Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Age-Dependent Pathogenesis of Murine Gammaherpesvirus 68 Infection of the Central Nervous System

  • Cho, Hye-Jeong (Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University) ;
  • Kim, Sungbum (Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University) ;
  • Kwak, Sung-Eun (Department of Anatomy and Neurobiology, College of Medicine, Hallym University) ;
  • Kang, Tae-Cheon (Department of Anatomy and Neurobiology, College of Medicine, Hallym University) ;
  • Kim, Hee-Sung (Department of Microbiology, College of Medicine, Hallym University) ;
  • Kwon, Hyung-Joo (Department of Microbiology, College of Medicine, Hallym University) ;
  • Kim, Yoon-Won (Department of Microbiology, College of Medicine, Hallym University) ;
  • Kim, Yong-Sun (Department of Microbiology, College of Medicine, Hallym University) ;
  • Choi, Eun-Kyung (Ilsong Institute of Life Science, Hallym University) ;
  • Song, Moon Jung (Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University)
  • Received : 2008.10.30
  • Accepted : 2008.11.11
  • Published : 2009.01.31
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Abstract

Gammaherpesvirus infection of the central nervous system (CNS) has been linked to various neurological diseases, including meningitis, encephalitis, and multiple sclerosis. However, little is known about the interactions between the virus and the CNS in vitro or in vivo. Murine gammaherpesvirus 68 (MHV-68 or ${\gamma}HV-68$) is genetically related and biologically similar to human gammaherpesviruses, thereby providing a tractable animal model system in which to study both viral pathogenesis and replication. In the present study, we show the successful infection of cultured neuronal cells, microglia, and astrocytes with MHV-68 to various extents. Upon intracerebroventricular injection of a recombinant virus (MHV-68/LacZ) into 4-5-week-old and 9-10-week-old mice, the 4-5-week-old mice displayed high mortality within 5-7 days, while the majority of the 9-10-week-old mice survived until the end of the experimental period. Until a peak at 3-4 days post-infection, viral DNA replication and gene expression were similar in the brains of both mouse groups, but only the 9-10-week-old mice were able to subdue viral DNA replication and gene expression after 5 days post-infection. Pro-inflammatory cytokine mRNAs of tumor necrosis factor-${\alpha}$, interleukin $1{\beta}$, and interleukin 6 were highly induced in the brains of the 4-5-week-old mice, suggesting their possible contributions as neurotoxic factors in the age-dependent control of MHV-68 replication of the CNS.

Keywords

Acknowledgement

Supported by : Korea Research Foundation

References

  1. Ascherio, A., and Munch, M. (2000). Epstein-Barr virus and multiple sclerosis. Epidemiology 11, 220-224 https://doi.org/10.1097/00001648-200003000-00023
  2. Ascherio, A., Munger, K.L., Lennette, E.T., Spiegelman, D., Hernan, M.A., Olek, M.J., Hankinson, S.E., and Hunter, D.J. (2001). Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 286, 3083-3088 https://doi.org/10.1001/jama.286.24.3083
  3. Blaskovic, D., Stancekova, M., Svobodova, J., and Mistrikova, J. (1980). Isolation of five strains of herpesviruses from two species of free living small rodents. Acta Virol. 24, 468
  4. Blaskovic, D., Stanekova, D., and Rajcani, J. (1984). Experimental pathogenesis of murine herpesvirus in newborn mice. Acta Virol. 28, 225-231
  5. Bossolasco, S., Falk, K.I., Ponzoni, M., Ceserani, N., Crippa, F., Lazzarin, A., Linde, A., and Cinque, P. (2006). Ganciclovir is associated with low or undetectable Epstein-Barr virus DNA load in cerebrospinal fluid of patients with HIV-related primary central nervous system lymphoma. Clin. Infect. Dis.42, e21-25 https://doi.org/10.1086/499956
  6. Brabers, N.A., and Nottet, H.S. (2006). Role of the pro-inflammatory cytokines TNF-alpha and IL-1$\beta$ in HIV-associated dementia. Eur. J. Clin. Invest. 36, 447-458 https://doi.org/10.1111/j.1365-2362.2006.01657.x
  7. Chan, P.K., Ng, H.K., Hui, M., Ip, M., Cheung, J.L., and Cheng, A.F. (1999). Presence of human herpesviruses 6, 7, and 8 DNA sequences in normal brain tissue. J. Med. Virol. 59, 491-495 https://doi.org/10.1002/(SICI)1096-9071(199912)59:4<491::AID-JMV11>3.0.CO;2-1
  8. Chan, P.K., Ng, H.K., Cheung, J.L., and Cheng, A.F. (2000). Survey for the presence and distribution of human herpesvirus 8 in healthy brain. J. Clin. Microbiol. 38, 2772-2773
  9. Corbellino, M., Poirel, L., Bestetti, G., Pizzuto, M., Aubin, J.T., Capra, M., Bifulco, C., Berti, E., Agut, H., Rizzardini, G.I et al. (1996). Restricted tissue distribution of extralesional Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS patients with Kaposi's sarcoma. AIDS Res. Hum. Retroviruses 12, 651-657 https://doi.org/10.1089/aid.1996.12.651
  10. Hoover, S.E., Ross, J.P., and Cohen, J.I. (2004). Epstein-Barr virus, In Infections of the central nervous system. W.M. Scheld, R.J. Whitley, and C.M. Marra, eds. (Philadelphia: Lippincott Williams & Wilkins), pp. 175-183
  11. Karatas, H., Gurer, G., Pinar, A., Soylemezoglu, F., Tezel, G.G., Hascelik, G., Akalan, N., Tuncer, S., Ciger, A., and Saygi, S. (2008). Investigation of HSV-1, HSV-2, CMV, HHV-6 and HHV-8 DNA by real-time PCR in surgical resection materials of epilepsy patients with mesial temporal lobe sclerosis. J. Neurol. Sci. 264, 151-156 https://doi.org/10.1016/j.jns.2007.08.010
  12. Kwak, S.E., Kim, J.E., Kim, D.S., Jung, J.Y., Won, M.H., Kwon, O.S., Choi, S.Y., and Kang, T.C. (2005). Effects of GABAergic transmissions on the immunoreactivities of calcium binding proteins in the gerbil hippocampus. J. Comp. Neurol. 485, 153-164 https://doi.org/10.1002/cne.20482
  13. Kwon, H.J., Lee, K.W., Yu, S.H., Han, J.H., and Kim, D.S. (2003). NF-$\kappa$B-dependent regulation of tumor necrosis factor-alpha gene expression by CpG-oligodeoxynucleotides. Biochem. Biophys. Res. Commun. 311, 129-138 https://doi.org/10.1016/j.bbrc.2003.09.168
  14. Lee, S., Cho, H.J., Park, J.J., Kim, Y.S., Hwang, S., Sun, R., and Song, M.J. (2007a). The ORF49 protein of murine gammaherpesvirus 68 cooperates with RTA in regulating virus replication. J. Virol. 81, 9870-9877 https://doi.org/10.1128/JVI.00001-07
  15. Lee, J.Y., Kim, J.Y., Lee, Y.G., Shin, W.C., Chun, T., Rhee, M.H., and Cho, J.Y. (2007b). Hydroquinone, a reactive metabolite of benzene, reduces macrophage-mediated immune responses. Mol. Cells. 23, 198-206
  16. Lokensgard, J.R., Hu, S., Sheng, W., vanOijen, M., Cox, D., Cheeran, M.C., and Peterson, P.K. (2001). Robust expression of TNF-$\alpha$, IL-1$\beta$, RANTES, and IP-10 by human microglial cells during nonproductive infection with herpes simplex virus. J. Neurovirol. 7, 208-219 https://doi.org/10.1080/13550280152403254
  17. Rajcani, J., Blaskovic, D., Svobodova, J., Ciampor, F., Huckova, D., and Stanekova, D. (1985). Pathogenesis of acute and persistent murine herpesvirus infection in mice. Acta Virol. 29, 51-60
  18. Said, J.W., Tasaka, T., de Vos, S., and Koeffler, H.P. (1997). Kaposi's sarcoma-associated herpesvirus/human herpesvirus type 8 encephalitis in HIV-positive and -negative individuals. AIDS 11, 1119-1122 https://doi.org/10.1097/00002030-199709000-00006
  19. Serafini, B., Rosicarelli, B., Franciotta, D., Magliozzi, R., Reynolds, R., Cinque, P., Andreoni, L., Trivedi, P., Salvetti, M., Faggioni, A., et al. (2007). Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J. Exp. Med. 204, 2899-2912 https://doi.org/10.1084/jem.20071030
  20. Sergerie, Y., Rivest, S., and Boivin, G. (2007). Tumor necrosis factor-$\alpha$ and interleukin-1 $\beta$ play a critical role in the resistance against lethal herpes simplex virus encephalitis. J. Infect. Dis. 196, 853-860 https://doi.org/10.1086/520094
  21. Simas, J.P., and Efstathiou, S. (1998). Murine gammaherpesvirus 68: a model for the study of gammaherpesvirus pathogenesis. Trends Microbiol 6, 276-282 https://doi.org/10.1016/S0966-842X(98)01306-7
  22. Song, M.J., Hwang, S., Wong, W., Round, J., Martinez-Guzman, D., Turpaz, Y., Liang, J., Wong, B., Johnson, R.C., Carey, M., et al. (2004). The DNA architectural protein HMGB1 facilitates RTAmediated viral gene expression in gamma-2 herpesviruses. J. Virol. 78, 12940-12950 https://doi.org/10.1128/JVI.78.23.12940-12950.2004
  23. Song, M.J., Hwang, S., Wong, W.H., Wu, T.T., Lee, S., Liao, H.I., and Sun, R. (2005). Identification of viral genes essential for replication of murine gamma-herpesvirus 68 using signaturetagged mutagenesis. Proc. Natl. Acad. Sci. USA 102, 3805-3810 https://doi.org/10.1073/pnas.0404521102
  24. Stewart, J.P., Usherwood, E.J., Ross, A., Dyson, H., and Nash, T. (1998). Lung epithelial cells are a major site of murine gammaherpesvirus persistence. J. Exp. Med. 187, 1941-1951 https://doi.org/10.1084/jem.187.12.1941
  25. Sunil-Chandra, N.P., Efstathiou, S., Arno, J., and Nash, A.A. (1992a). Virological and pathological features of mice infected with murine gamma-herpesvirus 68. J. Gen. Virol. 73, 2347-2356 https://doi.org/10.1099/0022-1317-73-9-2347
  26. Sunil-Chandra, N.P., Efstathiou, S., and Nash, A.A. (1992b). Murine gammaherpesvirus 68 establishes a latent infection in mouse B lymphocytes in vivo. J. Gen. Virol. 73, 3275-3279 https://doi.org/10.1099/0022-1317-73-12-3275
  27. Sunil-Chandra, N.P., Arno, J., Fazakerley, J., and Nash, A.A. (1994). Lymphoproliferative disease in mice infected with murine gammaherpesvirus 68. Am. J. Pathol. 145, 818-826
  28. Taylor, W.R., Rasley, A., Bost, K.L., and Marriott, I. (2003). Murine gammaherpesvirus-68 infects microglia and induces high levels of pro-inflammatory cytokine production. J. Neuroimmunol. 136, 75-83 https://doi.org/10.1016/S0165-5728(03)00011-0
  29. Terry, L.A., Stewart, J.P., Nash, A.A., and Fazakerley, J.K. (2000). Murine gammaherpesvirus-68 infection of and persistence in the central nervous system. J. Gen. Virol. 81, 2635-2643 https://doi.org/10.1099/0022-1317-81-11-2635
  30. Weck, K.E., Kim, S.S., Virgin, H.I., and Speck, S.H. (1999). Macrophages are the major reservoir of latent murine gammaherpesvirus 68 in peritoneal cells. J. Virol. 73, 3273-3283
  31. Weinberg, A., Bloch, K.C., Li, S., Tang, Y.W., Palmer, M., and Tyler, K.L. (2005). Dual infections of the central nervous system with Epstein-Barr virus. J. Infect. Dis.191, 234-237 https://doi.org/10.1086/426402
  32. Wu, T.T., Tong, L., Rickabaugh, T., Speck, S., and Sun, R. (2001). Function of Rta is essential for lytic replication of murine gammaherpesvirus 68. J. Virol. 75, 9262-9273 https://doi.org/10.1128/JVI.75.19.9262-9273.2001

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