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. 2003 Mar 24;117(1):148–158. doi: 10.1016/0022-510X(93)90167-W

Contrasting effects of immunosuppression on herpes simplex virus type I (HSV I) induced central nervous system (CNS) demyelination in mice

Lorne F Kastrukoff a,1, Allen S Lau a, George Y Leung a, Eva E Thomas b
PMCID: PMC7172415  PMID: 8410049

Abstract

We previously reported that lip inoculation of Herpes simplex virus type I (HSV I) in specific strains of mice would induce multifocal brain demyelination (MBD). The mechanisms mediating the development of MBD are unknown. In this study, five inbred strains of mice (C57BL/6J, Balb/cByJ, A/J, SJL/J, PL/J) immunosuppressed with either irradiation (IR), cyclophosphamide (CY), or cyclosporin A (CP) along with three immune deficient strains (C57BL/6J nu/nu, Balb/cByJ nu/nu, C57BL/6J bg/bg) were lip inoculated with HSV I to determine the effect of immunosuppression on viral spread throughout the brain and the development of demyelination during the acute stage of infection. Mortality increased in all groups when compared with controls but was greatest in A/J, SJL/J, and PL/J strains, where all mice died before day 6 PI. In contrast with immunocompetent C57BL/6J mice where virus is restricted to the brainstem, virus spread throughout the brain of immunosuppressed C57BL/6J, C57BL/6J nu/nu, and C57BL/6J bg/bg mice. Despite viral spread throughout the brain of immunosuppressed C57BL/6J, C57BL/6J nu/nu, Balb/cByJ and Balb/cByJ nu/nu mice, MBD did not develop. MBD did develop however, in both HSV I infected C57BL/6J bg/bg and CP treated Balb/cByJ mice. Immunosuppression of HSV I infected Balb/cByJ mice prevents the development of demyelination at the trigeminal root entry zone (TREZ) of the brainstem while in Balb/cByJ nu/nu mice, the extent of demyelination at TREZ was reduced and delayed when compared with immunocompetent controls. These results suggest that the immune system plays an important role in limiting viral spread in the brain as well as in the development of demyelination at TREZ and of MBD throughout the brain during the acute phase of infection. Virus alone does not induce MBD in this animal model of virus induced CNS demyelination but is a prerequisite for its development.

Keywords: Immunosuppression, X-irradiation, Cyclophosphamide, Cyclosporin A, Athymic mice, Beige mice, Central nervous system demyelination, Herpes simplex virus

References

  1. Cabrera C.V., Wohlenberg C., Openshaw H., Rey-Mendez M., Puga A., Notkins A.L. Herpes simplex virus DNA sequences in the CNS of latently infected mice. Nature. 1980;288:288–290. doi: 10.1038/288288a0. [DOI] [PubMed] [Google Scholar]
  2. Chan W.L., Javanovic T., Lukic M.L. Infiltration of immune T cells in the brain of mice with herpes simplex virus-induced encephalitis. J. Neuroimmunol. 1989;23:195–201. doi: 10.1016/0165-5728(89)90051-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cook M.L., Stevens J.G. Pathogenesis of herpetic neuritis and ganglionitis in mice: evidence for intra-axonal transport of infection. Infect. Immun. 1973;7:272–288. doi: 10.1128/iai.7.2.272-288.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dal Canto M.C. Experimental models of virus-induced demyelination. In: Cook S.d., editor. Marcel Dekker, Inc; New York and Basel: 1990. pp. 63–100. (Handbook of Multiple Sclerosis). [Google Scholar]
  5. Habu S., Akamatsu K., Tamaoki N., Okumura K. In vivo significance of NK cells on resistance against virus (HSV I) infections in mice. J. Immunol. 1984;133:2743–2747. [PubMed] [Google Scholar]
  6. Hess A.D., Tutschka P.J., Pu Z., Santos G.W. Effect of cyclosporin A on human lymphocyte responses in vitro. IV. Production of T cell stimulatory growth factors and development of responsiveness to these factors in CsA-treated primary MLR cultures. J. Immunol. 1982;128:360–367. [PubMed] [Google Scholar]
  7. Kahan B.D. Cyclosporine. N. Eng. J. Med. 1989;321:1725–1738. doi: 10.1056/NEJM198912213212507. [DOI] [PubMed] [Google Scholar]
  8. Kapoor A.K., Nash A.A., Wildy P., Phelan J., McLean C.S., Field H.J. Pathogenesis of herpes simplex virus in congenitally athymic mice: the relative roles of cell-mediated and humoral immunity. J. Gen. Virol. 1982;60:225–233. doi: 10.1099/0022-1317-60-2-225. [DOI] [PubMed] [Google Scholar]
  9. Kastrukoff L.F., Hamada T., Schumacher U., Long C., Doherty P.C., Koprowski H. Central nervous system infection and immune response in mice inoculated into the lip with herpes simplex virus type. I. J. Neuroimmunol. 1982;2:295–305. doi: 10.1016/0165-5728(82)90062-5. [DOI] [PubMed] [Google Scholar]
  10. Kastrukoff L.F., Lau A.S., Puterman M.L. Genetics of natural resistance to herpes simplex virus type 1 latent infection of the peripheral nervous system in mice. J. gen. VIrol. 1986;67:613–621. doi: 10.1099/0022-1317-67-4-613. [DOI] [PubMed] [Google Scholar]
  11. Kastrukoff L.F., Lau A.S., Kim S.U. Multifocal CNS demyelination following peripheral inoculation with herpes simplex virus type 1. Ann. Neurol. 1987;22:52–59. doi: 10.1002/ana.410220113. [DOI] [PubMed] [Google Scholar]
  12. Kastrukoff L.F., Lau A.S., Osborne D., Kim S.U. Herpes simplex virus type I (HSV 1): A murine model of virus induced central nervous system demyelination. In: Kim S.U., editor. Myelination and Demyelination: Implications for Multiple Sclerosis. Plenum Press; New York: 1989. pp. 153–171. [Google Scholar]
  13. Kastrukoff L.F., Lau A.S., Leung G.Y., Walker D., Thomas E. Herpes simplex virus type I (HSV I) induced multifocal central nervous system (CNS) demyelination in mice. J. Neuropathol. Exp. Neurol. 1992;51:432–439. doi: 10.1097/00005072-199207000-00005. [DOI] [PubMed] [Google Scholar]
  14. Knoblich A., Gortz J., Harle-Grupp V., Falke D. Kinetics and genetics of herpes simplex virus-induced antibody formation in mice. Infect. Immun. 1983;39:15–23. doi: 10.1128/iai.39.1.15-23.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kristensson K., Svennerholm B., Persson L., Vahlne A., Lycke E. Latent herpes simplex virus trigeminal ganglionic infection in mice and demyelination in the central nervous system. J. Neurol. Sci. 1979;43:253–264. doi: 10.1016/0022-510x(79)90119-9. [DOI] [PubMed] [Google Scholar]
  16. Lipton H.L., Dal Canto M.C. Theiler's virus induced demyelination: prevention by immunosuppression. Science. 1976;192:62–64. doi: 10.1126/science.176726. [DOI] [PubMed] [Google Scholar]
  17. Margolis T.P., LaVail J.H., Setzer P.Y., Dawson C.R. Selective spread of herpes simplex virus in the central nervous system after ocular inoculation. J. Virol. 1989;63:4756–4761. doi: 10.1128/jvi.63.11.4756-4761.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. McKenzie R.C., Epand R.M., Johnson D.C. Cyclosporine A inhibits herpes simplex virus-induced cell fusion but not virus penetration into cells. Virology. 1987;159:1–9. doi: 10.1016/0042-6822(87)90341-2. [DOI] [PubMed] [Google Scholar]
