1887

Abstract

Although the association remains controversial, enteroviruses have been implicated in the aetiology of several chronic diseases of humans. To further understand the mechanism of enterovirus persistence and its relationship to organ pathology, virus infectivity and viral RNA kinetics in the heart and other target organs during acute and persistent phases of murine coxsackievirus B3 infection were investigated. These studies revealed a biphasic pattern of virus clearance. Thus, there was a rapid but incomplete clearance of viral RNA from the myocardium following the acute phase of virus replication, which paralleled the elimination of virus infectivity. The mean half-life of viral RNA between days 5 and 14 post-infection (p.i.) was 13·4 h. In contrast, a much slower rate of decline in viral RNA levels was observed during the post-infectious inflammatory phase of myocarditis. The mean half-life of viral RNA between days 14 and 90 p.i. was 14·1 days. Viral RNA persisted in the myocardium beyond the resolution of inflammation and was still detectable in a proportion of animals 90 days after infection. Clearance of viral RNA from other target organs occurred more rapidly, but the rate of clearance was largely independent of the level of viral RNA present during the acute phase of infection. Thus, while antiviral immune responses effectively eliminated infectious virus, clearance of residual viral RNA from the myocardium and other target organs was significantly delayed, despite a prolonged inflammatory response. These findings suggest that clearance of persistent enterovirus infection requires mechanisms different from those responsible for the elimination of virus infectivity.

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2000-11-01
2019-10-14
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References

  1. Anderson, D. R., Wilson, J. E., Carthy, C. M., Yang, D., Kandolf, R. & McManus, B. M. ( 1996; ). Direct interactions of coxsackievirus B3 with immune cells in the splenic compartment of mice susceptible or resistant to myocarditis. Journal of Virology 70, 4632-4645.
    [Google Scholar]
  2. Badorff, C., Lee, G.-H., Lamphear, B. J., Martone, M. E., Campbell, K. P., Rhoads, R. E. & Knowlton, K. U. ( 1999; ). Enteroviral protease 2A cleaves dystrophin: evidence of cytoskeletal disruption in an acquired cardiomyopathy. Nature Medicine 5, 320-326.[CrossRef]
    [Google Scholar]
  3. Cunningham, L., Bowles, N. E., Lane, R. J. M., Dubowitz, V. & Archard, L. C. ( 1990; ). Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA. Journal of General Virology 71, 1399-1402.[CrossRef]
    [Google Scholar]
  4. Destombes, J., Couderc, T., Thiesson, D., Girard, S., Wilt, S. G. & Blondel, B. ( 1997; ). Persistent poliovirus infection in mouse motorneurons. Journal of Virology 71, 1621-1628.
    [Google Scholar]
  5. Godeny, E. K. & Gauntt, C. J. ( 1987; ). Murine natural killer cells limit coxsackievirus B3 replication. Journal of Immunology 139, 913-918.
    [Google Scholar]
  6. Grodums, E. I. & Dempster, G. ( 1959; ). Myocarditis in experimental coxsackie B3 infection. Canadian Journal of Microbiology 5, 605-615.
    [Google Scholar]
  7. Henke, A., Huber, S., Stelzner, A. & Whitton, J. L. ( 1995; ). The role of CD8+ T lymphocytes in coxsackievirus B3-induced myocarditis. Journal of Virology 69, 6720-6728.
    [Google Scholar]
  8. Jubelt, B., Gallez-Hawkins, G., Narayan, O. & Johnson, R. T. ( 1980; ). Pathogenesis of human poliovirus infection in mice. I. Clinical and pathological studies. Journal of Neuropathology & Experimental Neurology 39, 138-148.[CrossRef]
    [Google Scholar]
  9. Kandolf, R. & Hofschneider, P. H. ( 1985; ). Molecular cloning of the genome of a cardiotropic coxsackie B3 virus: full length reverse-transcribed recombinant cDNA generates infectious virus in mammalian cells. Proceedings of the National Academy of Sciences, USA 82, 4818-4822.[CrossRef]
    [Google Scholar]
  10. Klingel, K., Hoenadl, C., Canu, A., Albrecht, M., Seemann, M., Mall, G. & Kandolf, R. ( 1992; ). Ongoing enterovirus-induced myocarditis is associated with persistent heart muscle infection: quantitative analysis of virus replication, tissue damage and inflammation. Proceedings of the National Academy of Sciences, USA 89, 314-318.[CrossRef]
    [Google Scholar]
  11. Klingel, K., Stephan, S., Sauter, M., Zell, R., McManus, B. M., Bultmann, B. & Kandolf, R. ( 1996; ). Pathogenesis of murine enterovirus myocarditis: virus dissemination and immune cell targets. Journal of Virology 70, 8888-8895.
