1887

Abstract

Exposure of inbred mice to murine hepatitis virus strain 3 (MHV-3) causes a strain dependent spectrum of disease symptoms which correlates with induction of procoagulant activity (PCA) by macrophages. Previous studies have demonstrated a role for interferons in resistance to MHV-3 infection. These cytokines have both antiviral and immunoregulatory effects which may be crucial for MHV-3 resistance. One of their antiviral effects is the ability to induce 2′,5′-oligoadenylate (2-5A) synthetase leading to activation of the latent endoribonuclease RNase L. Once activated, RNase L degrades ssRNA thereby inhibiting viral-induced protein synthesis. These studies were undertaken to determine the effects of Oragen 0004 (Oragen), an RNase L activating 2-5A analogue, on MHV-3 replication and induction of PCA and on the course of MHV-3 infection in susceptible BALB/cJ mice . Oragen inhibited MHV-3 replication in peritoneal macrophages derived from resistant A/J and susceptible BALB/cJ mice in a dose-dependent fashion. Concentrations of Oragen greater than 110 µg/2 × 10 macrophages decreased viral replication by greater than 89% in peritoneal macrophages obtained from both BALB/cJ and A/J mice and by 86% in livers from MHV-3-infected mice . However, Oragen failed to inhibit induction of PCA following exposure of BALB/cJ mice-derived peritoneal macrophages to MHV-3 and failed to prevent the development of fulminant hepatitis in BALB/cJ mice . Thus, these studies demonstrate clearly that induction of 2-5A synthase and inhibition of viral replication is not sufficient to prevent MHV-3-related hepatocellular injury, and these data further support the role of PCA in the pathogenesis of MHV-3 infection.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-76-2-373
1995-02-01
2021-10-22
Loading full text...

Full text loading...

/deliver/fulltext/jgv/76/2/JV0760020373.html?itemId=/content/journal/jgv/10.1099/0022-1317-76-2-373&mimeType=html&fmt=ahah

References

  1. Abecassis M., Falk J. A., Makowka L., Dindzans V. J., Falk R. E., Levy G. A. 1987; 16, 16 dimethyl prostaglandin E2 prevents the development of fulminant hepatitis and blocks the induction of monocyte/macrophage procoagulant activity after murine hepatitis virus strain 3 infection. Journal of Clinical Investigation 80:881–889
    [Google Scholar]
  2. Borden E. C. 1992; Interferons: pleiotropic cellular modulators. Clinical Immunology and Immunopathology 62:S18–S24
    [Google Scholar]
  3. Carter W. A., Suhadolnik R. J., Muller W. E. G., Korba B. E., Hubbell H. R., Garcia G., Strayer D. R. 1993; Specific RNA drug therapy of hepatitis viruses. Annals of the New York Academy of Science 6785:758–761
    [Google Scholar]
  4. Charachon G., Sobol R. W., Bisbal C., Salehzada T., Silhol M., Charubala R., Pfleiderer W., Lebleu B., Suhadolnik R. J. 1990; Phosphorothioate analogues of (2′-5′)(A)4: agonist and antagonist activities in intact cells. Biochemistry 29:2550–2556
    [Google Scholar]
  5. Chebath J., Benech P., Revel M., Vigneron M. 1987; Constitutive expression of (2′-5′) oligo A synthetase confers resistance in picornavirus infection. Nature 330:587–588
    [Google Scholar]
  6. Chung S., Gorczynski R., Cruz B., Fingerote R., Skamene E., Perlman S., Leibowitz J., Fung L., Flowers M., Levy G. 1994; Characterization of murine hepatitis virus strain 3 (MFIV-3) specific T cell lines: effect on induction of macrophage procoagulant activity in vitro and course of MHV-3 infection in vivo . Immunology (in press)
    [Google Scholar]
  7. de Vries P., Versteeg-van Oosten J. P., Visser I. K., van Binnendijk R. S., Langeveld S. A., Osterhaus A. D., Uytdehaag P. G. 1989; Measles virus-specific murine T cell clones: characterization of fine specificity and function. Journal of Immunology 142:2841–2846
    [Google Scholar]
  8. Dindzans V. J., MacPhee P. J., Fung L. S., Leibowitz J. L., Levy G. A. 1985; The immune response to mouse hepatitis virus: expression of monocyte procoagulant activity and plasminogen activator during infection in vivo. Journal of Immunology 135:4189–4197
    [Google Scholar]
  9. Dindzans V. J., Skamene E., Levy G. A. 1986; Susceptibility/ resistance to mouse hepatitis virus strain 3 and macrophage procoagulant activity are genetically linked and controlled by two non-H-2-linked genes. Journal of Immunology 137:2355–2360
    [Google Scholar]
  10. Fung L. S., Neil G., Leibowitz J., Cole E. H., Chung S., Crow A., Levy G. A. 1991; Monoclonal antibody analysis of a unique macrophage procoagulant activity induced by murine hepatitis virus strain 3 infection. Journal of Biological Chemistry 266:1789–1795
    [Google Scholar]
  11. Grossberg S. E. 1987; Interferons: an overview of their biological and biochemical properties. In Mechanisms of Interferon Actions pp 1–32 Edited by Pfeffer L. M. Boca Raton FL: CRC Press;
    [Google Scholar]
  12. Hirano N., Fujiwara K., Hino S., Matumoto M. 1974; Replication and plaque formation of mouse hepatitis virus (MHV-2) in mouse cell line DBT culture. Archiv fur die Gesante Virusforschung 44:298–302
    [Google Scholar]
  13. Kanou M., Ohomori H., Takaku H., Yokoyama S., Kawai G., Suhadolnik R. J., Sobol R. Jr 1990; Chemical synthesis and biological activity of analogues of 2′, 5′-oligoadenylates containing 8-substituted adenosine derivatives. Nucleic Acids Research 18:4439–1446
    [Google Scholar]
  14. Kanou M., Ohomori H., Nagai K., Yokoyama S., Suhadolnik R. J., Sobol R. Jr, Takaku H. 1991; Purine 8-substitution modulates the ribonuclease L binding and activation abilities of 2′, 5′-oligoadenylates. Biochemical and Biophysical Research Communications 176:769–774
    [Google Scholar]
  15. Kariko K., Sobol R. W. Jr, Suhadolnik L., Li S. W., Reichenbach N. L., Suhadolnik R. J., Charubala R., Pfleiderer W. 1987; Phosphorothioate analogues of 2′, 5′-oligoadenylate. Enzymatically synthesized 2′, 5′-phosphorothioate dimer and trimer: unequivocal structural assignment and activation of 2′, 5′-oligoadenylate-dependent endoribonuclease. Biochemistry 26:7127–7135
    [Google Scholar]
  16. Kato Y., Noda Y., Unoura M., Tanaka N., Kobayashi K., Hattori N., Hatano K., Kobayashi S. 1986; Effect of exogenous mouse interferon on murine fulminant hepatitis virus type 2. Digestive Diseases and Science 31:177–180
    [Google Scholar]
  17. Korner H., Schliephake A., Winter J., Zimprich F., Lassmann H., Sedgwick J., Siddell S., Wege H. 1991; Nucleocapsid or spike protein-specific CD8+ T lymphocytes protect against coronavirus-induced encephalomyelitis in the absence of CD8+ T cells. Journal of Immunology 147:2317–2323
    [Google Scholar]
  18. Kumar R., Choubey D., Lengyel P., Sen G. C. 1988; Studies on the role of the 2′-5′-oligoadenylate synthetase-RNase L pathway in beta-interferon mediated inhibition of encephalomyocarditis virus replication. Journal of Virology 62:3175–3181
    [Google Scholar]
  19. Laemmli U. K. 1970; Cleavage of structural protein during the assembly of the head of bacteriophage T4. Nature 221:680–685
    [Google Scholar]
  20. Lengyel P. 1982; Biochemistry of interferons and their actions. Annual Reviews of Biochemistry 51:251–282
    [Google Scholar]
  21. Le Prevost C., Levy-Leblond E., Virelizier J. L., Dupuy J. M. 1975; Immunopathology of mouse hepatitis virus type 3 infection Role of humoral and cell-mediated immunity in resistance mechanism. Journal of Immunology 114:221–225
    [Google Scholar]
  22. Levy G. A., Leibowitz J. L., Edgington T. S. 1981; Induction of monocyte procoagulant activity by murine hepatitis virus type 3 parallels disease susceptibility in mice. Journal of Experimental Medicine 154:1150–1163
    [Google Scholar]
  23. Levy G. A., Leibowitz J. L., Edgington T. S. 1982; Lymphocyte-instructed monocyte induction of the coagulation pathway parallels the induction of hepatitis by the murine hepatitis virus. In Progress in Liver Disease Vol 7 pp 393–409 Edited by Popper H., Schaffner F. New York: Grune & Stratton;
    [Google Scholar]
  24. Li C., Fung L. S., Chung S., Crow A., Myers-Mason N., Phillips M. J., Leibowitz J. L., Cole E., Ottaway C. A., Levy G. 1992; Monoclonal antiprothrombinase (3D4.3) prevents mortality from murine hepatitis virus (MHV-3) infection. Journal of Experimental Medicine 176:689–697
    [Google Scholar]
  25. Lucas A., Flintoff W., Anderson R., Percy D., Coulter M., Dales S. 1977; In vivo and in vitro models of demyelinating diseases: tropism of the JHM strain of murine hepatitis virus for cells of glial origin. Cell 12:553–560
    [Google Scholar]
  26. Lucchiari M. A., Pereira C. A. 1989; A major role of macrophage activation by interferon-gamma during mouse hepatitis virus type 3 infection. I. Genetically dependent resistance. Immunobiology 180:12–22
    [Google Scholar]
  27. Lucchiari M. A., Pereira C. A. 1990; A major role of macrophage activation by interferon-gamma during mouse hepatitis virus type 3 infection. II. Age dependent resistance. Immunobiology 181:31–39
    [Google Scholar]
  28. Lucchiari M. A., Martin J. P., Modolell M., Pereira C. A. 1991; Acquired immunity of A/J mice to mouse hepatitis virus strain 3 infection: dependence on interferon-y synthesis and macrophage sensitivity to interferon-y. Journal of General Virology 72:1317–1322
    [Google Scholar]
  29. Lucchiari M. A., Modolell M., Eichmann K., Pereira C. A. 1991; In vivo depletion of interferon gamma leads to susceptibility of A/J mice to mouse hepatitis virus 3 infection. Immunobiology 185:475–482
    [Google Scholar]
  30. Lucin P., Pavic I., Polic B., Jonjic S., Koszinowski U. H. 1992; Gamma interferon-dependent clearance of cytomegalovirus infection in salivary glands. Journal of Virology 66:1977–1984
    [Google Scholar]
  31. MacNaughton M. R., Patterson S. 1980; Mouse hepatitis virus strain 3 infection of C57, A/Sn and A/J strain mice and their macrophages. Archives of Virology 66:71–75
    [Google Scholar]
  32. Minagawa H., Takenaka A., Mohri S., Mori R. 1987; Protective effect of recombinant murine interferon beta against mouse hepatitis virus infection. Antiviral Research 8:85–95
    [Google Scholar]
  33. Montefiori D. C., Sobol R. W. Jr, Li S. W., Reichenbach N. L., Suhadolnik R. J., Charubala R., Pfleiderer W., Modliszewski A., Robinson W. E. Jr, Mitchell W. M. 1989; Phosphorothioate and cordycepin analogues of 2′, 5′-oligoadenylate: inhibition of human immunodeficiency virus type 1 reverse transcriptase and infection in vitro . Proceedings of the National Academv of Sciences, USA 86:7191–7194
    [Google Scholar]
  34. Moon D. K., Geczy C. L. 1988; Recombinant IFN-gamma synergizes with lipopolysaccharide to induce macrophage membrane procoagulants. Journal of Immunology 141:1536–1542
    [Google Scholar]
  35. Mosmann T. R., Coffman R. L. 1989; TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annual Review of Immunology 7:145–173
    [Google Scholar]
  36. Muller W. E. G., Weiler B. E., Charubala R., Pfleiderer W., Leserman L., Sobol R. W., Suhadolnik R. J., Schroder H. C. 1991; Cordycepin analogues of 2′, 5′-oligoadenylate inhibit human immunodeficiency virus infection via inhibition of reverse transcriptase. Biochemistry 30:2027–2033
    [Google Scholar]
  37. Nagai K., Kanbara K., Nakashima H., Yamamoto N., Torrence P. F., Suhadolnik R. J., Takaku H. 1993; Characterization and biological activity of 8-substituted analogues of 2′, 5′-oligoadenylates. Biochimica et Biophysica Acta 1156:321–326
    [Google Scholar]
  38. Palladino G., Scherle P. A., Gerhard W. 1991; Activity of CD4 + T-cell clones of type 1 and type 2 in generation of influenza virus-specific cytotoxic responses in vitro. Journal of Virology 65:6071–6076
    [Google Scholar]
  39. Pestka S., Langer J. A. 1987; Interferons and their actions. Annual Reviews of Biochemistry 56:727–777
    [Google Scholar]
  40. Rothfels K. H., Axelrad A. A., Siminovitch L., McCulloch E. A., Parker R. C. 1959; The origin of altered cell lines from mouse, monkey, and man, as indicated by chromosome and transplantation studies. Canadian Cancer Conferences 3:189–214
    [Google Scholar]
  41. Samuel C. E. 1987; Interferon induction of the antiviral state: proteins induced by interferons and their possible roles in the antiviral mechanisms of interferon action. In Mechanisms of Interferon Actions pp 111–130 Edited by Pfeffer L. M. Boca Raton FL: CRC Press;
    [Google Scholar]
  42. Schindler L., Engler H., Kirchner H. 1982; Activation of natural killer cells and induction of interferon after injection of mouse hepatitis virus type 3 in mice. Infection and Immunity 35:869–873
    [Google Scholar]
  43. Sinclair S. B., Rotstein O. D., Levy G. A. 1990; Disparate mechanisms of induction of procoagulant activity by live and inactivated bacteria and viruses. Infection and Immunity 58:1821–1827
    [Google Scholar]
  44. Staeheli P. 1990; Interferon-induced proteins and the antiviral state. Advances in Virus Research 38:147–200
    [Google Scholar]
  45. Stohlman S. A., Matsushima G. K., Casteel N., Weiner L. P. 1986; In vivo effects of coronavirus-specific T cell clones: DTH inducer cells prevent a lethal infection but do not inhibit virus replication. Journal of Immunology 136:3052–3056
    [Google Scholar]
  46. Sturman L. S., Takemoto K. K. 1972; Enhanced growth of a murine coronavirus in transformed mouse cells. Infection and Immunology 6:501–507
    [Google Scholar]
  47. Towbin H., Staehelin T., Gordon J. 1979; Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proceedings of the National Academy of Sciences, USA 76:4350–1354
    [Google Scholar]
  48. Virelizier J.-L., Allison A. C. 1976; Correlation of persistent mouse hepatitis vims (MHV-3) infection with its effect on mouse macrophage culture. Archives of Virology 50:279–285
    [Google Scholar]
  49. Virelizier J.-L., Gresser I. 1978; Role of interferon in the pathogenesis of viral disease of mice as demonstrated by the use of anti-interferon serum: V. Protective role in mouse hepatitis vims type 3 infection of susceptible and resistant strains of mice. Journal of Immunology 120:1616–1619
    [Google Scholar]
  50. Whitaker-Dowling P., Youngner J. S. 1987; Antiviral effects of interferons in different virus-host systems. In Mechanisms of Interferon Actions pp 83–99 Edited by Pfeffer L. M. Boca Raton FL: CRC Press;
    [Google Scholar]
  51. Woodward J. G., Matsushima G., Frelinger J. A., Stohlman S. A. 1984; Production and characterization of T cell clones specific for mouse hepatitis virus strain, JHM: in vivo and in vitro analysis. Journal of Immunology 133:1016–1021
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-76-2-373
Loading
/content/journal/jgv/10.1099/0022-1317-76-2-373
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error