Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1997 Nov;71(11):8592–8601. doi: 10.1128/jvi.71.11.8592-8601.1997

The immune system preferentially clears Theiler's virus from the gray matter of the central nervous system.

M K Njenga 1, K Asakura 1, S F Hunter 1, P Wettstein 1, L R Pease 1, M Rodriguez 1
PMCID: PMC192323  PMID: 9343217

Abstract

Infection of susceptible strains of mice with Daniel's (DA) strains of Theiler's murine encephalomyelitis virus (DAV) results in virus persistence in the central nervous system (CNS) white matter and chronic demyelination similar to that observed in multiple sclerosis. We investigated whether persistence is due to the immune system more efficiently clearing DAV from gray than from white matter of the CNS. Severe combined immunodeficient (SCID) and immunocompetent C.B-17 mice were infected with DAV to determine the kinetics, temporal distribution, and tropism of the virus in CNS. In early disease (6 h to 7 days postinfection), DAV replicated with similar kinetics in the brains and spinal cords of SCID and immunocompetent mice and in gray and white matter. DAV RNA was localized within 48 h in CNS cells of all phenotypes, including neurons, oligodendrocytes, astrocytes, and macrophages/microglia. In late disease (13 to 17 days postinfection), SCID mice became moribund and permitted higher DAV replication in both gray and white matter. In contrast, immunocompetent mice cleared virus from the gray matter but showed replication in the white matter of their brains and spinal cords. Reconstitution of SCID mice with nonimmune splenocytes or anti-DAV antibodies after establishment of infection demonstrated that both cellular and humoral immune responses decreased virus from the gray matter; however, the cellular responses were more effective. SCID mice reconstituted with splenocytes depleted of CD4+ or CD8+ T lymphocytes cleared virus from the gray matter but allowed replication in the white matter. These studies demonstrate that both neurons and glia are infected early following DAV infection but that virus persistence in the white matter is due to preferential clearance of virus from the gray matter by the immune system.

Full Text

The Full Text of this article is available as a PDF (967.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Asakura K., Miller D. J., Murray K., Bansal R., Pfeiffer S. E., Rodriguez M. Monoclonal autoantibody SCH94.03, which promotes central nervous system remyelination, recognizes an antigen on the surface of oligodendrocytes. J Neurosci Res. 1996 Feb 1;43(3):273–281. doi: 10.1002/(SICI)1097-4547(19960201)43:3<273::AID-JNR2>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]
  2. Aubert C., Brahic M. Early infection of the central nervous system by the GDVII and DA strains of Theiler's virus. J Virol. 1995 May;69(5):3197–3200. doi: 10.1128/jvi.69.5.3197-3200.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. Borrow P., Tonks P., Welsh C. J., Nash A. A. The role of CD8+T cells in the acute and chronic phases of Theiler's murine encephalomyelitis virus-induced disease in mice. J Gen Virol. 1992 Jul;73(Pt 7):1861–1865. doi: 10.1099/0022-1317-73-7-1861. [DOI] [PubMed] [Google Scholar]
  5. Brahic M., Stroop W. G., Baringer J. R. Theiler's virus persists in glial cells during demyelinating disease. Cell. 1981 Oct;26(1 Pt 1):123–128. doi: 10.1016/0092-8674(81)90040-4. [DOI] [PubMed] [Google Scholar]
  6. Bureau J. F., Montagutelli X., Bihl F., Lefebvre S., Guénet J. L., Brahic M. Mapping loci influencing the persistence of Theiler's virus in the murine central nervous system. Nat Genet. 1993 Sep;5(1):87–91. doi: 10.1038/ng0993-87. [DOI] [PubMed] [Google Scholar]
  7. Cash E., Chamorro M., Brahic M. Quantitation, with a new assay, of Theiler's virus capsid protein in the central nervous system of mice. J Virol. 1986 Nov;60(2):558–563. doi: 10.1128/jvi.60.2.558-563.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cash E., Chamorro M., Brahic M. Theiler's virus RNA and protein synthesis in the central nervous system of demyelinating mice. Virology. 1985 Jul 15;144(1):290–294. doi: 10.1016/0042-6822(85)90327-7. [DOI] [PubMed] [Google Scholar]
  9. Ceredig R., Lowenthal J. W., Nabholz M., MacDonald H. R. Expression of interleukin-2 receptors as a differentiation marker on intrathymic stem cells. Nature. 1985 Mar 7;314(6006):98–100. doi: 10.1038/314098a0. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. Dal Canto M. C., Lipton H. L. Primary demyelination in Theiler's virus infection. An ultrastructural study. Lab Invest. 1975 Dec;33(6):626–637. [PubMed] [Google Scholar]
  13. Dal Canto M. C., Lipton H. L. Ultrastructural immunohistochemical localization of virus in acute and chronic demyelinating Theiler's virus infection. Am J Pathol. 1982 Jan;106(1):20–29. [PMC free article] [PubMed] [Google Scholar]
  14. Dialynas D. P., Wilde D. B., Marrack P., Pierres A., Wall K. A., Havran W., Otten G., Loken M. R., Pierres M., Kappler J. Characterization of the murine antigenic determinant, designated L3T4a, recognized by monoclonal antibody GK1.5: expression of L3T4a by functional T cell clones appears to correlate primarily with class II MHC antigen-reactivity. Immunol Rev. 1983;74:29–56. doi: 10.1111/j.1600-065x.1983.tb01083.x. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Fiette L., Brahic M., Pena-Rossi C. Infection of class II-deficient mice by the DA strain of Theiler's virus. J Virol. 1996 Jul;70(7):4811–4815. doi: 10.1128/jvi.70.7.4811-4815.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fu J., Rodriguez M., Roos R. P. Strains from both Theiler's virus subgroups encode a determinant for demyelination. J Virol. 1990 Dec;64(12):6345–6348. doi: 10.1128/jvi.64.12.6345-6348.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Graves M. C., Bologa L., Siegel L., Londe H. Theiler's virus in brain cell cultures: lysis of neurons and oligodendrocytes and persistence in astrocytes and macrophages. J Neurosci Res. 1986;15(4):491–501. doi: 10.1002/jnr.490150406. [DOI] [PubMed] [Google Scholar]
  19. Jarousse N., Fiette L., Grant R. A., Hogle J. M., McAllister A., Michiels T., Aubert C., Tangy F., Brahic M., Peña Rossi C. Chimeric Theiler's virus with altered tropism for the central nervous system. J Virol. 1994 May;68(5):2781–2786. doi: 10.1128/jvi.68.5.2781-2786.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jarousse N., Grant R. A., Hogle J. M., Zhang L., Senkowski A., Roos R. P., Michiels T., Brahic M., McAllister A. A single amino acid change determines persistence of a chimeric Theiler's virus. J Virol. 1994 May;68(5):3364–3368. doi: 10.1128/jvi.68.5.3364-3368.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Levy M., Aubert C., Brahic M. Theiler's virus replication in brain macrophages cultured in vitro. J Virol. 1992 May;66(5):3188–3193. doi: 10.1128/jvi.66.5.3188-3193.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lipton H. L., Kratochvil J., Sethi P., Dal Canto M. C. Theiler's virus antigen detected in mouse spinal cord 2 1/2 years after infection. Neurology. 1984 Aug;34(8):1117–1119. doi: 10.1212/wnl.34.8.1117. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Lipton H. L., Twaddle G., Jelachich M. L. The predominant virus antigen burden is present in macrophages in Theiler's murine encephalomyelitis virus-induced demyelinating disease. J Virol. 1995 Apr;69(4):2525–2533. doi: 10.1128/jvi.69.4.2525-2533.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Liu C., Collins J., Sharp E. The pathogenesis of Theiler's GD VII encephalomyelitis virus infection in mice as studied by immunofluorescent technique and infectivity titrations. J Immunol. 1967 Jan;98(1):46–55. [PubMed] [Google Scholar]
