1887

Abstract

Severity of alphavirus infection in humans tends to be strongly age-dependent and several studies using laboratory-adapted Sindbis virus (SB) AR339 strains have indicated that SB-induced disease in mice is similarly contingent upon host developmental status. In the current studies, the consensus wild-type SB, TR339, and imaging technology have been utilized to examine virus replication and disease manifestations in mice infected subcutaneously at 5 days of age (5D) vs 11D. Initial virulence studies with TR339 indicated that this age range is coincident with rapid transition from fatal to non-fatal outcome. Fatal infection of 5D mice is characterized by high-titre serum viraemia, extensive virus replication in skin, fibroblast connective tissue, muscle and brain, and hyperinflammatory cytokine induction. In contrast, 11D-infected mice experience more limited virus replication and tissue damage and develop mild, immune-mediated pathologies including encephalitis. These results further establish the linkage between hyperinflammatory cytokine induction and fatal outcome of infection. imaging using luciferase-expressing viruses and non-propagative replicons revealed that host development results in a restriction of virus replication within individual infected cells that is manifested as a delay in reduction of virus replication in the younger mice. Thus, an important contributing factor in age-dependent resistance to alphavirus infection is restriction of replication within first infected cells in peripheral tissues, which may augment other developmentally regulated attenuating effects, such as increasing neuronal resistance to virus infection and apoptotic death.

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2007-02-01
2019-10-23
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References

  1. Brouckaert, P. & Fiers, W. ( 1996; ). Tumor necrosis factor and the systemic inflammatory response syndrome. Curr Top Microbiol Immunol 216, 167–187.
    [Google Scholar]
  2. Conti, B., Tabarean, I., Andrei, C. & Bartfai, T. ( 2004; ). Cytokines and fever. Front Biosci 9, 1433–1449.[CrossRef]
    [Google Scholar]
  3. Cook, S. H. & Griffin, D. E. ( 2003; ). Luciferase imaging of a neurotropic viral infection in intact animals. J Virol 77, 5333–5338.[CrossRef]
    [Google Scholar]
  4. Elenkov, I. J., Iezzoni, D. G., Daly, A., Harris, A. G. & Chrousos, G. P. ( 2005; ). Cytokine dysregulation, inflammation and well-being. Neuroimmunomodulation 12, 255–269.[CrossRef]
    [Google Scholar]
  5. Griffin, D. E. ( 1976; ). Role of the immune response in age-dependent resistance of mice to encephalitis due to Sindbis virus. J Infect Dis 133, 456–464.[CrossRef]
    [Google Scholar]
  6. Griffin, D. E. ( 2005; ). Neuronal cell death in alphavirus encephalomyelitis. Curr Top Microbiol Immunol 289, 57–77.
    [Google Scholar]
  7. Griffin, D. E. & Johnson, R. T. ( 1977; ). Role of the immune response in recovery from Sindbis virus encephalitis in mice. J Immunol 118, 1070–1075.
    [Google Scholar]
  8. Griffin, D. E., Mokhtarian, F., Park, M. M. & Hirsch, R. L. ( 1983; ). Immune responses to acute alphavirus infection of the central nervous system: Sindbis virus encephalitis in mice. Prog Brain Res 59, 11–21.
    [Google Scholar]
  9. Griffin, D. E., Levine, B., Tyor, W. R., Tucker, P. C. & Hardwick, J. M. ( 1994; ). Age-dependent susceptibility to fatal encephalitis: alphavirus infection of neurons. Arch Virol 9, 31–39.
    [Google Scholar]
  10. Hackbarth, S. A., Reinarz, A. B. & Sagik, B. P. ( 1973; ). Age-dependent resistance of mice to sindbis virus infection: reticuloendothelial role. J Reticuloendothel Soc 14, 405–425.
    [Google Scholar]
  11. Hotchkiss, R. S., Tinsley, K. W. & Karl, I. E. ( 2003; ). Role of apoptotic cell death in sepsis. Scand J Infect Dis 35, 585–592.[CrossRef]
    [Google Scholar]
  12. Johnson, R. T., McFarland, H. F. & Levy, S. E. ( 1972; ). Age-dependent resistance to viral encephalitis: studies of infections due to Sindbis virus in mice. J Infect Dis 125, 257–262.[CrossRef]
    [Google Scholar]
  13. Johnston, C., Jiang, W., Chu, T. & Levine, B. ( 2001; ). Identification of genes involved in the host response to neurovirulent alphavirus infection. J Virol 75, 10431–10445.[CrossRef]
    [Google Scholar]
  14. Klimstra, W. B., Ryman, K. D. & Johnston, R. E. ( 1998; ). Adaptation of Sindbis virus to BHK cells selects for use of heparan sulfate as an attachment receptor. J Virol 72, 7357–7366.
    [Google Scholar]
  15. Klimstra, W. B., Ryman, K. D., Bernard, K. A., Nguyen, K. B., Biron, C. A. & Johnston, R. E. ( 1999; ). Infection of neonatal mice with sindbis virus results in a systemic inflammatory response syndrome. J Virol 73, 10387–10398.
    [Google Scholar]
  16. Labrada, L., Liang, X. H., Zheng, W., Johnston, C. & Levine, B. ( 2002; ). Age-dependent resistance to lethal alphavirus encephalitis in mice: analysis of gene expression in the central nervous system and identification of a novel interferon-inducible protective gene, mouse ISG12. J Virol 76, 11688–11703.[CrossRef]
    [Google Scholar]
  17. Laine, M., Luukkainen, R. & Toivanen, A. ( 2004; ). Sindbis viruses and other alphaviruses as cause of human arthritic disease. J Intern Med 256, 457–471.[CrossRef]
    [Google Scholar]
  18. Levine, B., Goldman, J. E., Jiang, H. H., Griffin, D. E. & Hardwick, J. M. ( 1996; ). Bcl-2 protects mice against fatal alphavirus encephalitis. Proc Natl Acad Sci U S A 93, 4810–4815.[CrossRef]
    [Google Scholar]
  19. Lewis, J., Oyler, G. A., Ueno, K., Fannjiang, Y. R., Chau, B. N., Vornov, J., Korsmeyer, S. J., Zou, S. & Hardwick, J. M. ( 1999; ). Inhibition of virus-induced neuronal apoptosis by Bax. Nat Med 5, 832–835.[CrossRef]
    [Google Scholar]
  20. Liang, X. H., Kleeman, L. K., Jiang, H. H., Gordon, G., Goldman, J. E., Berry, G., Herman, B. & Levine, B. ( 1998; ). Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol 72, 8586–8596.
    [Google Scholar]
  21. Lustig, S., Jackson, A. C., Hahn, C. S., Griffin, D. E., Strauss, E. G. & Strauss, J. H. ( 1988; ). Molecular basis of Sindbis virus neurovirulence in mice. J Virol 62, 2329–2336.
    [Google Scholar]
  22. Lustig, S., Danenberg, H. D., Kafri, Y., Kobiler, D. & Ben-Nathan, D. ( 1992a; ). Viral neuroinvasion and encephalitis induced by lipopolysaccharide and its mediators. J Exp Med 176, 707–712.[CrossRef]
    [Google Scholar]
  23. Lustig, S., Halevy, M., Ben-Nathan, D. & Akov, Y. ( 1992b; ). A novel variant of Sindbis virus is both neurovirulent and neuroinvasive in adult mice. Arch Virol 122, 237–248.[CrossRef]
    [Google Scholar]
  24. McKnight, K. L., Simpson, D. A., Lin, S. C., Knott, T. A., Polo, J. M., Pence, D. F., Johannsen, D. B., Heidner, H. W., Davis, N. L. & Johnston, R. E. ( 1996; ). Deduced consensus sequence of Sindbis virus strain AR339: mutations contained in laboratory strains which affect cell culture and in vivo phenotypes. J Virol 70, 1981–1989.
    [Google Scholar]
  25. Ryman, K. D., Klimstra, W. B., Nguyen, K. B., Biron, C. A. & Johnston, R. E. ( 2000; ). Alpha/beta interferon protects adult mice from fatal Sindbis virus infection and is an important determinant of cell and tissue tropism. J Virol 74, 3366–3378.[CrossRef]
    [Google Scholar]
  26. Ryman, K. D., White, L. J., Johnston, R. E. & Klimstra, W. B. ( 2002; ). Effects of PKR/RNase L-dependent and alternative antiviral pathways on alphavirus replication and pathogenesis. Viral Immunol 15, 53–76.[CrossRef]
    [Google Scholar]
  27. Ryman, K. D., Meier, K. C., Nangle, E. M., Ragsdale, S. L., Korneeva, N. L., Rhoads, R. E., Macdonald, M. R. & Klimstra, W. B. ( 2005; ). Sindbis virus translation is inhibited by a PKR/RNase L-independent effector induced by alpha/beta interferon priming of dendritic cells. J Virol 79, 1487–1499.[CrossRef]
    [Google Scholar]
  28. Silverman, M. N., Miller, A. H., Biron, C. A. & Pearce, B. D. ( 2004; ). Characterization of an interleukin-6- and adrenocorticotropin-dependent, immune-to-adrenal pathway during viral infection. Endocrinology 145, 3580–3589.[CrossRef]
    [Google Scholar]
  29. Silverman, M. N., Pearce, B. D., Biron, C. A. & Miller, A. H. ( 2005; ). Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunol 18, 41–78.[CrossRef]
    [Google Scholar]
  30. Smith, J. F., Davis, M., Hart, M. K., Ludwig, G. V., McClain, D. J., Parker, M. D. & Pratt, W. D. ( 1997; ). Viral encephalitides. In Medical Aspects of Chemical and Biological Warfare, pp. 561–590. Edited by F. R. Sidell, E. T. Takafuji & D. R. Franz. Washington, DC: Office of the Surgeon General, Department of the Army.
  31. Trgovcich, J., Aronson, J. F. & Johnston, R. E. ( 1996; ). Fatal Sindbis virus infection of neonatal mice in the absence of encephalitis. Virology 224, 73–83.[CrossRef]
    [Google Scholar]
  32. Trgovcich, J., Ryman, K., Extrom, P., Eldridge, J. C., Aronson, J. F. & Johnston, R. E. ( 1997; ). Sindbis virus infection of neonatal mice results in a severe stress response. Virology 227, 234–238.[CrossRef]
    [Google Scholar]
  33. Trgovcich, J., Aronson, J. F., Eldridge, J. C. & Johnston, R. E. ( 1999; ). TNFalpha, interferon, and stress response induction as a function of age-related susceptibility to fatal Sindbis virus infection of mice. Virology 263, 339–348.[CrossRef]
    [Google Scholar]
  34. Tucker, P. C., Strauss, E. G., Kuhn, R. J., Strauss, J. H. & Griffin, D. E. ( 1993; ). Viral determinants of age-dependent virulence of Sindbis virus for mice. J Virol 67, 4605–4610.
    [Google Scholar]
  35. Valero, N., Anez, F., Larreal, Y., Arias, J., Rodriguez, Z. & Espina, L. M. ( 2001; ). Evaluation of immunity against Venezuelan equine encephalitis virus and dengue in the human population of San Carlos, the Almirante Padilla Island Municipality, Zulia State, Venezuela. 1996. Invest Clin 42, 161–169 (in Spanish).
    [Google Scholar]
  36. Vilcek, J. ( 1964; ). Production of interferon by newborn and adult mice infected with Sindbis virus. Virology 22, 651–652.[CrossRef]
    [Google Scholar]
  37. Wang, T., Town, T., Alexopoulou, L., Anderson, J. F., Fikrig, E. & Flavell, R. A. ( 2004; ). Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med 10, 1366–1373.[CrossRef]
    [Google Scholar]
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