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. 1996 Mar;70(3):1729–1737. doi: 10.1128/jvi.70.3.1729-1737.1996

Theiler's virus persistence and demyelination in major histocompatibility complex class II-deficient mice.

M K Njenga 1, K D Pavelko 1, J Baisch 1, X Lin 1, C David 1, J Leibowitz 1, M Rodriguez 1
PMCID: PMC189997  PMID: 8627694

Abstract

Mice with targeted disruption of the A beta gene of major histocompatibility complex class II molecules (Abo) were used to investigate the role of class II gene products in resistance or susceptibility to virus-induced chronic demyelination in the central nervous system (CNS). Class-II-deficient mice from the resistant H-2b [H-2b(Abo)] and nonmutant H-2b backgrounds were infected with Theiler's murine encephalomyelitis virus intracerebrally and examined for CNS virus persistence, demyelination, and neurologic clinical signs. Virus titers measured by plaque assays showed that 8 of 10 normally resistant nonmutant H-2b mice had cleared the virus within 21 days, whereas the other 2 mice had low titers. In contrast, all class II-deficient Abo mice had high virus titers for up to 90 days after infection (4.30 log10 PFU per g of CNS tissue). Virus antigens and RNA were localized to the brains (cortex, hippocampus, thalamus, and brain stem) and spinal cords of Abo mice. Colocalization identified persistent Theiler's murine encephalomyelitis virus in oligodendrocytes and astrocytes but not in macrophages. There was demyelination in 11 of 23 and 6 of 9 Abo mice 45 and 90 days after virus infection, respectively, whereas no demyelination was observed in infected nonmutant H-2b mice. Demyelinating lesions in Abo mice showed virus-specific CD8+ T cells and macrophages but no CD4+ T cells. Spasticity and paralysis were observed in chronically infected Abo mice but not in the nonmutant H-2b mice. These findings demonstrate that class II gene products are required for virus clearance from the CNS but not for demyelination and neurologic disease.

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Selected References

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  1. 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]
  2. Bender B. S., Croghan T., Zhang L., Small P. A., Jr Transgenic mice lacking class I major histocompatibility complex-restricted T cells have delayed viral clearance and increased mortality after influenza virus challenge. J Exp Med. 1992 Apr 1;175(4):1143–1145. doi: 10.1084/jem.175.4.1143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cash E., Bandeira A., Chirinian S., Brahic M. Characterization of B lymphocytes present in the demyelinating lesions induced by Theiler's virus. J Immunol. 1989 Aug 1;143(3):984–988. [PubMed] [Google Scholar]
  4. Clatch R. J., Melvold R. W., Miller S. D., Lipton H. L. Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease in mice is influenced by the H-2D region: correlation with TEMV-specific delayed-type hypersensitivity. J Immunol. 1985 Aug;135(2):1408–1414. [PubMed] [Google Scholar]
  5. Clatch R. J., Miller S. D., Metzner R., Dal Canto M. C., Lipton H. L. Monocytes/macrophages isolated from the mouse central nervous system contain infectious Theiler's murine encephalomyelitis virus (TMEV). Virology. 1990 May;176(1):244–254. doi: 10.1016/0042-6822(90)90249-q. [DOI] [PubMed] [Google Scholar]
  6. Cosgrove D., Gray D., Dierich A., Kaufman J., Lemeur M., Benoist C., Mathis D. Mice lacking MHC class II molecules. Cell. 1991 Sep 6;66(5):1051–1066. doi: 10.1016/0092-8674(91)90448-8. [DOI] [PubMed] [Google Scholar]
  7. Doherty P. C., Hou S., Southern P. J. Lymphocytic choriomeningitis virus induces a chronic wasting disease in mice lacking class I major histocompatibility complex glycoproteins. J Neuroimmunol. 1993 Jul;46(1-2):11–17. doi: 10.1016/0165-5728(93)90228-q. [DOI] [PubMed] [Google Scholar]
  8. Doherty P. C. Virus infections in mice with targeted gene disruptions. Curr Opin Immunol. 1993 Aug;5(4):479–483. doi: 10.1016/0952-7915(93)90026-o. [DOI] [PubMed] [Google Scholar]
  9. Eichelberger M., Allan W., Zijlstra M., Jaenisch R., Doherty P. C. Clearance of influenza virus respiratory infection in mice lacking class I major histocompatibility complex-restricted CD8+ T cells. J Exp Med. 1991 Oct 1;174(4):875–880. doi: 10.1084/jem.174.4.875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fiette L., Aubert C., Brahic M., Rossi C. P. Theiler's virus infection of beta 2-microglobulin-deficient mice. J Virol. 1993 Jan;67(1):589–592. doi: 10.1128/jvi.67.1.589-592.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fiette L., Aubert C., Müller U., Huang S., Aguet M., Brahic M., Bureau J. F. Theiler's virus infection of 129Sv mice that lack the interferon alpha/beta or interferon gamma receptors. J Exp Med. 1995 Jun 1;181(6):2069–2076. doi: 10.1084/jem.181.6.2069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Friedmann A., Frankel G., Lorch Y., Steinman L. Monoclonal anti-I-A antibody reverses chronic paralysis and demyelination in Theiler's virus-infected mice: critical importance of timing of treatment. J Virol. 1987 Mar;61(3):898–903. doi: 10.1128/jvi.61.3.898-903.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fujinami R. S., Rosenthal A., Lampert P. W., Zurbriggen A., Yamada M. Survival of athymic (nu/nu) mice after Theiler's murine encephalomyelitis virus infection by passive administration of neutralizing monoclonal antibody. J Virol. 1989 May;63(5):2081–2087. doi: 10.1128/jvi.63.5.2081-2087.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hou S., Doherty P. C., Zijlstra M., Jaenisch R., Katz J. M. Delayed clearance of Sendai virus in mice lacking class I MHC-restricted CD8+ T cells. J Immunol. 1992 Aug 15;149(4):1319–1325. [PubMed] [Google Scholar]
  15. Hou S., Mo X. Y., Hyland L., Doherty P. C. Host response to Sendai virus in mice lacking class II major histocompatibility complex glycoproteins. J Virol. 1995 Mar;69(3):1429–1434. doi: 10.1128/jvi.69.3.1429-1434.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kaufmann S. H. Bacterial and protozoal infections in genetically disrupted mice. Curr Opin Immunol. 1994 Aug;6(4):518–525. doi: 10.1016/0952-7915(94)90135-x. [DOI] [PubMed] [Google Scholar]
  17. Lampert P. Electron microscopic studies on ordinary and hyperacute experimental allergic encephalomyelitis. Acta Neuropathol. 1967 Oct 20;9(2):99–126. doi: 10.1007/BF00691436. [DOI] [PubMed] [Google Scholar]
  18. Laufer T. M., von Herrath M. G., Grusby M. J., Oldstone M. B., Glimcher L. H. Autoimmune diabetes can be induced in transgenic major histocompatibility complex class II-deficient mice. J Exp Med. 1993 Aug 1;178(2):589–596. doi: 10.1084/jem.178.2.589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lin X., Thiemann N. R., Pease L. R., Rodriguez M. VP1 and VP2 capsid proteins of Theiler's virus are targets of H-2D-restricted cytotoxic lymphocytes in the central nervous system of B10 mice. Virology. 1995 Dec 1;214(1):91–99. doi: 10.1006/viro.1995.9951. [DOI] [PubMed] [Google Scholar]
  20. Lipton H. L., Dal Canto M. C. Theiler's virus-induced demyelination: prevention by immunosuppression. Science. 1976 Apr 2;192(4234):62–64. doi: 10.1126/science.176726. [DOI] [PubMed] [Google Scholar]
  21. Lipton H. L., Gonzalez-Scarano F. Central nervous system immunity in mice infected with theiler's virus. I. Local neutralizing antibody response. J Infect Dis. 1978 Feb;137(2):145–151. doi: 10.1093/infdis/137.2.145. [DOI] [PubMed] [Google Scholar]
  22. Lipton H. L. Theiler's virus infection in mice: an unusual biphasic disease process leading to demyelination. Infect Immun. 1975 May;11(5):1147–1155. doi: 10.1128/iai.11.5.1147-1155.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Patick A. K., Oleszak E. L., Leibowitz J. L., Rodriguez M. Persistent infection of a glioma cell line generates a Theiler's virus variant which fails to induce demyelinating disease in SJL/J mice. J Gen Virol. 1990 Sep;71(Pt 9):2123–2132. doi: 10.1099/0022-1317-71-9-2123. [DOI] [PubMed] [Google Scholar]
  25. Paya C. V., Leibson P. J., Patick A. K., Rodriguez M. Inhibition of Theiler's virus-induced demyelination in vivo by tumor necrosis factor alpha. Int Immunol. 1990;2(9):909–913. doi: 10.1093/intimm/2.9.909. [DOI] [PubMed] [Google Scholar]
  26. Prayoonwiwat N., Rodriguez M. The potential for oligodendrocyte proliferation during demyelinating disease. J Neuropathol Exp Neurol. 1993 Jan;52(1):55–63. doi: 10.1097/00005072-199301000-00007. [DOI] [PubMed] [Google Scholar]
  27. Pullen L. C., Miller S. D., Dal Canto M. C., Kim B. S. Class I-deficient resistant mice intracerebrally inoculated with Theiler's virus show an increased T cell response to viral antigens and susceptibility to demyelination. Eur J Immunol. 1993 Sep;23(9):2287–2293. doi: 10.1002/eji.1830230935. [DOI] [PubMed] [Google Scholar]
  28. Rahemtulla A., Kündig T. M., Narendran A., Bachmann M. F., Julius M., Paige C. J., Ohashi P. S., Zinkernagel R. M., Mak T. W. Class II major histocompatibility complex-restricted T cell function in CD4-deficient mice. Eur J Immunol. 1994 Sep;24(9):2213–2218. doi: 10.1002/eji.1830240942. [DOI] [PubMed] [Google Scholar]
  29. Rodriguez M., Dunkel A. J., Thiemann R. L., Leibowitz J., Zijlstra M., Jaenisch R. Abrogation of resistance to Theiler's virus-induced demyelination in H-2b mice deficient in beta 2-microglobulin. J Immunol. 1993 Jul 1;151(1):266–276. [PubMed] [Google Scholar]
  30. Rodriguez M., Kenny J. J., Thiemann R. L., Woloschak G. E. Theiler's virus-induced demyelination in mice immunosuppressed with anti-IgM and in mice expressing the xid gene. Microb Pathog. 1990 Jan;8(1):23–35. doi: 10.1016/0882-4010(90)90005-b. [DOI] [PubMed] [Google Scholar]
  31. Rodriguez M., Lafuse W. P., Leibowitz J., David C. S. Partial suppression of Theiler's virus-induced demyelination in vivo by administration of monoclonal antibodies to immune-response gene products (Ia antigens). Neurology. 1986 Jul;36(7):964–970. doi: 10.1212/wnl.36.7.964. [DOI] [PubMed] [Google Scholar]
  32. Rodriguez M., Leibowitz J. L., Lampert P. W. Persistent infection of oligodendrocytes in Theiler's virus-induced encephalomyelitis. Ann Neurol. 1983 Apr;13(4):426–433. doi: 10.1002/ana.410130409. [DOI] [PubMed] [Google Scholar]
  33. Rodriguez M., Leibowitz J. L., Powell H. C., Lampert P. W. Neonatal infection with the Daniels strain of Theiler's murine encephalomyelitis virus. Lab Invest. 1983 Dec;49(6):672–679. [PubMed] [Google Scholar]
  34. Rodriguez M., Lindsley M. D. Immunosuppression promotes CNS remyelination in chronic virus-induced demyelinating disease. Neurology. 1992 Feb;42(2):348–357. doi: 10.1212/wnl.42.2.348. [DOI] [PubMed] [Google Scholar]
  35. Rodriguez M., Lindsley M. D., Pierce M. L. Role of T cells in resistance to Theiler's virus infection. Microb Pathog. 1991 Oct;11(4):269–281. doi: 10.1016/0882-4010(91)90031-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Rodriguez M., Oleszak E., Leibowitz J. Theiler's murine encephalomyelitis: a model of demyelination and persistence of virus. Crit Rev Immunol. 1987;7(4):325–365. [PubMed] [Google Scholar]
  37. Rodriguez M., Pavelko K. D., McKinney C. W., Leibowitz J. L. Recombinant human IL-6 suppresses demyelination in a viral model of multiple sclerosis. J Immunol. 1994 Oct 15;153(8):3811–3821. [PubMed] [Google Scholar]
  38. Rodriguez M., Pavelko K., Coffman R. L. Gamma interferon is critical for resistance to Theiler's virus-induced demyelination. J Virol. 1995 Nov;69(11):7286–7290. doi: 10.1128/jvi.69.11.7286-7290.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rodriguez M., Quddus J. Effect of cyclosporin A, silica quartz dust, and protease inhibitors on virus-induced demyelination. J Neuroimmunol. 1986 Dec;13(2):159–174. doi: 10.1016/0165-5728(86)90062-7. [DOI] [PubMed] [Google Scholar]
  40. Rodriguez M., Sriram S. Successful therapy of Theiler's virus-induced demyelination (DA strain) with monoclonal anti-Lyt-2 antibody. J Immunol. 1988 May 1;140(9):2950–2955. [PubMed] [Google Scholar]
  41. Rodriguez M. Virus-induced demyelination in mice: "dying back" of oligodendrocytes. Mayo Clin Proc. 1985 Jul;60(7):433–438. doi: 10.1016/s0025-6196(12)60865-9. [DOI] [PubMed] [Google Scholar]
  42. Roos R. P., Firestone S., Wollmann R., Variakojis D., Arnason B. G. The effect of short-term and chronic immunosuppression on Theiler's virus demyelination. J Neuroimmunol. 1982 Jun;2(3-4):223–234. doi: 10.1016/0165-5728(82)90057-1. [DOI] [PubMed] [Google Scholar]
  43. Spriggs M. K., Koller B. H., Sato T., Morrissey P. J., Fanslow W. C., Smithies O., Voice R. F., Widmer M. B., Maliszewski C. R. Beta 2-microglobulin-, CD8+ T-cell-deficient mice survive inoculation with high doses of vaccinia virus and exhibit altered IgG responses. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6070–6074. doi: 10.1073/pnas.89.13.6070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Tripp R. A., Sarawar S. R., Doherty P. C. Characteristics of the influenza virus-specific CD8+ T cell response in mice homozygous for disruption of the H-2lAb gene. J Immunol. 1995 Sep 15;155(6):2955–2959. [PubMed] [Google Scholar]
  45. Welsh C. J., Tonks P., Nash A. A., Blakemore W. F. The effect of L3T4 T cell depletion on the pathogenesis of Theiler's murine encephalomyelitis virus infection in CBA mice. J Gen Virol. 1987 Jun;68(Pt 6):1659–1667. doi: 10.1099/0022-1317-68-6-1659. [DOI] [PubMed] [Google Scholar]

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