  26. Lorch Y., Friedmann A., Lipton H. L., Kotler M. Theiler's murine encephalomyelitis virus group includes two distinct genetic subgroups that differ pathologically and biologically. J Virol. 1981 Nov;40(2):560–567. doi: 10.1128/jvi.40.2.560-567.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. McAllister A., Tangy F., Aubert C., Brahic M. Genetic mapping of the ability of Theiler's virus to persist and demyelinate. J Virol. 1990 Sep;64(9):4252–4257. doi: 10.1128/jvi.64.9.4252-4257.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Miller D. J., Rivera-Quiñones C., Njenga M. K., Leibowitz J., Rodriguez M. Spontaneous CNS remyelination in beta 2 microglobulin-deficient mice following virus-induced demyelination. J Neurosci. 1995 Dec;15(12):8345–8352. doi: 10.1523/JNEUROSCI.15-12-08345.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Njenga M. K., Pavelko K. D., Baisch J., Lin X., David C., Leibowitz J., Rodriguez M. Theiler's virus persistence and demyelination in major histocompatibility complex class II-deficient mice. J Virol. 1996 Mar;70(3):1729–1737. doi: 10.1128/jvi.70.3.1729-1737.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ohara Y., Konno H., Iwasaki Y., Yamamoto T., Terunuma H., Suzuki H. Cytotropism of Theiler's murine encephalomyelitis viruses in oligodendrocyte-enriched cultures. Arch Virol. 1990;114(3-4):293–298. doi: 10.1007/BF01310760. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. 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]
  33. 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]
  34. 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]
  35. 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]
  36. Rodriguez M., Leibowitz J., David C. S. Susceptibility to Theiler's virus-induced demyelination. Mapping of the gene within the H-2D region. J Exp Med. 1986 Mar 1;163(3):620–631. doi: 10.1084/jem.163.3.620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. 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]
  38. Rodriguez M., Patick A. K., Pease L. R. Abrogation of resistance to Theiler's virus-induced demyelination in C57BL mice by total body irradiation. J Neuroimmunol. 1990 Mar;26(3):189–199. doi: 10.1016/0165-5728(90)90001-4. [DOI] [PubMed] [Google Scholar]
  39. Rodriguez M., Pavelko K. D., Njenga M. K., Logan W. C., Wettstein P. J. The balance between persistent virus infection and immune cells determines demyelination. J Immunol. 1996 Dec 15;157(12):5699–5709. [PubMed] [Google Scholar]
  40. Rodriguez M., Roos R. P. Pathogenesis of early and late disease in mice infected with Theiler's virus, using intratypic recombinant GDVII/DA viruses. J Virol. 1992 Jan;66(1):217–225. doi: 10.1128/jvi.66.1.217-225.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. 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]
  42. 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]
  43. 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]
  44. Roos R. P., Wollmann R. DA strain of Theiler's murine encephalomyelitis virus induces demyelination in nude mice. Ann Neurol. 1984 May;15(5):494–499. doi: 10.1002/ana.410150516. [DOI] [PubMed] [Google Scholar]
  45. Rosenthal A., Fujinami R. S., Lampert P. W. Mechanism of Theiler's virus-induced demyelination in nude mice. Lab Invest. 1986 May;54(5):515–522. [PubMed] [Google Scholar]
  46. Rossi C. P., Delcroix M., Huitinga I., McAllister A., van Rooijen N., Claassen E., Brahic M. Role of macrophages during Theiler's virus infection. J Virol. 1997 Apr;71(4):3336–3340. doi: 10.1128/jvi.71.4.3336-3340.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Sarmiento M., Glasebrook A. L., Fitch F. W. IgG or IgM monoclonal antibodies reactive with different determinants on the molecular complex bearing Lyt 2 antigen block T cell-mediated cytolysis in the absence of complement. J Immunol. 1980 Dec;125(6):2665–2672. [PubMed] [Google Scholar]
  48. Simas J. P., Dyson H., Fazakerley J. K. The neurovirulent GDVII strain of Theiler's virus can replicate in glial cells. J Virol. 1995 Sep;69(9):5599–5606. doi: 10.1128/jvi.69.9.5599-5606.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Tangy F., McAllister A., Aubert C., Brahic M. Determinants of persistence and demyelination of the DA strain of Theiler's virus are found only in the VP1 gene. J Virol. 1991 Mar;65(3):1616–1618. doi: 10.1128/jvi.65.3.1616-1618.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Theiler M. SPONTANEOUS ENCEPHALOMYELITIS OF MICE--A NEW VIRUS DISEASE. Science. 1934 Aug 3;80(2066):122–122. doi: 10.1126/science.80.2066.122-a. [DOI] [PubMed] [Google Scholar]
  51. Wada Y., Pierce M. L., Fujinami R. S. Importance of amino acid 101 within capsid protein VP1 for modulation of Theiler's virus-induced disease. J Virol. 1994 Feb;68(2):1219–1223. doi: 10.1128/jvi.68.2.1219-1223.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Weber A., Schachner M. Maintenance of immunocytologically identified Purkinje cells from mouse cerebellum in monolayer culture. Brain Res. 1984 Oct 8;311(1):119–130. doi: 10.1016/0006-8993(84)91404-5. [DOI] [PubMed] [Google Scholar]
  53. Zurbriggen A., Yamada M., Thomas C., Fujinami R. S. Restricted virus replication in the spinal cords of nude mice infected with a Theiler's virus variant. J Virol. 1991 Feb;65(2):1023–1030. doi: 10.1128/jvi.65.2.1023-1030.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES