1887

Abstract

Murine gammaherpesvirus-68 (γHV-68) induces a lymphocytosis in mice and establishes a latent infection of B lymphocytes following intranasal administration in anaesthetized animals. Because γHV-68 is a gammaherpesvirus, it has been used as a model to understand the pathogenesis of Epstein–Barr virus (EBV) and human herpesvirus-8 (HHV-8) infections. In this study, we investigated the unlikely possibility that γHV-68 could survive the harsh gastrointestinal environment to efficiently infect intestinal epithelial cells, and then disseminate from mucosal sites to cause systemic disease. Surprisingly, oral administration, or gastric instillation which by-passed the oral cavity, readily caused a systemic lymphocytosis and established a latent infection in splenic leukocytes. The finding that γHV-68 could readily infect adult mice following gastric instillation strongly suggested that intestinal epithelial cells could be productively infected. Unlike the more routinely used method of intranasal inoculation, γHV-68 given intragastrically resulted in lytic virus, viral RNA and viral DNA being present in isolated intestinal epithelial cells. Furthermore, γHV-68 RNA and DNA, but not latent virus, could be detected in epithelial cells as long as 30 days post-infection, suggesting that some of these cells might be persistently infected. Taken together, these studies demonstrate that γHV-68 can survive passage through the gastrointestinal tract and infect intestinal epithelial cells. Following infection of gut epithelial cells, γHV-68 can disseminate from mucosal sites to induce a systemic lymphocytosis which is similar to the disease induced following intranasal inoculation.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-81-2-421
2000-02-01
2024-12-07
Loading full text...

Full text loading...

/deliver/fulltext/jgv/81/2/0810421a.html?itemId=/content/journal/jgv/10.1099/0022-1317-81-2-421&mimeType=html&fmt=ahah

