1887

Abstract

Hepatic involvement is commonly observed in arenavirus infections, but the viral determinants of liver disease are only partially understood. Here we exploited newly developed reverse-genetic techniques with (LCMV), the prototype arenavirus, to address specifically the contribution of the viral glycoprotein (GP) to liver pathogenicity. It is well established that strain WE, but not ARM, causes hepatitis in mice. We found that this property correlated with the superior capacity of WE to propagate in cultured macrophages and hepatocyte-derived cells. In mice, the ability to establish prolonged viraemia allowed the virus to propagate from initially infected Kupffer cells in the liver to neighbouring hepatocytes that underwent apoptosis. Reverse-genetic replacement of the GP in strain ARM with WE-GP resulted in only a very modest increase in liver pathogenicity, if any. Yet, an ARM-derived variant virus with a mutated polymerase gene caused severe liver disease when engineered to display WE-GP but considerably less when expressing ARM-GP. This reverse-genetic approach to an animal model of arenaviral hepatitis reveals a previously underestimated contributory role of the GP that alone is, however, insufficient to cause disease.

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2007-02-01
2019-08-22
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References

  1. Ahmed, R., Simon, R. S., Matloubian, M., Kolhekar, S. R., Southern, P. J. & Freedman, D. M. ( 1988; ). Genetic analysis of in vivo-selected viral variants causing chronic infection: importance of mutation in the L RNA segment of lymphocytic choriomeningitis virus. J Virol 62, 3301–3308.
    [Google Scholar]
  2. Ambrosio, M., Vallejos, A., Saavedra, C. & Maiztegui, J. I. ( 1990; ). Junin virus replication in peripheral blood mononuclear cells of patients with Argentine haemorrhagic fever. Acta Virol 34, 58–63.
    [Google Scholar]
  3. Arai, M., Wada, N., Maruyama, K., Nomiyama, T., Tanaka, S. & Okazaki, I. ( 1995; ). Acute hepatitis in an adult with acquired rubella infection. J Gastroenterol 30, 539–542.[CrossRef]
    [Google Scholar]
  4. Armstrong, C. & Lillie, R. D. ( 1934; ). Experimental lymphocytic choriomeningitis of monkeys and mice produced by a virus encountered in studies of the 1933 St. Louis encephalitis epidemic. Public Health Rep 49, 1019–1027.[CrossRef]
    [Google Scholar]
  5. Baize, S., Kaplon, J., Faure, C., Pannetier, D., Georges-Courbot, M. C. & Deubel, V. ( 2004; ). Lassa virus infection of human dendritic cells and macrophages is productive but fails to activate cells. J Immunol 172, 2861–2869.[CrossRef]
    [Google Scholar]
  6. Balkow, S., Kersten, A., Tran, T. T., Stehle, T., Grosse, P., Museteanu, C., Utermohlen, O., Pircher, H., von Weizsacker, F. & other authors ( 2001; ). Concerted action of the FasL/Fas and perforin/granzyme A and B pathways is mandatory for the development of early viral hepatitis but not for recovery from viral infection. J Virol 75, 8781–8791.[CrossRef]
    [Google Scholar]
  7. Battegay, M., Cooper, S., Althage, A., Banziger, J., Hengartner, H. & Zinkernagel, R. M. ( 1991; ). Quantification of lymphocytic choriomeningitis virus with an immunological focus assay in 24- or 96-well plates. J Virol Methods 33, 191–198.[CrossRef]
    [Google Scholar]
  8. Battegay, M., Moskophidis, D., Waldner, H., Brundler, M. A., Fung-Leung, W. P., Mak, T. W., Hengartner, H. & Zinkernagel, R. M. ( 1993; ). Impairment and delay of neutralizing antiviral antibody responses by virus-specific cytotoxic T cells. J Immunol 151, 5408–5415.
    [Google Scholar]
  9. Bergthaler, A., Gerber, N. U., Merkler, D., Horvath, E., de la Torre, J. C. & Pinschewer, D. D. ( 2006; ). Envelope exchange for the generation of live-attenuated arenavirus vaccines. PLoS Pathog 2, e51.[CrossRef]
    [Google Scholar]
  10. Beyer, W. R., Miletic, H., Ostertag, W. & von Laer, D. ( 2001; ). Recombinant expression of lymphocytic choriomeningitis virus strain WE glycoproteins: a single amino acid makes the difference. J Virol 75, 1061–1064.[CrossRef]
    [Google Scholar]
  11. Buchmeier, M. J., Bowen, M. D. & Peters, C. J. ( 2001; ). Arenaviridae: the viruses and their replication. In Fields Virology, 4th edn, vol. 2, pp. 1635–1668. Edited by D. M. Knipe & P. M. Howley. Philadelphia, PA: Lippincott Williams & Wilkins.
  12. Centers for Disease Control and Prevention ( 2000; ). Fatal illnesses associated with a New World arenavirus – California, 1999–2000. MMWR Morb Mortal Wkly Rep 49, 709–711.
    [Google Scholar]
  13. Djavani, M., Topisirovic, I., Zapata, J. C., Sadowska, M., Yang, Y., Rodas, J., Lukashevich, I. S., Bogue, C. W., Pauza, C. D. & other authors ( 2005; ). The proline-rich homeodomain (PRH/HEX) protein is down-regulated in liver during infection with lymphocytic choriomeningitis virus. J Virol 79, 2461–2473.[CrossRef]
    [Google Scholar]
  14. Fischer, S. A., Graham, M. B., Kuehnert, M. J., Kotton, C. N., Srinivasan, A., Marty, F. M., Comer, J. A., Guarner, J., Paddock, C. D. & other authors ( 2006; ). Transmission of lymphocytic choriomeningitis virus by organ transplantation. N Engl J Med 354, 2235–2249.[CrossRef]
    [Google Scholar]
  15. Flatz, L., Bergthaler, A., de la Torre, J. C. & Pinschewer, D. D. ( 2006; ). Recovery of an arenavirus entirely from RNA polymerase I/II-driven cDNA. Proc Natl Acad Sci U S A 103, 4663–4668.[CrossRef]
    [Google Scholar]
  16. Geisbert, T. W. & Jahrling, P. B. ( 2004; ). Exotic emerging viral diseases: progress and challenges. Nat Med 10 (Suppl. 12), S110–S121.[CrossRef]
    [Google Scholar]
  17. Gossmann, J., Lohler, J. & Lehmann-Grube, F. ( 1991; ). Entry of antivirally active T lymphocytes into the thymus of virus-infected mice. J Immunol 146, 293–297.
    [Google Scholar]
  18. Grande-Perez, A., Gomez-Mariano, G., Lowenstein, P. R. & Domingo, E. ( 2005; ). Mutagenesis-induced, large fitness variations with an invariant arenavirus consensus genomic nucleotide sequence. J Virol 79, 10451–10459.[CrossRef]
    [Google Scholar]
  19. Grob, P., Schijns, V. E., van den Broek, M. F., Cox, S. P., Ackermann, M. & Suter, M. ( 1999; ). Role of the individual interferon systems and specific immunity in mice in controlling systemic dissemination of attenuated pseudorabies virus infection. J Virol 73, 4748–4754.
    [Google Scholar]
  20. Guidotti, L. G., Borrow, P., Brown, A., McClary, H., Koch, R. & Chisari, F. V. ( 1999; ). Noncytopathic clearance of lymphocytic choriomeningitis virus from the hepatocyte. J Exp Med 189, 1555–1564.[CrossRef]
    [Google Scholar]
  21. Gunther, S. & Lenz, O. ( 2004; ). Lassa virus. Crit Rev Clin Lab Sci 41, 339–390.[CrossRef]
    [Google Scholar]
  22. Ho, J. K., Tha, S. P., Coupland, R., Dalal, B. I., Bowie, W. R., Sreenivasan, G. M., Krajden, M. & Yoshida, E. M. ( 2005; ). Parvovirus B19 in an immunocompetent adult patient with acute liver failure: an underdiagnosed cause of acute non-A-E viral hepatitis. Can J Gastroenterol 19, 161–162.
    [Google Scholar]
  23. Hotchin, J. ( 1962; ). The biology of lymphocytic choriomeningitis infection: virus-induced immune disease. Cold Spring Harb Symp Quant Biol 27, 479–499.[CrossRef]
    [Google Scholar]
  24. Ishak, K. G., Walker, D. H., Coetzer, J. A., Gardner, J. J. & Gorelkin, L. ( 1982; ). Viral hemorrhagic fevers with hepatic involvement: pathologic aspects with clinical correlations. Prog Liver Dis 7, 495–515.
    [Google Scholar]
  25. Johnson, K. M., McCormick, J. B., Webb, P. A., Smith, E. S., Elliott, L. H. & King, I. J. ( 1987; ). Clinical virology of Lassa fever in hospitalized patients. J Infect Dis 155, 456–464.[CrossRef]
    [Google Scholar]
  26. Kanda, T., Kobayashi, I., Suzuki, T., Murata, K., Radio, S. J. & McManus, B. M. ( 1995; ). Elevation of ALT to AST ratio in patients with enteroviral myocarditis. J Med 26, 153–162.
