.5.1507-1516.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Pilipenko E. V., Blinov V. M., Romanova L. I., Sinyakov A. N., Maslova S. V., Agol V. I. Conserved structural domains in the 5'-untranslated region of picornaviral genomes: an analysis of the segment controlling translation and neurovirulence. Virology. 1989 Feb;168(2):201–209. doi: 10.1016/0042-6822(89)90259-6. [DOI] [PubMed] [Google Scholar]
  29. Roos R. P., Kong W. P., Semler B. L. Polyprotein processing of Theiler's murine encephalomyelitis virus. J Virol. 1989 Dec;63(12):5344–5353. doi: 10.1128/jvi.63.12.5344-5353.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Roos R. P., Stein S., Ohara Y., Fu J. L., Semler B. L. Infectious cDNA clones of the DA strain of Theiler's murine encephalomyelitis virus. J Virol. 1989 Dec;63(12):5492–5496. doi: 10.1128/jvi.63.12.5492-5496.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Roos R. P., Stein S., Routbort M., Senkowski A., Bodwell T., Wollmann R. Theiler's murine encephalomyelitis virus neutralization escape mutants have a change in disease phenotype. J Virol. 1989 Oct;63(10):4469–4473. doi: 10.1128/jvi.63.10.4469-4473.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ruiz-Linares A., Bouloy M., Girard M., Cahour A. Modulations of the in vitro translational efficiencies of Yellow Fever virus mRNAs: interactions between coding and noncoding regions. Nucleic Acids Res. 1989 Apr 11;17(7):2463–2476. doi: 10.1093/nar/17.7.2463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Simoes E. A., Sarnow P. An RNA hairpin at the extreme 5' end of the poliovirus RNA genome modulates viral translation in human cells. J Virol. 1991 Feb;65(2):913–921. doi: 10.1128/jvi.65.2.913-921.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Svitkin Y. V., Cammack N., Minor P. D., Almond J. W. Translation deficiency of the Sabin type 3 poliovirus genome: association with an attenuating mutation C472----U. Virology. 1990 Mar;175(1):103–109. doi: 10.1016/0042-6822(90)90190-3. [DOI] [PubMed] [Google Scholar]
  35. Tangy F., McAllister A., Aubert C., Brahic M. Determinants of persistence and demyelination of the DA strain of Theiler's virus are found only in the VP1 gene. J Virol. 1991 Mar;65(3):1616–1618. doi: 10.1128/jvi.65.3.1616-1618.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Trono D., Andino R., Baltimore D. An RNA sequence of hundreds of nucleotides at the 5' end of poliovirus RNA is involved in allowing viral protein synthesis. J Virol. 1988 Jul;62(7):2291–2299. doi: 10.1128/jvi.62.7.2291-2299.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Westrop G. D., Wareham K. A., Evans D. M., Dunn G., Minor P. D., Magrath D. I., Taffs F., Marsden S., Skinner M. A., Schild G. C. Genetic basis of attenuation of the Sabin type 3 oral poliovirus vaccine. J Virol. 1989 Mar;63(3):1338–1344. doi: 10.1128/jvi.63.3.1338-1344.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Yamada M., Zurbriggen A., Fujinami R. S. The relationship between viral RNA, myelin-specific mRNAs, and demyelination in central nervous system disease during Theiler's virus infection. Am J Pathol. 1990 Dec;137(6):1467–1479. [PMC free article] [PubMed] [Google Scholar]
  39. Zuker M., Stiegler P. Optimal computer folding of large RNA sequences using thermodynamics and auxiliary information. Nucleic Acids Res. 1981 Jan 10;9(1):133–148. doi: 10.1093/nar/9.1.133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Zurbriggen A., Yamada M., Thomas C., Fujinami R. S. Restricted virus replication in the spinal cords of nude mice infected with a Theiler's virus variant. J Virol. 1991 Feb;65(2):1023–1030. doi: 10.1128/jvi.65.2.1023-1030.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. del Angel R. M., Papavassiliou A. G., Fernández-Tomás C., Silverstein S. J., Racaniello V. R. Cell proteins bind to multiple sites within the 5' untranslated region of poliovirus RNA. Proc Natl Acad Sci U S A. 1989 Nov;86(21):8299–8303. doi: 10.1073/pnas.86.21.8299. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES