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. 2004 Oct 7;11(2):109–127. doi: 10.1002/ana.410110202

Experimental models of virus‐induced demyelination of the central nervous system

Mauro C Dal Canto 1,✉, Stanley G Rabinowitz 2
PMCID: PMC7159566  PMID: 6280582

Abstract

One of the arguments in favor of a viral pathogenesis for multiple sclerosis is the existence of several experimental and natural animal models of virus‐induced primary demyelination. This review deals comprehensively with such models. Well‐known examples of demyelinating viral infections in their natural host are JHM, Theiler, visna, and canine distemper encephalomyelitides. Recent reports of experimental murine infections with pathogens such as vesicular stomatitis, Chandipura, herpes simplex, Venezuelan equine encephalomyelitis, and Semliki Forest viruses are also discussed. The thrust of the review is to include viral models suspected of producing primary demyelination on an immunopathological basis.

References

  • 1. Alter M, Leibowitz U, Speer J: Risk of multiple sclerosis related to age at immigration to Israel. Arch Neurol 15: 234–237, 1966. [DOI] [PubMed] [Google Scholar]
  • 2. Andrewes CH, Pereira HG, Wildy P: Herpetoviridae In Andrewes CH, Pereira HG, Wildy P. (eds): Viruses of Vertebrates. Fourth edition London, Bailliere Tindall, 1978, pp 312–355 [Google Scholar]
  • 3. Andrewes CH, Pereira HG, Wildy P: Paramyxoviridae In Andrews CH, Pereira HG, Wildy P. (eds): Viruses of Vertebrates. Fourth edition London, Bailliere Tindall, 1978, pp 221–254 [Google Scholar]
  • 4. Andrewes CH, Pereira HG, Wildy P: Retroviridae In Andrewes CH, Pereira HG, Wildy P. (eds): Viruses of Vertebrates. Fourth edition London, Bailliere Tindall, 1978, pp 133–165 [Google Scholar]
  • 5. Andrewes CH, Pereira HG, Wildy P: Togaviridae In Andrewes CH, Pereira HG, Wildy P. (eds): Viruses of Vertebrates. Fourth edition London, Bailliere Tindall, 1978, pp 67–118 [Google Scholar]
  • 6. Appel MJG: Pathogenesis of canine distemper. Am J Vet Res 30: 1167–1182, 1969. [PubMed] [Google Scholar]
  • 7. Bhatt PN, Rodrigues FM: Chandipura, a new rhabdovirus isolated in India from patients with febrile illness. Ind J Med Res 55: 1295–1305, 1976. [PubMed] [Google Scholar]
  • 8. Bradish CJ, Allner K, Maber HB: The virulence of original and derived strains of Semliki Forest virus for mice, guinea pigs and rabbits. J Gen Virol 12: 141–160, 1971. [DOI] [PubMed] [Google Scholar]
  • 9. Burks JS, DeVald BL, Jankovsky LD, Gerdes JC: Two coronaviruses isolated from central nervous system tissue of two multiple sclerosis patients. Science 209: 933–934, 1980. [DOI] [PubMed] [Google Scholar]
  • 10. Burridge MJ: Multiple sclerosis, house pets and canine distemper: critical review of recent reports. J Am Vet Med Assoc 173: 1439–1444, 1978. [Google Scholar]
  • 11. Bussell RH, Waters DJ, Seals MK: Measles, canine distemper and respiratory syncytial virions and nucleocapsids. A comparative study of their structure, polypeptide and nucleic acid composition. Med Microbiol Immunol 160: 105–124, 1974. [DOI] [PubMed] [Google Scholar]
  • 12. Cammer W, Bloom BR, Norton WT, Gordon S: Degradation of basic protein in myelin by neutral proteases secreted by stimulated macrophages: a possible mechanism of inflammatory demyelination. Proc Natl Acad Sci USA 75: 1554–1558, 1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Carp RI, Licursi PC, Merz PA, Merz GS: Decreased percentage of polymorphonuclear neutrophils in mouse peripheral blood after inoculation with material from multiple sclerosis patients. J Exp Med 136: 618–629, 1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Carpenter S, Lampert PW: Postinfectious perivenous encephalitis and acute hemorrhagic leukoencephalitis In Minckler J. (ed): Pathology of the Nervous System. New York, McGraw‐Hill, 1972, pp 2260–2269 [Google Scholar]
  • 15. Cheever FS, Daniels JB, Pappenheimer AM, Bailey OT: A murine virus (JHM) causing disseminated encephalomyelitis with extensive destruction of myelin. I. Isolation and biological properties of the virus. J Exp Med 90: 181–194, 1949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Chew‐Lim M, Suckling AJ, Webb HE: Demyelination in mice after two or three infections with avirulent Semliki Forest virus. Vet Pathol 14: 67–72, 1977. [DOI] [PubMed] [Google Scholar]
  • 17. Ciongoli AK, Lisak RP, Zweiman B, Koprowski H, Waters D: In vitro cellular responsiveness in multiple sclerosis patients to a purified measles virus nuclear core and to other viral antigens. J Neurol Sci 28: 331–338, 1976. [DOI] [PubMed] [Google Scholar]
  • 18. Cook SD, Dowling PC: A possible association between house pets and multiple sclerosis. Lancet 1: 980–982, 1977. [DOI] [PubMed] [Google Scholar]
  • 19. Cook SD, Dowling PC, Russell WC: Neutralizing antibodies to canine distemper and measles virus in multiple sclerosis. J Neurol Sci 41: 61–70, 1979. [DOI] [PubMed] [Google Scholar]
  • 20. Dal Canto MC: Uncoupled relationship between demyelination and primary infection of myelinating cells in Theiler's virus encephalomyelitis. Infect Immun (in press) [DOI] [PMC free article] [PubMed]
  • 21. Dal Canto MC, Lipton HL: Primary demyelination in Theiler's virus infection: an ultrastructural study. Lab Invest 33: 626–637, 1975. [PubMed] [Google Scholar]
  • 22. Dal Canto MC, Lipton HL: Schwann cell remyelination and recurrent demyelination in the central nervous system of mice infected with attenuated Theiler's virus. Am J Pathol 98: 101–122, 1980. [PMC free article] [PubMed] [Google Scholar]
  • 23. Dal Canto MC, Lipton HL: Ultrastructural immunohistochemical demonstration of Theiler's virus in acute and chronic Theiler's demyelinating encephalomyelitis. Am J Pathol (in press) [PMC free article] [PubMed]
  • 24. Dal Canto MC, Rabinowitz SG: Central nervous system demyelination in Venezuelan equine encephalomyelitis infection. An experimental model of virus‐induced myelin injury. J Neurol Sci 49: 397–418, 1981. [DOI] [PubMed] [Google Scholar]
  • 25. Dal Canto MC, Rabinowitz SG: Murine central nervous system infection by a viral temperature‐sensitive mutant. Am J Pathol 102: 412–426, 1981. [PMC free article] [PubMed] [Google Scholar]
  • 26. Dal Canto MC, Rabinowtiz SG, Johnson TC: Subacute infection with temperature‐sensitive vesicular stomatitis virus mutant G41 in the central nervous system of mice. II. Immunofluorescent, morphologic and immunologic studies. J Infect Dis 139: 36–51, 1979. [DOI] [PubMed] [Google Scholar]
  • 27. Dal Canto MC, Rabinowitz SG, Johnson TC: Virus‐induced demyelination. Production by a viral temperature‐sensitive mutant. J Neurol Sci 42: 155–168, 1979. [DOI] [PubMed] [Google Scholar]
  • 28. Dal Canto MC, Wisniewski HM, Johnson AB, Brostoff SW, Raine CS: Vesicular disruption of myelin in autoimmune demyelination. J Neurol Sci 24: 313–319, 1975. [DOI] [PubMed] [Google Scholar]
  • 29. Daniels JB, Pappenheimer AM, Richardson S: Observations on encephalomyelitis of mice (DA strain). J Exp Med 96: 517–530, 1952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Fleury HJA, Sheppard RD, Bornstein MB, Raine CS: Further ultrastructural observations of virus morphogenesis and myelin pathology of JHM virus encephalomyelitis. Neuropathol Appl Neurobiol 6: 165–179, 1980. [DOI] [PubMed] [Google Scholar]
  • 31. Gadkari DA, Pringle CR: Temperature‐sensitive mutants of Chandipura virus. I. Inter‐and intragroup complementation. J Virol 33: 100–106, 1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Georgsson G, Martin JR, Klein J, Palsson PA, Nathanson N, Petursson G: Primary demyelination in visna, An ultrastructural study of Icelandic sheep with clinical signs following experimental infection. Submitted for publication [DOI] [PubMed]
  • 33. Georgsson G, Nathanson N, Palsson PA, Petursson G: The pathology of visna and maedi in sheep In Kimberlin RH. (ed): Slow Virus Disease of Animals and Man. Amsterdam and New York, North‐Holland, 1976, pp 61–96 [PubMed] [Google Scholar]
  • 34. Georgsson G, Palsson PA, Panitch H, Nathanson N, Petursson G: The ultrastructure of early visna lesions. Acta Neuropathol (Berl) 37: 127–135, 1977. [DOI] [PubMed] [Google Scholar]
  • 35. Ghatak NR, Hirano A, Doron Y, Zimmerman HM: Remyelination in multiple sclerosis with peripheral type myelin. Arch Neurol 29: 262–267, 1973. [DOI] [PubMed] [Google Scholar]
  • 36. Harter DH: The detailed structure of visna‐maedi virus In Kimberlin RH. (ed): Slow Virus Diseases of Animals and Man. Amsterdam and New York, North‐Holland, 1976, pp 45–60 [PubMed] [Google Scholar]
  • 37. Haspel MV, Duff R, Rapp F: Experimental measles encephalitis: a genetic analysis. Infect Immun 12: 785–790, 1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Herndon RM, Griffin DE, McCormick U, Weiner LP: Mouse hepatitis virus‐induced recurrent demyelination. Arch Neurol 32: 32–35, 1975. [DOI] [PubMed] [Google Scholar]
  • 39. Howatson AF: Vesicular stomatitis and related viruses. Prog Virol 25: 195–256, 1973. [DOI] [PubMed] [Google Scholar]
  • 40. Jagelman S, Suckling AJ, Webb HE, Bowen ETW: The pathogenesis of avirulent Semliki Forest virus infection in athymic nude mice. J Gen Virol 41: 599–607, 1978. [DOI] [PubMed] [Google Scholar]
  • 41. Johnson RT, Weiner LP: The role of viral infections in demyelinating diseases In Wolfgram F, Ellison G, Stevens J, Andrews J. (eds): Multiple Sclerosis. New York and London, Academic, 1972, pp 245–264 [Google Scholar]
  • 42. Kelly WR, Blakemore WF, Jagelman S, Webb HE: An EM study of the focal demyelinating lesions in the mouse CNS during 29 days after an IP injection of avirulent Semliki Forest virus. J Neuropathol Appl Neurobiol (in press) [DOI] [PubMed]
  • 43. Koestner A, Long JF: Ultrastructure of canine distemper virus in explant tissue cultures of canine cerebellum. Lab Invest 23: 196–201, 1970. [PubMed] [Google Scholar]
  • 44. Krakowka S, McCullough B, Koestner A, Olsen RG: Myelin specific autoantibodies associated with central nervous system demyelination in canine distemper infection. Infect Immun 8: 819–827, 1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Krakowka S, Koestner A: Age‐related susceptibility to infection with canine distemper virus in gnotobiotic dogs. J Infect Dis 134: 629–632, 1976. [DOI] [PubMed] [Google Scholar]
  • 46. Krakowka S, Koestner A: Canine distemper virus and multiple sclerosis. Lancet 1: 1127–1128, 1978. [DOI] [PubMed] [Google Scholar]
  • 47. Krakowka S, Mador RA, Koestner A: Canine distemper virus‐associated encephalitis: modification by passive antibody administration. Acta Neuropathol (Berl) 43: 235–241, 1978. [DOI] [PubMed] [Google Scholar]
  • 48. Kurland L, Brian D: Multiple sclerosis and canine pets. Ann Neurol 3: 97–100, 1978. [DOI] [PubMed] [Google Scholar]
  • 49. Kurtzke JF, Hyllested K: Multiple sclerosis in the Faroe Islands: I. Clinical and epidemiological features. Ann Neurol 5: 6–21, 1979. [DOI] [PubMed] [Google Scholar]
  • 50. Lampert PW: Autoimmune and virus‐induced demyelinating diseases. A review. Am J Pathol 91: 176–208, 1978. [PMC free article] [PubMed] [Google Scholar]
  • 51. Lampert PW, Carpenter S: Electron microscopic studies on the vascular permeability and the mechanisms of demyelination in experimental allergic encephalomyelitis. J Neuropathol Exp Neurol 24: 11–24, 1965. [DOI] [PubMed] [Google Scholar]
  • 52. Lampert PW, Sims JK, Kniazeff AJ: Mechanism of demyelination in JHM virus encephalomyelitis. Electron microscopic studies. Acta Neuropathol (Berl) 24: 76–85, 1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Leon CA, Jaramillo R, Martinez S, Fernandez F, Teller H, Lasso B, De Guzman R: Sequelae of Venezuelan equine encephalitis in humans: a four‐year follow‐up. Int J Epidemiol 4: 131–140, 1975. [DOI] [PubMed] [Google Scholar]
  • 54. Levintow L: Reproduction of picornaviruses. Comp Virol 2: 109–169, 1976. [Google Scholar]
  • 55. Lipton HL: Theiler's virus infection in mice: an unusual biphasic disease process leading to demyelination. Infect Immun 11: 1147–1155, 1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Lipton HL, Dal Canto MC: Theiler's virus‐induced demyelination. Prevention by immunosuppression. Science 192: 62–64, 1976. [DOI] [PubMed] [Google Scholar]
  • 57. Lipton HL, Dal Canto MC, Rabinowitz SG: Chronic Theiler's virus infection in mice. Microbiology 1977: 505–508, 1977. [Google Scholar]
  • 58. Lipton HL, Friedman A: Purification of Theiler's murine encephalomyelitis virus and analysis of the structural virion polypeptides: correlation of the polypeptide profile with virulence. J Virol 33: 1165–1172, 1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59. Lumsden CE: Multiple sclerosis. In Vinken PJ, Bruyn GW. (eds): Amsterdam and New York, North‐Holland, 1970, pp 217–309 [Google Scholar]
  • 60. Lyons MJ, Hall WW, Petito C, Cam V, Zabriskie JB: Induction of chronic neurologic disease in mice with canine distemper virus. Neurology (NY) 30: 92–98, 1980. [DOI] [PubMed] [Google Scholar]
  • 61. Martin JR, Nathanson N: Animal models of virus‐induced demyelination In Zimmerman HM. (ed): Progress in Neuropathology. New York, Raven, 1979, pp 27–50 [Google Scholar]
  • 62. McCullough B, Krakowka S, Koestner A: Experimental canine distemper virus‐induced demyelination. Lab Invest 31: 216–222, 1974. [PubMed] [Google Scholar]
  • 63. McCullough B, Krakowka S, Koestner A, Shadduck J: Demyelinating activity of canine distemper virus isolates in gnotobiotic dogs. J Infect Dis 130: 343–350, 1974. [DOI] [PubMed] [Google Scholar]
  • 64. Nagashima K, Wege H, Meyermann R, ter Meulen V: Demyelinating encephalomyelitis induced by a long‐term corona virus infection in rats. Acta Neuropathol (Berl) 45: 205–213, 1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65. Narayan O, Griffin DE, Chase J: Antigenic drift of visna virus in persistently infected sheep. Science 197: 376–378, 1977. [DOI] [PubMed] [Google Scholar]
  • 66. Nathanson N, Panitch H, Palsson PA, Petursson G, Georgsson G: Pathogenesis of visna. II. Effect of immunosuppression upon early central nervous system lesions. Lab Invest 35: 444–451, 1976. [PubMed] [Google Scholar]
  • 67. Nathanson N, Petursson G, Georgsson G, Palsson PA, Martin JR, Miller A: Pathogenesis of visna. IV. Spinal fluid studies. J Neuropathol Exp Neurol 38: 197–208, 1979. [DOI] [PubMed] [Google Scholar]
  • 68. Norrby E, Link H, Olsson JE, Panelius M, Salmi A, Vandvik B: Comparison of antibodies against different viruses in cerebrospinal fluid and serum samples from patients with multiple sclerosis. Infect Immun 10: 688–694, 1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69. Olsson JE, Link H: Immunoglobulin abnormalities in multiple sclerosis. Relation to clinical parameters: exacerbations and remissions. Arch Neurol 28: 392–399, 1973. [DOI] [PubMed] [Google Scholar]
  • 70. Palsson PA: Maedi and visna in sheep In Kimberlin RH. (ed): Slow Virus Diseases of Animals and Man. Amsterdam and New York, North‐Holland, 1976, pp 17–43 [Google Scholar]
  • 71. Panitch HS, Swoveland P, Johnson KP: Antibodies to measles virus react with myelinic basic protein. Neurology (NY) 29: 548–549, 1979. [Google Scholar]
  • 72. Pasteur L: Méthode pour prévenir la rage aprés morsure. C R Acad Sci (Paris) 101: 765–774, 1885. [Google Scholar]
  • 73. Paterson PY: The demyelinating diseases: clinical and experimental studies in animals and man In Samter M, Alexander N, Rose B, Sherman WB, Talmage DW, Vaughn JH. (eds): Immunological Diseases. Boston, Little, Brown, 1978, pp 1400–1435 [Google Scholar]
  • 74. Paterson PY: Neuroimmunologic diseases of animals and humans. Rev Infect Dis 1: 468–482, 1979. [PubMed] [Google Scholar]
  • 75. Petursson G, Nathanson N, Georgsson G, Panitch H, Palsson PA: Pathogenesis of visna I. Sequential virologic, serologic and pathologic studies. Lab Invest 35: 402–412, 1976. [PubMed] [Google Scholar]
  • 76. Petursson G, Nathanson N, Palsson PA, Martin J, Georgsson G: Immunopathogenesis of visna. A slow virus disease of the central nervous system. Acta Neurol Scand 57 [Suppl 67]: 205–219, 1978. [PubMed] [Google Scholar]
  • 77. Powell HC, Lampert PW: Oligodendrocytes and their myelin‐plasma membrane connections in JHM mouse hepatits virus encephalomyelitis. Lab Invest 33: 440–445, 1975. [PubMed] [Google Scholar]
  • 78. Prineas JW: The etiology and pathogenesis of multiple sclerosis In Vinken PJ, Bruyn GW. (eds): Handbook of Clinical Neurology. Amsterdam and New York, North‐Holland, 1970, pp 107–160 [Google Scholar]
  • 79. Pringle CR: Genetic characteristics of conditional lethal mutants of vesicular stomatitis virus induced by 5‐fluorouracil, 5‐azacytidine and ethyl methane sulfonide. J Virol 5: 559–567, 1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80. Rabinowitz SG, Johnson TC, Dal Canto MC: Subacute infection with temperature‐sensitive vesicular stomatitis virus mutant G41 in the central nervous system of mice. I. Clinical and virological studies. J Infect Dis 139: 26–35, 1979. [DOI] [PubMed] [Google Scholar]
  • 81. Rabinowitz SG, Lipton HL: Cellular immunity in chronic Theiler's virus central nervous system infection. J Immunol 117: 357–363, 1976. [PubMed] [Google Scholar]
  • 82. Raine CS: Experimental allergic encephalomyelitis and related conditions In Zimmerman HM. (ed): Progress in Neuropathology. New York, Grune & Stratton, 1976, pp 225–251 [Google Scholar]
  • 83. Raine CS: On the development of CNS lesions in natural canine distemper encephalomyelitis. J Neurol Sci 30: 13–28, 1976. [DOI] [PubMed] [Google Scholar]
  • 84. Robb JA, Bond CW: Coronaviridae In Fraenkel‐Conrat H, Wagner RR. (eds): Comprehensive Virology. New York, Plenum, 1979, vol 14, pp 193–247 [Google Scholar]
  • 85. Ruddle NH, Waksman BH: Cytotoxicity mediated by soluble antigen and lymphocytes in delayed hypersensitivity, Part 1 (characterization of the phenomenon). J Exp Med 128: 1237–1254, 1968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86. Sheahan BJ, Barrett PN, Atkins GJ: Demyelination in mice resulting from infection with a mutant of Semliki Forest virus. Acta Neuropathol (Berl) 53: 129–136, 1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87. Sheremata W, Cosgrove JBR, Eylar EH: Cellular hypersensitivity to basic myelin (A1) protein and clinical multiple sclerosis. N Engl J Med 291: 14–17, 1974. [DOI] [PubMed] [Google Scholar]
  • 88. Sigurdsson B: Rida, a chronic encephalitis of sheep. Br Vet J 110: 341–354, 1954. [Google Scholar]
  • 89. Stohlman SA, Frelinger JA, Weiner LP: Resistance to fatal central nervous system disease by mouse hepatitis virus, strain JHM. II. Adherent cell‐mediated protection. J Immunol 124: 1733–1739, 1980. [PubMed] [Google Scholar]
  • 90. Stohlman SA, Weiner LP: Stability of neurotropic mouse hepatitis virus (JHM strain) during chronic infection of neuroblastoma cells. Arch Virol 57: 53–61, 1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91. Stohlman SA, Weiner LP: Chronic central nervous system demyelination in mice after JHM virus infection. Neurology (NY) 31: 38–44, 1981. [DOI] [PubMed] [Google Scholar]
  • 92. Storts RW, Koestner A, Dennis RA: The effects of canine distemper virus on explant tissue cultures of canine cerebellum. Acta Neuropathol (Berl) 1: 1–14, 1968. [DOI] [PubMed] [Google Scholar]
  • 93. Suckling AJ, Pathak S, Jagelman S, Webb HE: Virus‐associated demyelination. A model using avirulent Semliki Forest virus infection of mice. J Neurol Sci 39: 147–154, 1978. [DOI] [PubMed] [Google Scholar]
  • 94. Theiler M: Spontaneous encephalomyelitis of mice, a new virus disease. J Exp Med 65: 705–719, 1937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95. Townsend JJ, Baringer JR: Central nervous system susceptibility to herpes simplex virus infection. J Neuropathol Exp Neurol 37: 255–262, 1978. [DOI] [PubMed] [Google Scholar]
  • 96. Townsend JJ, Baringer JR: Morphology of central nervous system disease in immunosuppressed mice after peripheral herpes simplex virus inoculation. Trigeminal root entry zone. Lab Invest 40: 178–182, 1979. [PubMed] [Google Scholar]
  • 97. Weiner LP: Pathogenesis of demyelination induced by a mouse hepatitis virus (JHM virus). Arch Neurol 28: 298–303, 1973. [DOI] [PubMed] [Google Scholar]
  • 98. Wisniewski H, Raine CS, Kay WJ: Observations on viral demyelinating encephalomyelitis. Canine distemper. Lab Invest 26: 589–599, 1972. [PubMed] [Google Scholar]
  • 99. Wisniewski HM: Immunopathology of demyelination in autoimmune diseases and virus infections. Br Med Bull 33: 54–59, 1977. [DOI] [PubMed] [Google Scholar]
  • 100. Wisniewski HM, Bloom BR: Primary demyelination as a non‐specific consequence of a cell‐mediated immune reaction. J Exp Med 141: 346–359, 1975. [DOI] [PMC free article] [PubMed] [Google Scholar]

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