    [Google Scholar]
  12. Kyu, B., Matsumori, A., Sato, Y., Okada, Y., Chapman, N. & Tracy, S. ( 1992; ). Cardiac persistence of cardioviral RNA detected by polymerase chain reaction in a murine model of dilated cardiomyopathy. Circulation 86, 522-530.[CrossRef]
    [Google Scholar]
  13. Li, Y., Bourlet, T., Andreoletti, L., Mosnier, J.-F., Peng, T., Yang, Y., Archard, L. C., Pozzetto, B. & Zhang, H. ( 2000; ). Enteroviral capsid protein VP1 is present in myocardial tissues from some patients with myocarditis or dilated cardiomyopathy. Circulation 101, 231-234.[CrossRef]
    [Google Scholar]
  14. Lipton, H. L. ( 1975; ). Theiler’s virus infection in mice: an unusual biphasic disease process leading to demyelination. Infection and Immunity 11, 1147-1155.
    [Google Scholar]
  15. Lipton, H. L. & Dal Canto, M. C. ( 1976; ). Chronic neurological disease in Theiler’s virus infection of SJL/J mice. Journal of Neurological Sciences 34, 201-207.
    [Google Scholar]
  16. Lowenstein, C. J., Hill, S. L., Lafond-Walker, A., Wu, J., Allen, G., Landavere, M., Rose, N. R. & Herskowitz, A. ( 1996; ). Nitric oxide inhibits viral replication in murine myocarditis. Journal of Clinical Investigation 97, 1837-1843.[CrossRef]
    [Google Scholar]
  17. McKinney, R. E., Katz, S. L. & Wilfert, C. M. ( 1987; ). Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Reviews of Infectious Diseases 9, 334-356.[CrossRef]
    [Google Scholar]
  18. Melchers, W., Zoll, J., van Kuppeveld, F., Swanink, C. & Galama, J. ( 1994; ). There is no evidence for persistent enterovirus infections in chronic medical conditions in humans. Reviews of Medical Virology 4, 235-243.[CrossRef]
    [Google Scholar]
  19. Mena, I., Perry, C. M., Harkin, S., Rodriguez, F., Gebhard, J. & Whitton, J. L. ( 1999; ). The role of B lymphocytes in coxsackievirus B3 infection. American Journal of Pathology 155, 1205-1215.[CrossRef]
    [Google Scholar]
  20. Miller, J. R. ( 1981; ). Prolonged intracerebral infection with poliovirus in asymptomatic mice. Annals of Neurology 9, 590-596.[CrossRef]
    [Google Scholar]
  21. Modlin, J. F. ( 2000; ). Coxsackieviruses, echoviruses, and newer enteroviruses. In Mandell, Douglas & Bennett’s Principles & Practice of Infectious Diseases, pp. 1904-1919. Edited by G. L. Mandell, J. E. R. Bennett & R. Dolin. Philadelphia:Churchill Livingstone.
  22. Muir, P. & Archard, L. C. ( 1994; ). There is evidence for persistent enterovirus infections in chronic medical conditions in humans. Reviews in Medical Virology 4, 245-250.[CrossRef]
    [Google Scholar]
  23. Muir, P., Nicholson, F., Tilzey, A. J., Signy, M., English, T. A. H. & Banatvala, J. E. (1989). Chronic relapsing pericarditis and dilated cardiomyopathy: serological evidence of persistent enterovirus infection. Lancet i, 804–807.
