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. 1997 Apr;71(4):3105–3113. doi: 10.1128/jvi.71.4.3105-3113.1997

Major linear antibody epitopes and capsid proteins differentially induce protective immunity against Theiler's virus-induced demyelinating disease.

H Yahikozawa 1, A Inoue 1, C S Koh 1, Y K Choe 1, B S Kim 1
PMCID: PMC191442  PMID: 9060673

Abstract

Theiler's murine encephalomyelitis virus-induced immunologically mediated demyelinating disease (TMEV-IDD) in susceptible mice provides a relevant infectious model for multiple sclerosis. Previously, we have identified six major linear antibody epitopes on the viral capsid proteins. In this study, we utilized fusion proteins containing individual capsid proteins and synthetic peptides containing the linear antibody epitopes to determine the potential role of antibody response in the course of virus-induced demyelination. Preimmunization of susceptible mice with VPI and VP2 fusion proteins, but not VP3, resulted in the protection from subsequent development of TMEV-IDD. Mice free of clinical symptoms following preimmunizations with fusion proteins displayed high levels of antibodies to the capsid proteins corresponding to the immunogens. In contrast, the level of antibodies to a particular linear epitope, A1C (VP1(262-276)), capable of efficiently neutralizing virus in vitro increased with the progression of disease. Further immunization with synthetic peptides containing individual antibody epitopes indicated that antibodies to the epitopes are differentially effective in protecting from virus-induced demyelination. Taken together, these results suggest that antibodies to only certain linear epitopes are protective and such protection may be restricted during the early stages of viral infection.

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Selected References

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  1. Allen I., Brankin B. Pathogenesis of multiple sclerosis--the immune diathesis and the role of viruses. J Neuropathol Exp Neurol. 1993 Mar;52(2):95–105. doi: 10.1097/00005072-199303000-00001. [DOI] [PubMed] [Google Scholar]
  2. Bittle J. L., Houghten R. A., Alexander H., Shinnick T. M., Sutcliffe J. G., Lerner R. A., Rowlands D. J., Brown F. Protection against foot-and-mouth disease by immunization with a chemically synthesized peptide predicted from the viral nucleotide sequence. Nature. 1982 Jul 1;298(5869):30–33. doi: 10.1038/298030a0. [DOI] [PubMed] [Google Scholar]
  3. Boere W. A., Benaissa-Trouw B. J., Harmsen M., Kraaijeveld C. A., Snippe H. Neutralizing and non-neutralizing monoclonal antibodies to the E2 glycoprotein of Semliki Forest virus can protect mice from lethal encephalitis. J Gen Virol. 1983 Jun;64(Pt 6):1405–1408. doi: 10.1099/0022-1317-64-6-1405. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Chow M., Yabrov R., Bittle J., Hogle J., Baltimore D. Synthetic peptides from four separate regions of the poliovirus type 1 capsid protein VP1 induce neutralizing antibodies. Proc Natl Acad Sci U S A. 1985 Feb;82(3):910–914. doi: 10.1073/pnas.82.3.910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Clatch R. J., Lipton H. L., Miller S. D. Characterization of Theiler's murine encephalomyelitis virus (TMEV)-specific delayed-type hypersensitivity responses in TMEV-induced demyelinating disease: correlation with clinical signs. J Immunol. 1986 Feb 1;136(3):920–927. [PubMed] [Google Scholar]
  7. Crane M. A., Yauch R., Dal Canto M. C., Kim B. S. Effect of immunization with Theiler's virus on the course of demyelinating disease. J Neuroimmunol. 1993 Jun;45(1-2):67–73. doi: 10.1016/0165-5728(93)90165-u. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Dhib-Jalbut S., McFarlin D. E. Immunology of multiple sclerosis. Ann Allergy. 1990 May;64(5):433–444. [PubMed] [Google Scholar]
  10. Dietzschold B., Kao M., Zheng Y. M., Chen Z. Y., Maul G., Fu Z. F., Rupprecht C. E., Koprowski H. Delineation of putative mechanisms involved in antibody-mediated clearance of rabies virus from the central nervous system. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7252–7256. doi: 10.1073/pnas.89.15.7252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Engvall E., Perlmann P. Enzyme-linked immunosorbent assay (ELISA). Quantitative assay of immunoglobulin G. Immunochemistry. 1971 Sep;8(9):871–874. doi: 10.1016/0019-2791(71)90454-x. [DOI] [PubMed] [Google Scholar]
  12. Finkelman F. D., Holmes J., Katona I. M., Urban J. F., Jr, Beckmann M. P., Park L. S., Schooley K. A., Coffman R. L., Mosmann T. R., Paul W. E. Lymphokine control of in vivo immunoglobulin isotype selection. Annu Rev Immunol. 1990;8:303–333. doi: 10.1146/annurev.iy.08.040190.001511. [DOI] [PubMed] [Google Scholar]
  13. Francis M. J., Hastings G. Z., Brown F., McDermed J., Lu Y. A., Tam J. P. Immunological evaluation of the multiple antigen peptide (MAP) system using the major immunogenic site of foot-and-mouth disease virus. Immunology. 1991 Jul;73(3):249–254. [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. 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]
  16. Gerety S. J., Karpus W. J., Cubbon A. R., Goswami R. G., Rundell M. K., Peterson J. D., Miller S. D. Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus-induced demyelinating disease. V. Mapping of a dominant immunopathologic VP2 T cell epitope in susceptible SJL/J mice. J Immunol. 1994 Jan 15;152(2):908–918. [PubMed] [Google Scholar]
  17. Gerety S. J., Rundell M. K., Dal Canto M. C., Miller S. D. Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus-induced demyelinating disease. VI. Potentiation of demyelination with and characterization of an immunopathologic CD4+ T cell line specific for an immunodominant VP2 epitope. J Immunol. 1994 Jan 15;152(2):919–929. [PubMed] [Google Scholar]
  18. Giavedoni L. D., Kaplan G., Marcovecchio F., Piccone M. E., Palma E. L. Protection conferred by TrpE fusion proteins containing portions of the C-terminal region of capsid protein VP1 of foot-and-mouth disease virus. J Gen Virol. 1991 Apr;72(Pt 4):967–971. doi: 10.1099/0022-1317-72-4-967. [DOI] [PubMed] [Google Scholar]
  19. Grant R. A., Filman D. J., Fujinami R. S., Icenogle J. P., Hogle J. M. Three-dimensional structure of Theiler virus. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2061–2065. doi: 10.1073/pnas.89.6.2061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hall W. T., Madden D. L., Mundon F. K., Brandt D. E., Clarke N. A. Protective effect of immune serum globulin (ISG) against hepatitis A infection in a natural epidemic. Am J Epidemiol. 1977 Jul;106(1):72–75. doi: 10.1093/oxfordjournals.aje.a112435. [DOI] [PubMed] [Google Scholar]
  21. Inoue A., Choe Y. K., Kim B. S. Analysis of antibody responses to predominant linear epitopes of Theiler's murine encephalomyelitis virus. J Virol. 1994 May;68(5):3324–3333. doi: 10.1128/jvi.68.5.3324-3333.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kappel C. A., Dal Canto M. C., Melvold R. W., Kim B. S. Hierarchy of effects of the MHC and T cell receptor beta-chain genes in susceptibility to Theiler's murine encephalomyelitis virus-induced demyelinating disease. J Immunol. 1991 Dec 15;147(12):4322–4326. [PubMed] [Google Scholar]
  23. Kim B. S., Choe Y. K., Crane M. A., Jue C. R. Identification and localization of a limited number of predominant conformation-independent antibody epitopes of Theiler's murine encephalomyelitus virus. Immunol Lett. 1992 Feb;31(2):199–205. doi: 10.1016/0165-2478(92)90146-f. [DOI] [PubMed] [Google Scholar]
  24. Kurtz C. I., Sun X. M., Fujinami R. S. B-lymphocyte requirement for vaccine-mediated protection from Theiler's murine encephalomyelitis virus-induced central nervous system disease. J Virol. 1995 Aug;69(8):5152–5155. doi: 10.1128/jvi.69.8.5152-5155.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Levine B., Hardwick J. M., Trapp B. D., Crawford T. O., Bollinger R. C., Griffin D. E. Antibody-mediated clearance of alphavirus infection from neurons. Science. 1991 Nov 8;254(5033):856–860. doi: 10.1126/science.1658936. [DOI] [PubMed] [Google Scholar]
  26. Lipton H. L., Friedmann A. Purification of Theiler's murine encephalomyelitis virus and analysis of the structural virion polypeptides: correlation of the polypeptide profile with virulence. J Virol. 1980 Mar;33(3):1165–1172. doi: 10.1128/jvi.33.3.1165-1172.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Lipton H. L., Melvold R. Genetic analysis of susceptibility to Theiler's virus-induced demyelinating disease in mice. J Immunol. 1984 Apr;132(4):1821–1825. [PubMed] [Google Scholar]
  29. 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]
  30. 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]
  31. Luo M., He C., Toth K. S., Zhang C. X., Lipton H. L. Three-dimensional structure of Theiler murine encephalomyelitis virus (BeAn strain). Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2409–2413. doi: 10.1073/pnas.89.6.2409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mateu M. G. Antibody recognition of picornaviruses and escape from neutralization: a structural view. Virus Res. 1995 Sep;38(1):1–24. doi: 10.1016/0168-1702(95)00048-u. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. McIntyre T. M., Klinman D. R., Rothman P., Lugo M., Dasch J. R., Mond J. J., Snapper C. M. Transforming growth factor beta 1 selectivity stimulates immunoglobulin G2b secretion by lipopolysaccharide-activated murine B cells. J Exp Med. 1993 Apr 1;177(4):1031–1037. doi: 10.1084/jem.177.4.1031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Melvold R. W., Jokinen D. M., Knobler R. L., Lipton H. L. Variations in genetic control of susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. I. Differences between susceptible SJL/J and resistant BALB/c strains map near the T cell beta-chain constant gene on chromosome 6. J Immunol. 1987 Mar 1;138(5):1429–1433. [PubMed] [Google Scholar]
  36. Mikszta J. A., Kim B. S. Conversion of low antibody responders into high responders by up-regulating the T cell response to a selective epitope. J Immunol. 1996 Oct 1;157(7):2883–2890. [PubMed] [Google Scholar]
  37. Muir S., Weintraub J. P., Hogle J., Bittle J. L. Neutralizing antibody to Mengo virus, induced by synthetic peptides. J Gen Virol. 1991 May;72(Pt 5):1087–1092. doi: 10.1099/0022-1317-72-5-1087. [DOI] [PubMed] [Google Scholar]
  38. Nitayaphan S., Toth M. M., Roos R. P. Localization of a neutralization site of Theiler's murine encephalomyelitis viruses. J Virol. 1985 Dec;56(3):887–895. doi: 10.1128/jvi.56.3.887-895.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Ogra P. L., Faden H. S. Poliovirus vaccines: live or dead. J Pediatr. 1986 Jun;108(6):1031–1033. doi: 10.1016/s0022-3476(86)80957-x. [DOI] [PubMed] [Google Scholar]
  40. Ohara Y., Senkowski A., Fu J. L., Klaman L., Goodall J., Toth M., Roos R. P. Trypsin-sensitive neutralization site on VP1 of Theiler's murine encephalomyelitis viruses. J Virol. 1988 Sep;62(9):3527–3529. doi: 10.1128/jvi.62.9.3527-3529.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. 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]
  42. Peterson J. D., Waltenbaugh C., Miller S. D. IgG subclass responses to Theiler's murine encephalomyelitis virus infection and immunization suggest a dominant role for Th1 cells in susceptible mouse strains. Immunology. 1992 Apr;75(4):652–658. [PMC free article] [PubMed] [Google Scholar]
  43. Pevear D. C., Calenoff M., Rozhon E., Lipton H. L. Analysis of the complete nucleotide sequence of the picornavirus Theiler's murine encephalomyelitis virus indicates that it is closely related to cardioviruses. J Virol. 1987 May;61(5):1507–1516. doi: 10.1128/jvi.61.5.1507-1516.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Pincus S. H., Cole R., Ireland R., McAtee F., Fujisawa R., Portis J. Protective efficacy of nonneutralizing monoclonal antibodies in acute infection with murine leukemia virus. J Virol. 1995 Nov;69(11):7152–7158. doi: 10.1128/jvi.69.11.7152-7158.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Pullen L. C., Park S. H., Miller S. D., Dal Canto M. C., Kim B. S. Treatment with bacterial LPS renders genetically resistant C57BL/6 mice susceptible to Theiler's virus-induced demyelinating disease. J Immunol. 1995 Nov 1;155(9):4497–4503. [PubMed] [Google Scholar]
  46. Rodriguez M., David C. S. Demyelination induced by Theiler's virus: influence of the H-2 haplotype. J Immunol. 1985 Sep;135(3):2145–2148. [PubMed] [Google Scholar]
  47. 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]
  48. Roos R. P., Stein S., Routbort M., Senkowski A., Bodwell T., Wollmann R. Theiler's murine encephalomyelitis virus neutralization escape mutants have a change in disease phenotype. J Virol. 1989 Oct;63(10):4469–4473. doi: 10.1128/jvi.63.10.4469-4473.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Rossi C. P., Cash E., Aubert C., Coutinho A. Role of the humoral immune response in resistance to Theiler's virus infection. J Virol. 1991 Jul;65(7):3895–3899. doi: 10.1128/jvi.65.7.3895-3899.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Usherwood E. J., Johnston I. C., Lovelidge L. J., Tonks P., Nash A. A. Lymphocyte recognition elements on the VP1 protein of Theiler's virus. Immunology. 1995 Jun;85(2):190–197. [PMC free article] [PubMed] [Google Scholar]
  51. Usherwood E. J., Nash A. A. Lymphocyte recognition of picornaviruses. J Gen Virol. 1995 Mar;76(Pt 3):499–508. doi: 10.1099/0022-1317-76-3-499. [DOI] [PubMed] [Google Scholar]
  52. 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]
  53. Yauch R. L., Kerekes K., Saujani K., Kim B. S. Identification of a major T-cell epitope within VP3 amino acid residues 24 to 37 of Theiler's virus in demyelination-susceptible SJL/J mice. J Virol. 1995 Nov;69(11):7315–7318. doi: 10.1128/jvi.69.11.7315-7318.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Yauch R. L., Kim B. S. A predominant viral epitope recognized by T cells from the periphery and demyelinating lesions of SJL/J mice infected with Theiler's virus is located within VP1(233-244). J Immunol. 1994 Nov 15;153(10):4508–4519. [PubMed] [Google Scholar]
  55. Zamorano P., Wigdorovitz A., Perez-Filgueira M., Carrillo C., Escribano J. M., Sadir A. M., Borca M. V. A 10-amino-acid linear sequence of VP1 of foot and mouth disease virus containing B- and T-cell epitopes induces protection in mice. Virology. 1995 Oct 1;212(2):614–621. doi: 10.1006/viro.1995.1519. [DOI] [PubMed] [Google Scholar]
  56. Zurbriggen A., Hogle J. M., Fujinami R. S. Alteration of amino acid 101 within capsid protein VP-1 changes the pathogenicity of Theiler's murine encephalomyelitis virus. J Exp Med. 1989 Dec 1;170(6):2037–2049. doi: 10.1084/jem.170.6.2037. [DOI] [PMC free article] [PubMed] [Google Scholar]

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