    [Google Scholar]
  27. Kirk, W. E., Cash, P., Peters, C. J. & Bishop, D. H. L. ( 1980; ). Formation and characterization of an intertypic lymphocytic choriomeningitis recombinant virus. J Gen Virol 51, 213–218.[CrossRef]
    [Google Scholar]
  28. Leist, T., Althage, A., Haenseler, E., Hengartner, H. & Zinkernagel, R. M. ( 1989; ). Major histocompatibility complex-linked susceptibility or resistance to disease caused by a noncytopathic virus varies with the disease parameter evaluated. J Exp Med 170, 269–277.[CrossRef]
    [Google Scholar]
  29. Lukashevich, I. S., Djavani, M., Rodas, J. D., Zapata, J. C., Usborne, A., Emerson, C., Mitchen, J., Jahrling, P. B. & Salvato, M. S. ( 2002; ). Hemorrhagic fever occurs after intravenous, but not after intragastric, inoculation of rhesus macaques with lymphocytic choriomeningitis virus. J Med Virol 67, 171–186.[CrossRef]
    [Google Scholar]
  30. Lukashevich, I. S., Rodas, J. D., Tikhonov, I. I., Zapata, J. C., Yang, Y., Djavani, M. & Salvato, M. S. ( 2004; ). LCMV-mediated hepatitis in rhesus macaques: WE but not ARM strain activates hepatocytes and induces liver regeneration. Arch Virol 149, 2319–2336.[CrossRef]
    [Google Scholar]
  31. Maini, M. K., Boni, C., Lee, C. K., Larrubia, J. R., Reignat, S., Ogg, G. S., King, A. S., Herberg, J., Gilson, R. & other authors ( 2000; ). The role of virus-specific CD8+ cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med 191, 1269–1280.[CrossRef]
    [Google Scholar]
  32. Matloubian, M., Kolhekar, S. R., Somasundaram, T. & Ahmed, R. ( 1993; ). Molecular determinants of macrophage tropism and viral persistence: importance of single amino acid changes in the polymerase and glycoprotein of lymphocytic choriomeningitis virus. J Virol 67, 7340–7349.
    [Google Scholar]
  33. Merkler, D., Horvath, E., Bruck, W., Zinkernagel, R. M., de la Torre, J. C. & Pinschewer, D. D. ( 2006; ). ‘Viral deja vu’ elicits organ-specific immune disease independent of reactivity to self. J Clin Invest 116, 1254–1263.[CrossRef]
    [Google Scholar]
  34. Montali, R. J., Connolly, B. M., Armstrong, D. L., Scanga, C. A. & Holmes, K. V. ( 1995; ). Pathology and immunohistochemistry of callitrichid hepatitis, an emerging disease of captive New World primates caused by lymphocytic choriomeningitis virus. Am J Pathol 147, 1441–1449.
    [Google Scholar]
  35. Monto, A. S., Ceglarek, J. P. & Hayner, N. S. ( 1981; ). Liver function abnormalities in the course of a type A (H1N1) influenza outbreak: relation to Reye's syndrome. Am J Epidemiol 114, 750–759.
    [Google Scholar]
  36. Muraoka, H., Tokeshi, S., Abe, H., Miyahara, Y., Uchimura, Y., Noguchi, S., Sata, M. & Tanikawa, K. ( 1998; ). Two cases of adult varicella accompanied by hepatic dysfunction. Kansenshogaku Zasshi 72, 418–423.[CrossRef]
    [Google Scholar]
  37. Olert, J., Wiedorn, K. H., Goldmann, T., Kuhl, H., Mehraein, Y., Scherthan, H., Niketeghad, F., Vollmer, E., Muller, A. M. & Muller-Navia, J. ( 2001; ). HOPE fixation: a novel fixing method and paraffin-embedding technique for human soft tissues. Pathol Res Pract 197, 823–826.[CrossRef]
    [Google Scholar]
  38. Perez, M. & de la Torre, J. C. ( 2003; ). Characterization of the genomic promoter of the prototypic arenavirus lymphocytic choriomeningitis virus. J Virol 77, 1184–1194.[CrossRef]
    [Google Scholar]
  39. Perez, M., Craven, R. C. & de la Torre, J. C. ( 2003; ). The small RING finger protein Z drives arenavirus budding: implications for antiviral strategies. Proc Natl Acad Sci U S A 100, 12978–12983.[CrossRef]
    [Google Scholar]
  40. Peters, C. J., Jahrling, P. B., Liu, C. T., Kenyon, R. H., McKee, K. T., Jr & Barrera Oro, J. G. ( 1987; ). Experimental studies of arenaviral hemorrhagic fevers. Curr Top Microbiol Immunol 134, 5–68.
    [Google Scholar]
  41. Pinschewer, D. D., Perez, M. & de la Torre, J. C. ( 2003a; ). Role of the virus nucleoprotein in the regulation of lymphocytic choriomeningitis virus transcription and RNA replication. J Virol 77, 3882–3887.[CrossRef]
    [Google Scholar]
  42. Pinschewer, D. D., Perez, M., Sanchez, A. B. & de la Torre, J. C. ( 2003b; ). Recombinant lymphocytic choriomeningitis virus expressing vesicular stomatitis virus glycoprotein. Proc Natl Acad Sci U S A 100, 7895–7900.[CrossRef]
    [Google Scholar]
  43. Pinschewer, D. D., Perez, M., Jeetendra, E., Bächi, T., Horvath, E., Hengartner, H., Whitt, M. A., de la Torre, J. C. & Zinkernagel, R. M. ( 2004; ). Kinetics of protective antibodies are determined by the viral surface antigen. J Clin Invest 114, 988–993.[CrossRef]
    [Google Scholar]
  44. Pinschewer, D. D., Perez, M. & de la Torre, J. C. ( 2005; ). Dual role of the lymphocytic choriomeningitis virus intergenic region in transcription termination and virus propagation. J Virol 79, 4519–4526.[CrossRef]
    [Google Scholar]
  45. Probst, H. C., Tschannen, K., Gallimore, A., Martinic, M., Basler, M., Dumrese, T., Jones, E. & van den Broek, M. F. ( 2003; ). Immunodominance of an antiviral cytotoxic T cell response is shaped by the kinetics of viral protein expression. J Immunol 171, 5415–5422.[CrossRef]
    [Google Scholar]
  46. Rivers, T. M. & Scott, T. F. M. ( 1935; ). Meningitis in man caused by a filterable virus. Science 81, 439–440.
    [Google Scholar]
  47. Riviere, Y., Ahmed, R., Southern, P. J., Buchmeier, M. J. & Oldstone, M. B. ( 1985; ). Genetic mapping of lymphocytic choriomeningitis virus pathogenicity: virulence in guinea pigs is associated with the L RNA segment. J Virol 55, 704–709.
    [Google Scholar]
  48. Romanowski, V. & Bishop, D. H. ( 1983; ). The formation of arenaviruses that are genetically diploid. Virology 126, 87–95.[CrossRef]
    [Google Scholar]
  49. Seiler, P., Brundler, M. A., Zimmermann, C., Weibel, D., Bruns, M., Hengartner, H. & Zinkernagel, R. M. ( 1998; ). Induction of protective cytotoxic T cell responses in the presence of high titers of virus-neutralizing antibodies: implications for passive and active immunization. J Exp Med 187, 649–654.[CrossRef]
    [Google Scholar]
  50. Sevilla, N., Kunz, S., Holz, A., Lewicki, H., Homann, D., Yamada, H., Campbell, K. P., de la Torre, J. C. & Oldstone, M. B. ( 2000; ). Immunosuppression and resultant viral persistence by specific viral targeting of dendritic cells. J Exp Med 192, 1249–1260.[CrossRef]
    [Google Scholar]
  51. Sevilla, N., McGavern, D. B., Teng, C., Kunz, S. & Oldstone, M. B. ( 2004; ). Viral targeting of hematopoietic progenitors and inhibition of DC maturation as a dual strategy for immune subversion. J Clin Invest 113, 737–745.[CrossRef]
    [Google Scholar]
  52. Teng, M. N., Borrow, P., Oldstone, M. B. & de la Torre, J. C. ( 1996; ). A single amino acid change in the glycoprotein of lymphocytic choriomeningitis virus is associated with the ability to cause growth hormone deficiency syndrome. J Virol 70, 8438–8443.
    [Google Scholar]
  53. Zinkernagel, R. M., Haenseler, E., Leist, T., Cerny, A., Hengartner, H. & Althage, A. ( 1986; ). T cell-mediated hepatitis in mice infected with lymphocytic choriomeningitis virus. Liver cell destruction by H-2 class I-restricted virus-specific cytotoxic T cells as a physiological correlate of the 51Cr-release assay? J Exp Med 164, 1075–1092.[CrossRef]
    [Google Scholar]
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