  24. Nicholson, F., Meetoo, G., Aiyar, S., Banatvala, J. E. & Muir, P. ( 1994; ). Detection of enterovirus RNA in clinical samples by nested polymerase chain reaction for rapid diagnosis of enterovirus infection. Journal of Virological Methods 48, 155-166.[CrossRef]
    [Google Scholar]
  25. Reed, L. J. & Muench, H. ( 1938; ). A simple method of estimating fifty per cent endpoints. American Journal of Hygiene 27, 493-497.
    [Google Scholar]
  26. Reetoo, K. N., Osman, S. A., Illavia, S. J., Banatvala, J. E. & Muir, P. ( 1999; ). Development and evaluation of quantitative-competitive PCR for quantitation of coxsackievirus B3 RNA in experimentally infected murine tissues. Journal of Virological Methods 82, 145-156.[CrossRef]
    [Google Scholar]
  27. Ren, R. B., Costantini, F., Gorgacz, E. J., Lee, J. J. & Racaniello, V. R. ( 1991; ). Transgenic mice expressing a human poliovirus receptor: a new model for poliomyelitis. Cell 63, 353-362.
    [Google Scholar]
  28. See, D. M. & Tilles, J. G. ( 1995; ). Pathogenesis of virus-induced diabetes in mice. Journal of Infectious Diseases 171, 1131-1138.[CrossRef]
    [Google Scholar]
  29. Shioi, T., Matsumori, A. & Sasayama, S. ( 1996; ). Persistent expression of cytokine in the chronic stage of viral myocarditis in mice. Circulation 94, 2930-2937.[CrossRef]
    [Google Scholar]
  30. Strongwater, S. L., Dorivini-Zis, K., Ball, R. D. & Schnitzer, T. J. ( 1984; ). A murine model of polymyositis-induced by coxsackievirus B1 (Tucson strain). Arthritis and Rheumatism 27, 422-433.[CrossRef]
    [Google Scholar]
  31. Tam, P. E. & Messner, R. P. ( 1999; ). Molecular mechanisms of coxsackievirus persistence in chronic inflammatory myopathy: viral RNA persists through formation of a double-stranded complex without associated genomic mutations or evolution. Journal of Virology 73, 10113-10121.
    [Google Scholar]
  32. Tam, P. E., Schmidt, A. M., Ytterberg, S. R. & Messner, R. P. ( 1991; ). Viral persistence during the developmental phase of coxsackie B1-induced murine polymyositis. Journal of Virology 65, 6654-6660.
    [Google Scholar]
  33. Tam, P. E., Schmidt, A. M., Ytterberg, S. R. & Messner, R. P. ( 1994; ). Duration of virus persistence and its relationship to inflammation in the chronic phase of coxsackievirus B1-induced murine polymyositis. Journal of Laboratory and Clinical Medicine 123, 346-356.
    [Google Scholar]
  34. Webb, S. R., Loria, R. M., Madge, G. E. & Kibrick, S. ( 1976; ). Susceptibility of mice to group B coxsackievirus is influenced by the diabetic gene. Journal of Experimental Medicine 143, 1239-1248.[CrossRef]
    [Google Scholar]
  35. Woodruff, J. F. & Kilbourne, E. D. ( 1970; ). The influence of quantitated post-weaning undernutrition on coxsackievirus B3 infection of adult mice. I. Viral persistence and increased severity of lesions. Journal of Infectious Diseases 121, 137-163.[CrossRef]
    [Google Scholar]
  36. Yoon, J. W., Onodera, T. & Notkins, A. L. ( 1978; ). Virus-induced diabetes mellitus. XV. Beta cell damage and insulin-dependent hyperglycaemia in mice infected with coxsackie virus B4. Journal of Experimental Medicine 148, 1068-1080.[CrossRef]
    [Google Scholar]
  37. Zhang, H., Yousef, G. E., Ouyang, X. & Archard, L. C. ( 1994; ). Characterization of a murine model of myocarditis induced by a reactivated coxsackievirus B3. International Journal of Experimental Pathology 75, 99-110.
    [Google Scholar]
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