References

  1. Benya, R. V., Schmidt, L. N., Sahi, J., Layden, T. J. & Rao, M. C. (1991). Isolation, characterization, and attachment of rabbit distal colon epithelial cells. Gastroenterology 101, 692-702. [Google Scholar]
  2. Blaskovic, D., Stanekova, D. & Rajcani, J. (1984). Experimental pathogenesis of murine herpesvirus in newborn mice. Acta Virologica 28, 225-231. [Google Scholar]
  3. Bost, K. L. & Clements, J. D. (1995). In vivo induction of interleukin-12 mRNA expression after oral immunization with Salmonella dublin or the B subunit of Escherichia coli heat-labile enterotoxin. Infection and Immunity 63, 1076-1083. [Google Scholar]
  4. Bost, K. L. & Mason, M. J. (1995). Thapsigargin and cyclopiazonic acid initiate rapid and dramatic increases of IL-6 mRNA expression and IL-6 secretion in murine peritoneal macrophages.Journal of Immunology 155, 285-296. [Google Scholar]
  5. Bost, K. L., Bieligk, S. C. & Jaffe, B. M. (1995). Lymphokine mRNA expression by transplantable murine B lymphocytic malignancies. Tumor-derived IL-10 as a possible mechanism for modulating the anti-tumor response. Journal of Immunology 154, 718-729. [Google Scholar]
  6. Cardin, R. D., Brooks, J. W., Sarawar, S. R. & Doherty, P. C. (1996). Progressive loss of CD8+ T cell-mediated control of a gamma-herpesvirus in the absence of CD4+ T cells. Journal of Experimental Medicine 184, 863-871.[CrossRef] [Google Scholar]
  7. Chandler, J. S., Calnek, D. & Quaroni, A. (1991). Identification and characterization of rat intestinal keratins. Molecular cloning of cDNAs encoding cytokeratins 8, 19, and a new 49-kDa type I cytokeratin (cytokeratin 21) expressed by differentiated intestinal epithelial cells. Journal of Biological Chemistry 266, 11932-11938. [Google Scholar]
  8. Del Sal, G., Manfioletti, G. & Schneider, C. (1988). A one-tube plasmid DNA mini-preparation suitable for sequencing. Nucleic Acids Research 16, 9878.[CrossRef] [Google Scholar]
  9. Doherty, P. C., Tripp, R. A., Hamilton-Easton, A. M., Cardin, R. D., Woodland, D. L. & Blackman, M. A. (1997). Tuning into immunological dissonance: an experimental model for infectious mononucleosis [see comments]. Current Opinion in Immunology 9, 477-483.[CrossRef] [Google Scholar]
  10. Efstathiou, S., Ho, Y. M., Hall, S., Styles, C. J., Scott, S. D. & Gompels, U. A. (1990a). Murine herpesvirus 68 is genetically related to the gammaherpesviruses Epstein–Barr virus and herpesvirus saimiri. Journal of General Virology 71, 1365-1372.[CrossRef] [Google Scholar]
  11. Efstathiou, S., Ho, Y. M. & Minson, A. C. (1990b). Cloning and molecular characterization of the murine herpesvirus 68 genome. Journal of General Virology 71, 1355-1364.[CrossRef] [Google Scholar]
  12. Glaser, R., de The, G., Lenoir, G. & Ho, J. H. (1976). Superinfection epithelial nasopharyngeal carcinoma cells with Epstein–Barr virus. Proceedings of the National Academy of Sciences, USA 73, 960-963.[CrossRef] [Google Scholar]
  13. Grotsky, H. W., Hirshaut, Y., Sorokin, C., Sachar, D., Janowitz, H. D. & Glade, P. R. (1971). Epstein–Barr virus and inflammatory bowel disease. Experientia 27, 1474-1475.[CrossRef] [Google Scholar]
  14. Gu, H., Kitamura, D. & Rajewsky, K. (1991). B cell development regulated by gene rearrangement: arrest of maturation by membrane-bound D mu protein and selection of DH element reading frames. Cell 65, 47-54.[CrossRef] [Google Scholar]
  15. Gulley, M. L., Pulitzer, D. R., Eagan, P. A. & Schneider, B. G. (1996). Epstein–Barr virus infection is an early event in gastric carcinogenesis and is independent of bcl-2 expression and p53 accumulation. Human Pathology 27, 20-27.[CrossRef] [Google Scholar]
  16. Imai, S., Koizumi, S., Sugiura, M., Tokunaga, M., Uemura, Y., Yamamoto, N., Tanaka, S., Sato, E. & Osato, T. (1994). Gastric carcinoma: monoclonal epithelial malignant cells expressing Epstein–Barr virus latent infection protein. Proceedings of the National Academy of Sciences, USA 91, 9131-9135.[CrossRef] [Google Scholar]
  17. Imai, S., Nishikawa, J. & Takada, K. (1998). Cell-to-cell contact as an efficient mode of Epstein–Barr virus infection of diverse human epithelial cells. Journal of Virology 72, 4371-4378. [Google Scholar]
  18. Kaschka-Dierich, C., Adams, A., Lindahl, T., Bornkamm, G. W., Bjursell, G., Klein, G., Giovanella, B. C. & Singh, S. (1976). Intracellular forms of Epstein–Barr virus DNA in human tumour cells in vivo. Nature 260, 302-306.[CrossRef] [Google Scholar]
  19. Klein, G., Giovanella, B. C., Lindahl, T., Fialkow, P. J., Singh, S. & Stehlin, J. S. (1974). Direct evidence for the presence of Epstein–Barr virus DNA and nuclear antigen in malignant epithelial cells from patients with poorly differentiated carcinoma of the nasopharynx. Proceedings of the National Academy of Sciences, USA 71, 4737-4741.[CrossRef] [Google Scholar]
  20. Lemon, S. M., Hutt, L. M., Shaw, J. E., Li, J. L. & Pagano, J. S. (1977). Replication of EBV in epithelial cells during infectious mononucleosis. Nature 268, 268-270.[CrossRef] [Google Scholar]
  21. Nash, A. A. & Sunil-Chandra, N. P. (1994). Interactions of the murine gammaherpesvirus with the immune system. Current Opinion in Immunology 6, 560-563.[CrossRef] [Google Scholar]
  22. Nonoyama, M. & Pagano, J. S. (1973). Homology between Epstein–Barr virus DNA and viral DNA from Burkitt’s lymphoma and nasopharyngeal carcinoma determined by DNA–DNA reassociation kinetics. Nature 242, 44-47.[CrossRef] [Google Scholar]
  23. Nonoyama, M., Huang, C. H., Pagano, J. S., Klein, G. & Singh, S. (1973). DNA of Epstein–Barr virus detected in tissue of Burkitt’s lymphoma and nasopharyngeal carcinoma. Proceedings of the National Academy of Sciences, USA 70, 3265-3268.[CrossRef] [Google Scholar]
  24. Pascual, D. W., McGhee, J. R., Kiyono, H. & Bost, K. L. (1991). Neuroimmune modulation of lymphocyte function. I. Substance P enhances immunoglobulin synthesis in lipopolysaccharide activated murine splenic B cell cultures. International Immunology 3, 1223-1229.[CrossRef] [Google Scholar]
  25. Rajcani, J., Blaskovic, D., Svobodova, J., Ciampor, F., Huckova, D. & Stanekova, D. (1985). Pathogenesis of acute and persistent murine herpesvirus infection in mice. Acta Virologica 29, 51-60. [Google Scholar]
  26. Ruther, U., Nunnensiek, C., Muller, H. A., Bader, H., May, U. & Jipp, P. (1998). Interferon alpha (IFN alpha 2a) therapy for herpes virus-associated inflammatory bowel disease (ulcerative colitis and Crohn’s disease). Hepatogastroenterology 45, 691-699. [Google Scholar]
  27. Sarawar, S. R., Cardin, R. D., Brooks, J. W., Mehrpooya, M., Tripp, R. A. & Doherty, P. C. (1996). Cytokine production in the immune response to murine gammaherpesvirus 68. Journal of Virology 70, 3264-3268. [Google Scholar]
  28. Sarawar, S. R., Cardin, R. D., Brooks, J. W., Mehrpooya, M., Hamilton-Easton, A. M., Mo, X. Y. & Doherty, P. C. (1997). Gamma interferon is not essential for recovery from acute infection with murine gammaherpesvirus 68. Journal of Virology 71, 3916-3921. [Google Scholar]
  29. Selves, J., Bibeau, F., Brousset, P., Meggetto, F., Mazerolles, C., Voigt, J. J., Pradere, B., Chiotasso, P. & Delsol, G. (1996). Epstein–Barr virus latent and replicative gene expression in gastric carcinoma. Histopathology 28, 121-127.[CrossRef] [Google Scholar]
  30. Shapiro, I. M. & Volsky, D. J. (1983). Infection of normal human epithelial cells by Epstein–Barr virus. Science 219, 1225-1228.[CrossRef] [Google Scholar]
  31. Shinohara, K., Miyazaki, K., Noda, N., Saitoh, D., Terada, M. & Wakasugi, H. (1998). Gastric diseases related to Helicobacter pylori and Epstein–Barr virus infection.Microbiology and Immunology 42, 415-421.[CrossRef] [Google Scholar]
  32. Simas, J. P. & Efstathiou, S. (1998). Murine gammaherpesvirus 68: a model for the study of gammaherpesvirus pathogenesis. Trends in Microbiology 6, 276-282.[CrossRef] [Google Scholar]
  33. Sixbey, J. W., Nedrud, J. G., Raab-Traub, N., Hanes, R. A. & Pagano, J. S. (1984). Epstein–Barr virus replication in oropharyngeal epithelial cells. New England Journal of Medicine 310, 1225-1230.[CrossRef] [Google Scholar]
  34. Speck, S. H. & Virgin, H. W. (1999). Host and viral genetics of chronic infection: a mouse model of gamma-herpesvirus pathogenesis. Current Opinion in Microbiology 2, 403-409.[CrossRef] [Google Scholar]
  35. Stevenson, P. G., Cardin, R. D., Christensen, J. P. & Doherty, P. C. (1999). Immunological control of a murine gammaherpesvirus independent of CD8+ T cells. Journal of General Virology 80, 477-483. [Google Scholar]
  36. Stewart, J. P., Janjua, N. J., Pepper, S. D., Bennion, G., Mackett, M., Allen, T., Nash, A. A. & Arrand, J. R. (1996). Identification and characterization of murine gammaherpesvirus 68 gp150: a virion membrane glycoprotein. Journal of Virology 70, 3528-3535. [Google Scholar]
  37. Stewart, J. P., Usherwood, E. J., Ross, A., Dyson, H. & Nash, T. (1998). Lung epithelial cells are a major site of murine gammaherpesvirus persistence. Journal of Experimental Medicine 187, 1941-1951.[CrossRef] [Google Scholar]
  38. Sunil-Chandra, N. P., Efstathiou, S., Arno, J. & Nash, A. A. (1992a). Virological and pathological features of mice infected with murine gammaherpesvirus 68. Journal of General Virology 73, 2347-2356.[CrossRef] [Google Scholar]
  39. Sunil-Chandra, N. P., Efstathiou, S. & Nash, A. A. (1992b). Murine gammaherpesvirus 68 establishes a latent infection in mouse B lymphocytes in vivo. Journal of General Virology 73, 3275-3279.[CrossRef] [Google Scholar]
  40. Sunil-Chandra, N. P., Arno, J., Fazakerley, J. & Nash, A. A. (1994). Lymphoproliferative disease in mice infected with murine gammaherpesvirus 68. American Journal of Pathology 145, 818-826. [Google Scholar]
  41. Tajima, M., Komuro, M. & Okinaga, K. (1998). Establishment of Epstein–Barr virus-positive human gastric epithelial cell lines. Japanese Journal of Cancer Research 89, 262-268.[CrossRef] [Google Scholar]
  42. Takasaka, N., Tajima, M., Okinaga, K., Satoh, