Entry of Viruses into the Central Nervous System

  • John K. Fazakerley


Viral meningitis and encephalitis are not rare diseases. In adults in Europe and the USA, incidences from 11 to 26 per 100,000 population per annum have been reported for viral meningitis and 3 to 7 per 100,000 for viral encephalitis (Ponka and Pettersson, 1982; Beghi et al.,1984). Encephalitis is more common in children, a 20 year survey in Finland determined a peak incidence of 17 per 100,000 child years in the second year of life (Koskiniemi et al.,1991). In one study of an endemic area of India, the incidence of Japanese encephalitis cases was 15 per 10,000 children aged 5–9 years with total population morbidity rates estimated at 0.30 to 1.5 per 100,000 (Gajanana et al.,1995; Reuben and Gajanana, 1997). In addition to meningitis and encephalitis, viruses are associated with subacute and chronic demyelinating disease for example measles virus and subacute sclerosing panencephalitis; with dementia, for example AIDS dementia; with hydrocephalus, for example mumps virus in children; with neurodegenerative disease, for example spongiform degeneration with murine (Cas-Br-E) retroviruses; with neuro-developmental abnormalities, for example rubella virus or feline panleukopenia virus and cerebellar hypoplasia and possibly with a number of neurological diseases of unknown aetiology such as multiple sclerosis, motor neurone disease or some Parkinsonian conditions. For reviews see Johnson, 1998; Fazakerley, 2001.


Olfactory Bulb Rabies Virus Measle Virus Japanese Encephalitis Olfactory Nerve 
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  1. Allsopp, T.E., and Fazakerley, J.K. 2000. Altruistic cell suicide and the specialised case of the virus-infected central nervous system. Trends in Neurosci. 23: 284–290.CrossRefGoogle Scholar
  2. Amor, S., Scallan, M.F., Morris, M.M., Dyson, H., and Fazakerley, J.K. 1996. Role of immune responses in protection and pathogenesis during Semliki Forest virus encephalitis. J. Gen. Virol. 77: 281–291.PubMedCrossRefGoogle Scholar
  3. Balluz, I.M., Glasgow, G.M., Killen, H.M., Mabruk, M.F., Sheahan, B.J., and Atkins, G.J. 1993. Virulent and avirulent strains of semliki forest virus show similar cell tropism for the murine central-nervous-system but differ in the severity and rate of induction of cytolytic damage. Neuropath. Appl. Neurobiol. 19: 233–239.CrossRefGoogle Scholar
  4. Beghi, E., Nicolosi, A., Kurland, L.T., Mulder, D.W., Hauser W.A., and Shuster, L. 1984. Encephalitis and aseptic meningitis, Olmsted County, Minnesota, 1950-1981. Epidemiology. Ann. Neurol. 16: 283–294.PubMedCrossRefGoogle Scholar
  5. Brahic, M., Stowring, L., Ventura, P., and Haase, A.T. 1981. Gene expression in visna virus infection in sheep. Nature 292: 240.PubMedCrossRefGoogle Scholar
  6. Constantine, D.G. 1962. Rabies transmission by nonbite route. Public Health Rep. 77: 287–289.PubMedCrossRefGoogle Scholar
  7. Cross, A.H., Cannella, B., Brosnan, C.F., and Raine, C.S. 1990. Homing to CNS vasculature by antigen-specific lymphocytes. Lab. Invest. 63: 162–170.PubMedGoogle Scholar
  8. Detels, R., Brody, J.A., McNew, J., and Edgar, A.H. 1973. Further epidemiological studies of subacute sclerosing panencephalitis. Lancet 21: 11–14.CrossRefGoogle Scholar
  9. Donnelly, S.M., Sheahan, B.J., and Atkins, G.J. 1997. Long-term effects of Semliki Forest virus infection in the mouse central nervous system. Neuropath. Appl. Neurobiol. 23: 235–241.CrossRefGoogle Scholar
  10. Dropulic, B. and Masters, C.L. 1990. Entry of neurotropic arboviruses into the central nervous system: An in vitro study using mouse brain endothelium. J. Infect. Dis. 161, 685–691.PubMedCrossRefGoogle Scholar
  11. Fazakerley, J.K. 2001. Neurovirology and developmental neurobiology. Adv Vir. Res. 56: 75–126.Google Scholar
  12. Fazakerley, J.K. and Webb, H.E. 1987. Semliki Forest virus-induced, immune-mediated demyelination — adoptive transfer studies and viral persistence in nude-mice. J. Gen. Virol. 68: 377–385.PubMedCrossRefGoogle Scholar
  13. Fazakerley, J.K., Pathak, S., Scallan, M., Amor, S., and Dyson, H. 1993. Replication of the A7(74) Strain of Semliki Forest virus is restricted in neurons. Virology 195: 627–637.PubMedCrossRefGoogle Scholar
  14. Fazakerley, J.K. and Allsopp, T.E. 2001. Programmed cell death in virus infections of the nervous system. Curr. Top. Microbiol. Immunol. 253: 69–93.Google Scholar
  15. Gajanana, A., Thenmozhi, V., Samuel, P.P., and Reuben, R. 1995. A community-based study of subclinical flavivirus infections in children in an area of Tamil Nadu, India, where Japanese encephalitis is endemic. Bull. World Hlth Org 73: 237–244.Google Scholar
  16. Gates, M.C., Sheahan, B.J., and Atkins, G.J. 1984. The pathogenicity of the M9 mutant of Semliki Forest virus in immune-compromised mice. J. Gen. Virol. 65: 73–80.PubMedCrossRefGoogle Scholar
  17. Hamashima, Y., Kyogoku, M., Hiramatusu, S., Nakashima, Y., and Yamaucki, R. 1959. Immuno-cytological studies employing labeled active protein. III. Encephalitis Japonica. Acta Pathol Jpn 9: 89–108.Google Scholar
  18. Herndon, R.M., Johnson, R.T., Davis, L.E., and Descalzi, L.R. 1974. Ependymitis in mumps virus meningitis: electronmicroscopical studies of cerebrospinal fluid. Arch Neurol 30: 475–479.PubMedCrossRefGoogle Scholar
  19. Johnson, R.T. 1964. The pathogenesis of herpes virus encephalitis. I. Virus pathways to the nervous system of suckling mice demonstrated by fluorescent antibody staining. J.Exp.Med. 119: 343–356.PubMedCrossRefGoogle Scholar
  20. Johnson, R.T. 1998. Viral infections of the nervous system (second edition), Lippincott-Raven; Philadelphia.Google Scholar
  21. Johnson, R.T., and Mims, C.A. 1968. Medical progress, pathogenesis of viral infections of the nervous system. N. Engl. J. Med. 278: 23–30.PubMedCrossRefGoogle Scholar
  22. Kaluza, G., Lell, G., Reinacher, M., Stitz, L., and Willems, W.R. 1987. Neurogenic spread of Semliki Forest virus in mice. Arch. Virol. 93: 97–110.PubMedCrossRefGoogle Scholar
  23. Koskiniemi, M., Rautonen, J., Lehtokoski-Lehtiniemi, E., and Vaheri, A. 1991. Epidemiology of encephalitis in children: a 20-year survey. Ann. Neurol. 29: 492–497.PubMedCrossRefGoogle Scholar
  24. Kristensson, K., Lycke, E., and Sjostrand, J. 1971. Spread of herpes simplex virus in peripheral nerves. Acta Neuropathol. 17: 44–53.PubMedCrossRefGoogle Scholar
  25. Kristensson, K., Ghetti, B., and Wisniewski, H.M. 1974. Study on the propagation of herpes simplex virus (type 2) into brain after intraocular injection. Br. Res. 69: 189–201.CrossRefGoogle Scholar
  26. Lavi, E., Fishman, P.S., Highkin, M.K., and Weiss, S.R. 1988. Limbic encephalitis after inhalation of a murine Coronavirus. Lab. Invest. 58: 31–36.PubMedGoogle Scholar
  27. Liu, C., Yoth, D.W., Rodina, P., Shauf, L.R., Gonzalez, G. 1970. A comparative study of the pathogenesis of western equine and eastern equine encephalomyelitis viral infections in mice by intracerebral and subcutaneous inoculations. J. Infect Dis. 122: 53–63.PubMedCrossRefGoogle Scholar
  28. Lois, C. and Alvarez-Buylla, A. 1994. Long-distance neuronal migration in the adult mammalian brain. Science 264: 1145–1148.PubMedCrossRefGoogle Scholar
  29. Lunch, B., Kristensson, K., and Norrby, E. 1987. Selective infections of olfactory and respiratory epithelium by vesicular stomatitis and Sendai viruses. Neuropath. Appl. Neurobiol 13: 111–122.CrossRefGoogle Scholar
  30. Mims, C.A. 1964. Aspects of the pathogenesis of virus diseases. Bacteriol. Rev. 28: 30–71.PubMedGoogle Scholar
  31. Morris, M.M., Dyson, H., Baker, D., Harbige, L.S., Fazakerley, J.K., and Amor, S. 1997. Characterization of the cellular and cytokine response in the central nervous system following Semliki Forest virus infection. J. Neuroimmunol. 74: 185–197.PubMedCrossRefGoogle Scholar
  32. Murphy, F.A., Buchmeier, M.J., and Rawls, W.E.(1977). The reticuloendothlium as the target in a virus infection. Lab. Invest. 37: 502–515.Google Scholar
  33. Oliver, K.R., Scallan, M.F., Dyson, H., and Fazakerley, J.K. 1997. Susceptibility to a neurotropic virus and its changing distribution in the developing brain is a function of CNS maturity. J. Neurovirol. 3: 38–48.PubMedCrossRefGoogle Scholar
  34. Oliver, K.R. and Fazakerley, J.K. 1998. Transneuronal spread of Semliki Forest virus in the developing mouse olfactory system is determined by neuronal maturity. Neurosci. 82: 867–877.CrossRefGoogle Scholar
  35. Parsons, L.M. and Webb, H.E. 1982. Blood brain barrier disturbance and immunoglobulin G levels in the cerebrospinal fluid of the mouse following peripheral infection with the demyelinating strain of Semliki Forest virus. J. Neurol. Sci. 57: 307–318.PubMedCrossRefGoogle Scholar
  36. Parsons, L.M. and Webb, H.E. 1982. Virus titers and persistently raised white cell counts in cerebrospinal-fluid in mice after peripheral infection with demyelinating Semliki Forest virus. Neuropath. Appl. Neurobiol. 8: 395–401.CrossRefGoogle Scholar
  37. Parsons, L.M. and Webb, H.E. 1984. Specific immunoglobulin G in serum and cerebrospinal fluid of mice infected with the demyelinating strain of Semliki Forest virus. Microbios Letts. 25: 135–140.Google Scholar
  38. Parsons, L.M. and Webb, H.E. 1989. Identification of immunoglobulin-containing cells in the central nervous system of the mouse following infection with the demyelinating strain of Semliki Forest virus. Br. J. Exp. Pathol. 70: 247–255.PubMedGoogle Scholar
  39. Pathak, S. and Webb, H.E. 1974. Possible mechanisms for the transport of Semliki Forest virus into and within mouse brain: An electron microscopic study. J. Neurol. Sci. 23: 175–184.PubMedCrossRefGoogle Scholar
  40. Pathak, S. and Webb, H.E. 1980. The entry and the transport of arboviruses into and throughout mouse brain: An electron-microscopic study. Electron Microscopy 2: 492–493.Google Scholar
  41. Ponka, A. and Pettersson, T. 1982. The incidence and aetiology of central nervous system infections in Helsinki in 1980. Acta Neuropath. Scand. 66: 529–535.CrossRefGoogle Scholar
  42. Pusztai, R., Gould, E., and Smith, H. 1971. Infection pattern in mice of an avirulent and virulent strain of Semliki Forest virus. Br. J. Exp. Pathol. 52: 669–677.PubMedGoogle Scholar
  43. Reuben, R., and Gajanana, A. 1997. Japanese encephalitis in India. Ind. J. Pediatr. 64: 243–251.CrossRefGoogle Scholar
  44. Smith, J-P., Morris-Downes, M., Brennan, F.R., Wallace, G.J. and Amor, S. 2000. A role for a4-integrin in the pathology following Semliki Forest virus infection. J. Neuroimmunol. 106: 60–68.PubMedCrossRefGoogle Scholar
  45. SoiluHanninen, M., Eralinna, J.P., Hukkanen, V., Roytta, M., Salmi, A.A., and Salonen, R. 1994. Semliki-forest virus infects mouse-brain endothelial-cells and causes blood-brain-barrier damage. J. Virol. 68: 6291–6298.Google Scholar
  46. SoiluHanninen, M., Roytta, M., Salmi, A.A., and Salonen, R. 1997. Semliki Forest virus infection leads to increased expression of adhesion molecules on splenic T-cells and on brain vascular endothelium. J. Neurovirol. 3: 350–360.CrossRefGoogle Scholar
  47. Subak-Sharpe, I., Dyson, H., and Fazakerley, J.K. 1993. In vivo depletion of CD8+ T cells prevents lesions of demyelination in Semliki Forest virus infection. J. Virol. 67: 7629–7633.PubMedGoogle Scholar
  48. Theiler, M, and Gard, S. 1940. Encephalomyelitis of mice. III Epidemiology. J. Exp. Med. 79: 79–90.CrossRefGoogle Scholar
  49. Tyler, K.L., McPhee, D.A., and Fields, B.N. 1986. Distinct pathways of viral spread in the host determined by reovirus S1 gene segment. Science, 233: 770–774.PubMedCrossRefGoogle Scholar
  50. Ugolini G., Kuypers, H.G. and Strick, P.L. 1989. Transneuronal transfer of herpes virus from peripheral nerves to cortex and brainstem. Science 243: 89–91.PubMedCrossRefGoogle Scholar
  51. Wekerle, H., Sun, D., Oropeza Wekerle, R.L., and Meyermann, R. 1987. Immune reactivity in the nervous system: modulation of T-lymphocyte activation by glial cells. J. Exp. Biol. 132: 43–57.PubMedGoogle Scholar
  52. Wolinsky, J.S., Baringer, J.R., Margolis, G., Kilham, L. 1974. Ultrastructure of mumps virus replication in newborn hamster central nervous system. Lab Invest. 31: 403–412.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • John K. Fazakerley
    • 1
  1. 1.Laboratory for Clinical and Molecular Virology University of EdinburghUK

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