Abstract
Infection of athymic (nu/nu) mice with Theiler's murine encephalomyelitis virus results in an acute encephalitis which resembles poliomyelitis. Immunohistochemistry and in situ hybridization were used to delineate the presence of viral proteins and RNA in the nervous systems of nude mice infected with the Daniels strain of Theiler's virus. This system permits the analysis of a viral infection in the absence of an effective immune response. By immunohistochemistry, viral antigen was found in the processes and cell bodies of neurons and glial cells. Besides the presence of viral antigen in these cell types, by in situ hybridization, Theiler's virus RNA was also found in cells associated with vascular endothelium in the brains and spinal cords of these infected mice. Theiler's virus RNA-positive endothelial cells were observed not only near the primary lesions but also away from demonstrable lesions in normal-appearing regions in the central nervous system. Earlier work had suggested an intra-axonal dissemination for this virus (M. C. Dal Canto and H. L. Lipton, Am. J. Pathol. 106:20-29, 1982). Our findings are consistent with this model but also suggest an additional mechanism for virus spread within the central nervous system, i.e., by infecting vascular cells and crossing the blood-brain barrier. Lastly, after Theiler's murine encephalomyelitis virus infection, not only glial cells but also endothelial cells express major histocompatibility complex class II (la) antigen on their surface (M. Rodriguez, M. L. Pierce, and E. A. Howie, J. Immunol. 138:3438-3442, 1987). Our demonstration of Theiler's virus-infected endotheliumlike cells may explain interactions of virus products in stimulating antigen presentation.
Full text
PDF![3589](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb73/253498/a7a3092ae19d/jvirol00089-0057.png)
![3590](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb73/253498/d8064edd4ea0/jvirol00089-0058.png)
![3591](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb73/253498/e20c568f32e1/jvirol00089-0059.png)
![3592](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb73/253498/77328d19312d/jvirol00089-0060.png)
![3593](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb73/253498/dce689ffa007/jvirol00089-0061.png)
![3594](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb73/253498/d4229c95c83a/jvirol00089-0062.png)
![3595](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb73/253498/d48b8046c077/jvirol00089-0063.png)
![3596](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb73/253498/db911caacba9/jvirol00089-0064.png)
Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Brahic M., Haase A. T., Cash E. Simultaneous in situ detection of viral RNA and antigens. Proc Natl Acad Sci U S A. 1984 Sep;81(17):5445–5448. doi: 10.1073/pnas.81.17.5445. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Brown A. M., McFarlin D. E. Relapsing experimental allergic encephalomyelitis in the SJL/J mouse. Lab Invest. 1981 Sep;45(3):278–284. [PubMed] [Google Scholar]
- 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]
- 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]
- Chamorro M., Aubert C., Brahic M. Demyelinating lesions due to Theiler's virus are associated with ongoing central nervous system infection. J Virol. 1986 Mar;57(3):992–997. doi: 10.1128/jvi.57.3.992-997.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chandra V., Bharucha N. E., Schoenberg B. S. Patterns of mortality from types of dementia in the United States, 1971 and 1973-1978. Neurology. 1986 Feb;36(2):204–208. doi: 10.1212/wnl.36.2.204. [DOI] [PubMed] [Google Scholar]
- DANIELS J. B., PAPPENHEIMER A. M., RICHARDSON S. Observations on encephalomyelitis of mice (DA strain). J Exp Med. 1952 Dec;96(6):517–530. doi: 10.1084/jem.96.6.517. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dal Canto M. C., Barbano R. L., Jubelt B. Ultrastructural immunohistochemical localization of poliovirus during virulent infection of mice. J Neuropathol Exp Neurol. 1986 Nov;45(6):613–618. doi: 10.1097/00005072-198611000-00001. [DOI] [PubMed] [Google Scholar]
- Dal Canto M. C., Lipton H. L. Multiple sclerosis. Animal model:Theiler's virus infection in mice. Am J Pathol. 1977 Aug;88(2):497–500. [PMC free article] [PubMed] [Google Scholar]
- 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]
- 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]
- Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
- Kindred B. Nude mice in immunology. Prog Allergy. 1979;26:137–238. [PubMed] [Google Scholar]
- Lang W., Wiley C., Lampert P. Theiler's virus encephalomyelitis is unaffected by treatment with myelin components. J Neuroimmunol. 1985 Jul;9(1-2):109–113. doi: 10.1016/s0165-5728(85)80011-4. [DOI] [PubMed] [Google Scholar]
- Lehrich J. R., Arnason B. G., Hochberg F. H. Demyelinative myelopathy in mice induced by the DA virus. J Neurol Sci. 1976 Oct;29(2-4):149–160. doi: 10.1016/0022-510x(76)90167-2. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- Massa P. T., ter Meulen V. Analysis of Ia induction on Lewis rat astrocytes in vitro by virus particles and bacterial adjuvants. J Neuroimmunol. 1987 Jan;13(3):259–271. doi: 10.1016/0165-5728(87)90062-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Matsumoto Y., Fujiwara M. In situ detection of class I and II major histocompatibility complex antigens in the rat central nervous system during experimental allergic encephalomyelitis. An immunohistochemical study. J Neuroimmunol. 1986 Oct;12(4):265–277. doi: 10.1016/0165-5728(86)90033-0. [DOI] [PubMed] [Google Scholar]
- Ozden S., Tangy F., Chamorro M., Brahic M. Theiler's virus genome is closely related to that of encephalomyocarditis virus, the prototype cardiovirus. J Virol. 1986 Dec;60(3):1163–1165. doi: 10.1128/jvi.60.3.1163-1165.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- Rodriguez M., Pierce M. L., Howie E. A. Immune response gene products (Ia antigens) on glial and endothelial cells in virus-induced demyelination. J Immunol. 1987 May 15;138(10):3438–3442. [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- Rueckert R. R., Pallansch M. A. Preparation and characterization of encephalomyocarditis (EMC) virus. Methods Enzymol. 1981;78(Pt A):315–325. [PubMed] [Google Scholar]
- Shivers B. D., Harlan R. E., Pfaff D. W., Schachter B. S. Combination of immunocytochemistry and in situ hybridization in the same tissue section of rat pituitary. J Histochem Cytochem. 1986 Jan;34(1):39–43. doi: 10.1177/34.1.3510246. [DOI] [PubMed] [Google Scholar]
- Stroop W. G., Baringer J. R., Brahic M. Detection of Theiler's virus RNA in mouse central nervous system by in situ hybridization. Lab Invest. 1981 Dec;45(6):504–509. [PubMed] [Google Scholar]
- Vass K., Lassmann H., Wekerle H., Wisniewski H. M. The distribution of Ia antigen in the lesions of rat acute experimental allergic encephalomyelitis. Acta Neuropathol. 1986;70(2):149–160. doi: 10.1007/BF00691433. [DOI] [PubMed] [Google Scholar]
- Wiley C. A., Schrier R. D., Nelson J. A., Lampert P. W., Oldstone M. B. Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7089–7093. doi: 10.1073/pnas.83.18.7089. [DOI] [PMC free article] [PubMed] [Google Scholar]