Skip to main content

Advertisement

Log in

Experimental Usutu virus infection of suckling mice causes neuronal and glial cell apoptosis and demyelination

  • Regular Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Usutu virus (USUV), a mosquito-borne flavivirus of the Japanese encephalitis virus group has been responsible for avian mortality in Austria since 2001. In the present study, the neuropathogenicity and neuroinvasiveness of USUV for 1-week-old suckling mice was investigated. After intraperitoneal inoculation, clinical signs like depression, disorientation, paraplegia, paralysis and coma were observed between 6 and 11 days post infection. Histologically, there was widespread neuronal apoptosis especially in the brain stem. Inflammatory infiltrates were scarce. Apoptosis was also present in white matter of cerebellum, medulla and spinal cord, and was frequently accompanied by primary demyelination. While apoptosis of neurons was clearly associated with presence of viral signals, the cause of apoptosis of white matter cells was more ambiguous. However, focal immunostaining was found in the white matter, especially in the spinal cord. As with all flaviviruses, USUV proved to be neuropathogenic for mice. In contrast to other flaviviruses, neuroinvasion occurred only in animals that were not older than 1 week at the time of inoculation. While neuronal apoptosis is a general aspect of flavivirus pathogenicity, demyelination seems to be a unique feature of USUV infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1 Fig. 2 Fig. 3
Fig. 4
Fig. 5 Fig. 6 Fig. 7 Fig. 8 A–C Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 A–D

Similar content being viewed by others

References

  1. Adam F, Digoutte J-P Virus d’Afrique (base de donnes). Centre collaborateur OMS de référence et de recherche pour les arbovirus et les virus de fièvres hémorrhagiques (CRORA). URL:http://www.pasteur.fr/recherche/banques/CRORA

  2. Andersen AA, Hanson RP (1974) Influence of sex and age on natural resistance to St. Louis encephalitis virus infection in mice. Infect Immun 9:1123–1125

    CAS  PubMed  Google Scholar 

  3. Bhatt PN, Jacoby RO (1976) Genetic resistance to lethal flavirus encephalitis. II. Effect of immunosuppression. J Infect Dis 134:166–173

    CAS  PubMed  Google Scholar 

  4. Chiba N, Iwasaki T, Mizutani T, Kariwa H, Kurata T, Takashima I (1999) Pathogenicity of tick-borne encephalitis virus isolated in Hokkaido, Japan in mouse model. Vaccine 17:779–787

    Google Scholar 

  5. Dubuisson J, Lustig S, Ruggli N, Akov Y, Rice CM (1997) Genetic determinants of Sindbis virus neuroinvasiveness. J Virol 71:2636–2646

    CAS  PubMed  Google Scholar 

  6. Eldadah AH, Nathanson N, Sarsitis R (1967) Pathogenesis of West Nile virus encephalitis in mice and rats. 1. Influence of age and species on mortality and infection. Am J Epidemiol 86:765–775

    CAS  PubMed  Google Scholar 

  7. Fazakerley JK (2002) Pathogenesis of Semliki Forest virus encephalitis. J Neurovirol 8 Suppl 2:66–74

    Google Scholar 

  8. Fazakerley JK, Walker R (2003) Virus demyelination. J Neurovirol 9:148–164

    CAS  PubMed  Google Scholar 

  9. Fazakerley JK, Khalili-Shirazi A, Webb HE (1988) Semliki Forest virus (A7[74]) infection of adult mice induces an immune-mediated demyelinating encephalomyelitis. Ann N Y Acad Sci 540:672–673

    CAS  PubMed  Google Scholar 

  10. Gold R, Schmied M, Giegerich G, Breitschopf H, Hartung HP, Toyka KV, Lassmann H (1994) Differentiation between cellular apoptosis and necrosis by the combined use of in situ tailing and nick translation techniques. Lab Invest 71:219–225

    CAS  PubMed  Google Scholar 

  11. Graber HU, Müller CF, Vandevelde M, Zurbriggen A (1995) Restricted infection with canine distemper virus leads to down- regulation of myelin gene transcription in cultured oligodendrocytes. Acta Neuropathol 90:312–318

    Article  CAS  PubMed  Google Scholar 

  12. Griffin DE, Hardwick JM (1998) Apoptosis in alphavirus encephalitis. Semin Virol 8:481–489

    Article  Google Scholar 

  13. Griffin DE, Levine B, Tyor WR, Tucker PC, Hardwick JM (1994) Age-dependent susceptibility to fatal encephalitis: alphavirus infection of neurons. Arch Virol Suppl 9:31–39

    CAS  PubMed  Google Scholar 

  14. Griffin DE, Ubol S, Despres P, Kimura T, Byrnes A (2001) Role of antibodies in controlling alphavirus infection of neurons. Curr Top Microbiol Immunol 260:191–200

    CAS  PubMed  Google Scholar 

  15. Jackson AC, Rossiter JP (1997) Apoptotic cell death is an important cause of neuronal injury in experimental Venezuelan equine encephalitis virus infection of mice. Acta Neuropathol 93:349–353

    Article  CAS  PubMed  Google Scholar 

  16. Jacoby RO, Bhatt PN (1976) Genetic resistance to lethal flavivirus encephalitis. I. Infection of congenic mice with Banzi virus. J Infect Dis 134:158–165

    CAS  PubMed  Google Scholar 

  17. Kerr DA, Larsen T, Cook SH, Fannjiang YR, Choi E, Griffin DE, Hardwick JM, Irani DN (2002) BCL-2 and BAX protect adult mice from lethal Sindbis virus infection but do not protect spinal cord motor neurons or prevent paralysis. J Virol 76:10393–10400

    Article  CAS  PubMed  Google Scholar 

  18. Lewis J, Wesselingh SL, Griffin DE, Hardwick JM (1996) Alphavirus-induced apoptosis in mouse brains correlates with neurovirulence. J Virol 70:1828–1835

    CAS  PubMed  Google Scholar 

  19. Leyssen P, Croes R, Rau P, Heiland S, Verbeken E, Sciot R, Paeshuyse J, Charlier N, De Clercq E, Meyding-Lamade U, Neyts J (2003) Acute encephalitis, a poliomyelitis-like syndrome and neurological sequelae in a hamster model for flavivirus infections. Brain Pathol 13:279–290

    PubMed  Google Scholar 

  20. Mann MA, Knipe DM, Fischbach GD, Fields BN (2002) Type 3 reovirus neuroinvasion after intramuscular inoculation: direct invasion of nerve terminals and age-dependent pathogenesis. Virology 303:222–231

    Article  CAS  PubMed  Google Scholar 

  21. Matthews V, Robertson T, Kendrick T, Abdo M, Papadimitriou J, McMinn P (2000) Morphological features of Murray Valley encephalitis virus infection in the central nervous system of Swiss mice. Int J Exp Pathol 81:31–40

    Article  CAS  PubMed  Google Scholar 

  22. Medeot SI, Contigiani MS, Sabattini MS, Diaz G (1992) Experimental neuroinvasiveness of wild and laboratory Junin virus strains. Res Virol 143:259–267

    CAS  PubMed  Google Scholar 

  23. Monath TP, Cropp CB, Harrison AK (1983) Mode of entry of a neurotropic arbovirus into the central nervous system. Reinvestigation of an old controversy. Lab Invest 48:399–410

    CAS  PubMed  Google Scholar 

  24. Mundle SD, Gao XZ, Khan S, Gregory SA, Preisler HD, Raza A (1995) Two in situ labeling techniques reveal different patterns of DNA fragmentation during spontaneous apoptosis in vivo and induced apoptosis in vitro. Anticancer Res 15:1895–1904

    CAS  PubMed  Google Scholar 

  25. Odelola HA, Oduye OO (1977) West Nile virus infection of adult mice by oral route. Arch Virol 54:251–253

    CAS  PubMed  Google Scholar 

  26. Wang Y, Lobigs M, Lee E, Mullbacher A (2003) CD8+ T cells mediate recovery and immunopathology in West Nile virus encephalitis. J Virol 77:13323–13334

    Article  CAS  PubMed  Google Scholar 

  27. Weiner LP, Cole GA, Nathanson N (1970) Experimental encephalitis following peripheral inoculation of West Nile virus in mice of different ages. J Hyg 68:435–446

    CAS  Google Scholar 

  28. Weissenböck H, Kolodziejek J, Url A, Lussy H, Rebel-Bauder B, Nowotny N (2002) Emergence of Usutu virus, an African mosquito-borne flavivirus of the Japanese encephalitis virus group, central Europe. Emerg Infect Dis 8:652–656

    PubMed  Google Scholar 

  29. Weissenböck H, Kolodziejek J, Fragner K, Kuhn R, Pfeffer M, Nowotny N (2003) Usutu virus activity in Austria, 2001–2002. Microbes Infect 5:1132–1136

    Article  PubMed  Google Scholar 

  30. Xiao SY, Guzman H, Zhang H, Travassos da Rosa AP, Tesh RB (2001) West Nile virus infection in the golden hamster (Mesocricetus auratus): a model for West Nile encephalitis. Emerg Infect Dis 7:714–721

    CAS  PubMed  Google Scholar 

  31. Zurbriggen A, Schmid I, Graber HU, Vandevelde M (1998) Oligodendroglial pathology in canine distemper. Acta Neuropathol 95:71–77

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Karin Fragner, Ingrid Friedl and Gudrun Kurz for excellent technical assistance and Klaus Bittermann for the professional digital artwork.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Herbert Weissenböck.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weissenböck, H., Bakonyi, T., Chvala, S. et al. Experimental Usutu virus infection of suckling mice causes neuronal and glial cell apoptosis and demyelination. Acta Neuropathol 108, 453–460 (2004). https://doi.org/10.1007/s00401-004-0916-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-004-0916-1

Keywords

Navigation