1887

Abstract

Enterovirus 71 (EV71) is one of the major causative agents of hand, foot and mouth disease and is sometimes associated with serious neurological disorders. In this study, an attempt was made to identify molecular determinants of EV71 attenuation of neurovirulence in a monkey infection model. An infectious cDNA clone of the virulent strain of EV71 prototype BrCr was constructed; temperature-sensitive () mutations of an attenuated strain of EV71 or of poliovirus (PV) Sabin vaccine strains were then introduced into the infectious clone. and phenotypes of the parental and mutant viruses were analysed in cultured cells and in cynomolgus monkeys, respectively. Mutations in 3D polymerase (3D) and in the 3′ non-translated region (NTR), corresponding to determinants of Sabin 1, conferred distinct temperature sensitivity to EV71. An EV71 mutant [EV71(S1-3′)] carrying mutations in the 5′ NTR, 3D and in the 3′ NTR showed attenuated neurovirulence, resulting in limited spread of virus in the central nervous system of monkeys. These results indicate that EV71 and PV1 share common genetic determinants of neurovirulence in monkeys, despite the distinct properties in their original pathogenesis.

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2005-05-01
2024-12-06
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References

  1. Abubakar S., Chee H. Y., Shafee N., Chua K. B., Lam S. K. 1999; Molecular detection of enteroviruses from an outbreak of hand, foot and mouth disease in Malaysia in 1997. Scand J Infect Dis 31:331–335 [CrossRef]
    [Google Scholar]
  2. Ahmad K. 2000; Hand, foot, and mouth disease outbreak reported in Singapore. Lancet 356:1338
    [Google Scholar]
  3. Arita M., Shimizu H., Miyamura T. 2004; Characterization of in vitro and in vivo phenotypes of poliovirus type 1 mutants with reduced viral protein synthesis activity. J Gen Virol 85:1933–1944 [CrossRef]
    [Google Scholar]
  4. Bouchard M. J., Lam D.-H., Racaniello V. R. 1995; Determinants of attenuation and temperature sensitivity in the type 1 poliovirus Sabin vaccine. J Virol 69:4972–4978
    [Google Scholar]
  5. Brown B. A., Pallansch M. A. 1995; Complete nucleotide sequence of enterovirus 71 is distinct from poliovirus. Virus Res 39:195–205 [CrossRef]
    [Google Scholar]
  6. Brown B. A., Oberste M. S., Alexander J. P. Jr, Kennett M. L., Pallansch M. A. 1999; Molecular epidemiology and evolution of enterovirus 71 strains isolated from 1970 to 1998. J Virol 73:9969–9975
    [Google Scholar]
  7. Chan L. G., Parashar U. D., Lye M. S. 9 other authors 2000; Deaths of children during an outbreak of hand, foot, and mouth disease in Sarawak, Malaysia: clinical and pathological characteristics of the disease. Clin Infect Dis 31:678–683 [CrossRef]
    [Google Scholar]
  8. Chen Y.-C., Yu C.-K., Wang Y.-F., Liu C.-C., Su I.-J., Lei H.-Y. 2004; A murine oral enterovirus 71 infection model with central nervous system involvement. J Gen Virol 85:69–77 [CrossRef]
    [Google Scholar]
  9. Christodoulou C., Colbere-Garapin F., Macadam A., Taffs L. F., Marsden S., Minor P., Horaud F. 1990; Mapping of mutations associated with neurovirulence in monkeys infected with Sabin 1 poliovirus revertants selected at high temperature. J Virol 64:4922–4929
    [Google Scholar]
  10. Chumakov M., Voroshilova M., Shindarov L. 16 other authors 1979; Enterovirus 71 isolated from cases of epidemic poliomyelitis-like disease in Bulgaria. Arch Virol 60:329–340 [CrossRef]
    [Google Scholar]
  11. 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 1985; Increased neurovirulence associated with a single nucleotide change in a noncoding region of the Sabin type 3 poliovaccine genome. Nature 314:548–550 [CrossRef]
    [Google Scholar]
  12. Fujimoto T., Chikahira M., Yoshida S., Ebira H., Hasegawa A., Totsuka A., Nishio O. 2002; Outbreak of central nervous system disease associated with hand, foot, and mouth disease in Japan during the summer of 2000: detection and molecular epidemiology of enterovirus 71. Microbiol Immunol 46:621–627 [CrossRef]
    [Google Scholar]
  13. Georgescu M. M., Tardy-Panit M., Guillot S., Crainic R., Delpeyroux F. 1995; Mapping of mutations contributing to the temperature sensitivity of the Sabin 1 vaccine strain of poliovirus. J Virol 69:5278–5286
    [Google Scholar]
  14. Hagiwara A., Yoneyama T., Hashimoto I. 1983; Isolation of a temperature-sensitive strain of enterovirus 71 with reduced neurovirulence for monkeys. J Gen Virol 64:499–502 [CrossRef]
    [Google Scholar]
  15. Hansen J. L., Long A. M., Schultz S. C. 1997; Structure of the RNA-dependent RNA polymerase of poliovirus. Structure 5:1109–1122 [CrossRef]
    [Google Scholar]
  16. Hashimoto I., Hagiwara A. 1983; Comparative studies on the neurovirulence of temperature-sensitive and temperature-resistant viruses of enterovirus 71 in monkeys. Acta Neuropathol 60:266–270 [CrossRef]
    [Google Scholar]
  17. Hashimoto I., Hagiwara A., Kodama H. 1978; Neurovirulence in cynomolgus monkeys of enterovirus 71 isolated from a patient with hand, foot and mouth disease. Arch Virol 56:257–261 [CrossRef]
    [Google Scholar]
  18. Herrero L. J., Lee C. S. M., Hurrelbrink R. J., Chua B. H., Chua K. B., McMinn P. C. 2003; Molecular epidemiology of enterovirus 71 in peninsular Malaysia, 1997–2000. Arch Virol 148:1369–1385 [CrossRef]
    [Google Scholar]
  19. Ho M., Chen E.-R., Hsu K.-H., Twu S.-J., Chen K.-T., Tsai S.-F., Wang J.-R., Shih S.-R. 1999; An epidemic of enterovirus 71 infection in Taiwan. N Engl J Med 341:929–935 [CrossRef]
    [Google Scholar]
  20. Hogle J. M., Chow M., Filman D. J. 1985; Three-dimensional structure of poliovirus at 2·9 Å resolution. Science 229:1358–1365 [CrossRef]
    [Google Scholar]
  21. Horie H., Koike S., Kurata T. 11 other authors 1994; Transgenic mice carrying the human poliovirus receptor: new animal model for study of poliovirus neurovirulence. J Virol 68:681–688
    [Google Scholar]
  22. Kärber G. 1931; Beitrag zur kollektiven Behandlung pharmakologischer Reihenversuche. Arch Exp Pathol Pharmakol 162:480–483 (in German [CrossRef]
    [Google Scholar]
  23. Kauder S. E., Racaniello V. R. 2004; Poliovirus tropism and attenuation are determined after internal ribosome entry. J Clin Invest 113:1743–1753 [CrossRef]
    [Google Scholar]
  24. Kawamura N., Kohara M., Abe S., Komatsu T., Tago K., Arita M., Nomoto A. 1989; Determinants in the 5′ noncoding region of poliovirus Sabin 1 RNA that influence the attenuation phenotype. J Virol 63:1302–1309
    [Google Scholar]
  25. Koike S., Horie H., Sato Y., Ise I., Taya C., Nomura T., Yoshioka I., Yonekawa H., Nomoto A. 1993; Poliovirus-sensitive transgenic mice as a new animal model. Dev Biol Stand 78:101–107
    [Google Scholar]
  26. Komatsu H., Shimizu Y., Takeuchi Y., Ishiko H., Takada H. 1999; Outbreak of severe neurologic involvement associated with enterovirus 71 infection. Pediatr Neurol 20:17–23 [CrossRef]
    [Google Scholar]
  27. Kuo R.-L., Kung S.-H., Hsu Y.-Y., Liu W.-T. 2002; Infection with enterovirus 71 or expression of its 2A protease induces apoptotic cell death. J Gen Virol 83:1367–1376
    [Google Scholar]
  28. Li M.-L., Hsu T.-A., Chen T.-C., Chang S.-C., Lee J.-C., Chen C.-C., Stollar V., Shih S.-R. 2002; The 3C protease activity of enterovirus 71 induces human neural cell apoptosis. Virology 293:386–395 [CrossRef]
    [Google Scholar]
  29. Lin T.-Y., Twu S.-J., Ho M.-S., Chang L.-Y., Lee C.-Y. 2003; Enterovirus 71 outbreaks, Taiwan: occurrence and recognition. Emerg Infect Dis 9:291–293 [CrossRef]
    [Google Scholar]
  30. Lu H.-H., Alexander L., Wimmer E. 1995; Construction and genetic analysis of dicistronic polioviruses containing open reading frames for epitopes of human immunodeficiency virus type 1 gp120. J Virol 69:4797–4806
    [Google Scholar]
  31. Lu C.-Y., Lee C.-Y., Kao C.-L. 8 other authors 2002; Incidence and case-fatality rates resulting from the 1998 enterovirus 71 outbreak in Taiwan. J Med Virol 67:217–223 [CrossRef]
    [Google Scholar]
  32. Lum L. C. S., Wong K. T., Lam S. K. 7 other authors 1998; Fatal enterovirus 71 encephalomyelitis. J Pediatr 133:795–798 [CrossRef]
    [Google Scholar]
  33. Macadam A. J., Arnold C., Howlett J. 9 other authors 1989; Reversion of the attenuated and temperature-sensitive phenotypes of the Sabin type 3 strain of poliovirus in vaccinees. Virology 172:408–414 [CrossRef]
    [Google Scholar]
  34. Macadam A. J., Pollard S. R., Ferguson G., Dunn G., Skuce R., Almond J. W., Minor P. D. 1991; The 5′ noncoding region of the type 2 poliovirus vaccine strain contains determinants of attenuation and temperature sensitivity. Virology 181:451–458 [CrossRef]
    [Google Scholar]
  35. Malnou C. E., Werner A., Borman A. M., Westhof E., Kean K. M. 2003; Effects of vaccine strain mutations in domain V of the internal ribosome entry segment compared in the wild type poliovirus type 1 context. J Biol Chem 279:10261–10269
    [Google Scholar]
  36. McMinn P. C. 2002; An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol Rev 26:91–107 [CrossRef]
    [Google Scholar]
  37. McMinn P., Stratov I., Dowse G. 1999; Enterovirus 71 outbreak in Western Australia associated with acute flaccid paralysis. Preliminary report. Commun Dis Intell 23:199
    [Google Scholar]
  38. McMinn P., Lindsay K., Perera D., Chan H. M., Chan K. P., Cardosa M. J. 2001a; Phylogenetic analysis of enterovirus 71 strains isolated during linked epidemics in Malaysia, Singapore, and Western Australia. J Virol 75:7732–7738 [CrossRef]
    [Google Scholar]
  39. McMinn P., Stratov I., Nagarajan L., Davis S. 2001b; Neurological manifestations of enterovirus 71 infection in children during an outbreak of hand, foot, and mouth disease in Western Australia. Clin Infect Dis 32:236–242 [CrossRef]
    [Google Scholar]
  40. Minor P. D. 1992; The molecular biology of poliovaccines. J Gen Virol 73:3065–3077 [CrossRef]
    [Google Scholar]
  41. Minor P. D., Dunn G., Evans D. M. A. 8 other authors 1989; The temperature sensitivity of the Sabin type 3 vaccine strain of poliovirus: molecular and structural effects of a mutation in the capsid protein VP3. J Gen Virol 70:1117–1123 [CrossRef]
    [Google Scholar]
  42. Muzychenko A. R., Lipskaya G. Yu., Maslova S. V., Svitkin Y. V., Pilipenko E. V., Nottay B. K., Kew O. M., Agol V. I. 1991; Coupled mutations in the 5′-untranslated region of the Sabin poliovirus strains during in vivo passages: structural and functional implications. Virus Res 21:111–122 [CrossRef]
    [Google Scholar]
  43. Nagata N., Shimizu H., Ami Y. 7 other authors 2002; Pyramidal and extrapyramidal involvement in experimental infection of cynomolgus monkeys with enterovirus 71. J Med Virol 67:207–216 [CrossRef]
    [Google Scholar]
  44. Nagata N., Iwasaki T., Ami Y. 8 other authors 2004; Differential localization of neurons susceptible to enterovirus 71 and poliovirus type 1 in the central nervous system of cynomolgus monkeys after intravenous inoculation. J Gen Virol 85:2981–2989 [CrossRef]
    [Google Scholar]
  45. Omata T., Kohara M., Kuge S. 8 other authors 1986; Genetic analysis of the attenuation phenotype of poliovirus type 1. J Virol 58:348–358
    [Google Scholar]
  46. Paul A. V., Mugavero J., Yin J., Hobson S., Schultz S., van Boom J. H., Wimmer E. 2000; Studies on the attenuation phenotype of polio vaccines: poliovirus RNA polymerase derived from Sabin type 1 sequence is temperature sensitive in the uridylylation of VPg. Virology 272:72–84 [CrossRef]
    [Google Scholar]
  47. Pilipenko E. V., Blinov V. M., Romanova L. I., Sinyakov A. N., Maslova S. V., Agol V. I. 1989; Conserved structural domains in the 5′-untranslated region of picornaviral genomes: an analysis of the segment controlling translation and neurovirulence. Virology 168:201–209 [CrossRef]
    [Google Scholar]
  48. Pulli T., Koskimies P., Hyypiä T. 1995; Molecular comparison of coxsackie A virus serotypes. Virology 212:30–38 [CrossRef]
    [Google Scholar]
  49. Ren R., Costantini F., Gorgacz E. J., Lee J. J., Racaniello V. R. 1990; Transgenic mice expressing a human poliovirus receptor: a new model for poliomyelitis. Cell 63:353–362 [CrossRef]
    [Google Scholar]
  50. Rowe A., Ferguson G. L., Minor P. D., Macadam A. J. 2000; Coding changes in the poliovirus protease 2A compensate for 5′NCR domain V disruptions in a cell-specific manner. Virology 269:284–293 [CrossRef]
    [Google Scholar]
  51. Sambrook J., Russell D. 2001; Molecular Cloning: a Laboratory Manual . , 3rd edn.pp. 13.19–13.25 Cold Spring Harbor, NY: Cold Spring Harbor Laboratory;
  52. Schmidt N. J., Lennette E. H., Ho H. H. 1974; An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis 129:304–309 [CrossRef]
    [Google Scholar]
  53. Shimizu H., Utama A., Yoshii K. 13 other authors 1999; Enterovirus 71 from fatal and nonfatal cases of hand, foot and mouth disease epidemics in Malaysia, Japan and Taiwan in 1997-1998. Jpn J Infect Dis 52:12–15
    [Google Scholar]
  54. Svitkin Y. V., Maslova S. V., Agol V. I. 1985; The genomes of attenuated and virulent poliovirus strains differ in their in vitro translation efficiencies. Virology 147:243–252 [CrossRef]
    [Google Scholar]
  55. Svitkin Y. V., Pestova T. V., Maslova S. V., Agol V. I. 1988; Point mutations modify the response of poliovirus RNA to a translation initiation factor: a comparison of neurovirulent and attenuated strains. Virology 166:394–404 [CrossRef]
    [Google Scholar]
  56. Svitkin Y. V., Cammack N., Minor P. D., Almond J. W. 1990; Translation deficiency of the Sabin type 3 poliovirus genome: association with an attenuating mutation C472→U. Virology 175:103–109 [CrossRef]
    [Google Scholar]
  57. Tardy-Panit M., Blondel B., Martin A., Tekaia F., Horaud F., Delpeyroux F. 1993; A mutation in the RNA polymerase of poliovirus type 1 contributes to attenuation in mice. J Virol 67:4630–4638
    [Google Scholar]
  58. Thompson S. R., Sarnow P. 2003; Enterovirus 71 contains a type I IRES element that functions when eukaryotic initiation factor eIF4G is cleaved. Virology 315:259–266 [CrossRef]
    [Google Scholar]
  59. Wang J.-R., Tuan Y.-C., Tsai H.-P., Yan J.-J., Liu C.-C., Su I. J. 2002; Change of major genotype of enterovirus 71 in outbreaks of hand-foot-and-mouth disease in Taiwan between 1998 and 2000. J Clin Microbiol 40:10–15 [CrossRef]
    [Google Scholar]
  60. Wang S.-M., Lei H.-Y., Huang K.-J., Wu J.-M., Wang J.-R., Yu C.-K., Su I.-J., Liu C.-C. 2003; Pathogenesis of enterovirus 71 brainstem encephalitis in pediatric patients: roles of cytokines and cellular immune activation in patients with pulmonary edema. J Infect Dis 188:564–570 [CrossRef]
    [Google Scholar]
  61. Wang Y.-F., Chou C.-T., Lei H.-Y. 8 other authors 2004; A mouse-adapted enterovirus 71 strain causes neurological disease in mice after oral infection. J Virol 78:7916–7924 [CrossRef]
    [Google Scholar]
  62. Westrop G. D., Wareham K. A., Evans D. M. A. 8 other authors 1989; Genetic basis of attenuation of the Sabin type 3 oral poliovirus vaccine. J Virol 63:1338–1344
    [Google Scholar]
  63. Zhao W. D., Lahser F. C., Wimmer E. 2000; Genetic analysis of a poliovirus/hepatitis C virus (HCV) chimera: interaction between the poliovirus cloverleaf and a sequence in the HCV 5′ nontranslated region results in a replication phenotype. J Virol 74:6223–6226 [CrossRef]
    [Google Scholar]
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