  19. Metcalf J.F., Kaufman H.E. Herpetic stromal keratitis-evidence for cell-mediated immunopathogenesis. Am. J. Opthalmol. 1976;82:827–834. doi: 10.1016/0002-9394(76)90057-x. [DOI] [PubMed] [Google Scholar]
  20. Metcalf J.F., Hamilton D.S., Reichert R.W. Herpetic keratitis in athymic (nude) mice. Infect. Immun. 1979;26:1164–1171. doi: 10.1128/iai.26.3.1164-1171.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Morahan P.S., Coleman P.H., Morse S.S., Volkman A. Resistance to infections in mice with defects in the activities of mononuclear phagocytes and natural killer cells effects of immunomodulators in beige mice and 89Sr treated mice. Infect. Immun. 1982;37:1079–1085. doi: 10.1128/iai.37.3.1079-1085.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nathanson N., Panitch H., Palsson P.A., Petursson G., Georgsson G. Pathogenesis of visna. II. Effect of immunosuppression upon early central nervous system lesions. Lab. Invest. 1976;35:444–451. [PubMed] [Google Scholar]
  23. Orosz C.G., Zinn N.E., Adams P.W., Widmer M.B., Ferguson R.M. Influence of cyclosporine on CTL behavior invitro and in-vivo. Ann. N.Y. Acad. Sci. 1988;532:119–127. doi: 10.1111/j.1749-6632.1988.tb36331.x. [DOI] [PubMed] [Google Scholar]
  24. Rice G.P.A., Kastrukoff L.F. Virus-induced demyelination in man and viral experimental models for multiple sclerosis. In: Ebers G., Paty D., editors. Multiple Sclerosis, F.A. Davis Company, Philadelphia. 1993. in press. [Google Scholar]
  25. Rock D.L., Fraser N.W. Detection of HSV-I genome in central nervous system of latently infected mice. Nature. 1983;302:523–525. doi: 10.1038/302523a0. [DOI] [PubMed] [Google Scholar]
  26. Roder J., Duwe J. The beige mutation in the mouse selectively impairs natural killer cell function. Nature. 1979;278:451–453. doi: 10.1038/278451a0. [DOI] [PubMed] [Google Scholar]
  27. Russell R.G., Nasisse N.P., Larsen H.S., Rouse B.T. Role of T-lymphocytes in the pathogenesis of herpetic stromal keratitis. Invest. Ophthalmol. Vis. Sci. 1984;25:938–944. [PubMed] [Google Scholar]
  28. Sternberger L.A., Hardy P.H., Cuculis J.J., Meyer H.G. The unlabeled antibody enzyme method of immunohistochemistry. Preparation and properties of soluble antigen-antibody complex (PAP) and its use in identification of spirochetesJ. Histochem. Cytochem. 1979;18:315–333. doi: 10.1177/18.5.315. [DOI] [PubMed] [Google Scholar]
  29. Thomas E.E., Lau A.S., Kim S.U., Osborne D., Kastrukoff L.F. Variation in resistance to herpes simplex virus type 1 of oligodendrocytes derived from inbred strains of mice. J. Gen. Virol. 1991;72:2051–2057. doi: 10.1099/0022-1317-72-9-2051. [DOI] [PubMed] [Google Scholar]
  30. Townsend J.J. The demyelinating effect of corneal HSV infections in normal and nude (athymic) mice. J. Neurol. Sci. 1981;50:435–441. doi: 10.1016/0022-510x(81)90155-6. [DOI] [PubMed] [Google Scholar]
  31. Townsend J.J. Macrophage response to herpes simplex encephalitis in immune competent and T cell-deficient mice. J. Neuroimmunol. 1985;7:195–206. doi: 10.1016/s0165-5728(84)80019-3. [DOI] [PubMed] [Google Scholar]
  32. Townsend J.J, Baringer J.R. Morphlogy of central nervous system disease in immunosuppressed mice after peripheral herpes simplex virus inoculation. Trigeminal root entry zoneLab. Invest. 1979;40:178–182. [PubMed] [Google Scholar]
  33. Ugolini G., Kuypers H.G.J.M., Strick P.L. Transneuronal transfer of herpes virus from peripheral neurons to cortex and brainstem. Science. 1989;243:89–91. doi: 10.1126/science.2536188. [DOI] [PubMed] [Google Scholar]
  34. Weiner L.P. Pathogenesis of demyelination induced by a mouse hepatitis virus (JHM virus) Arch. Neurol. 1973;28:298–303. doi: 10.1001/archneur.1973.00490230034003. [DOI] [PubMed] [Google Scholar]
  35. Worthington M., Conliffe M.A., Baron S. Mechanism of recovery from systemic herpes simplex virus infection. I. Comparative effectiveness of antibody and reconstitution of immune spleen cells on immunosuppressed mice. J. Infect. Dis. 1980;142:163–174. doi: 10.1093/infdis/142.2.163. [DOI] [PubMed] [Google Scholar]

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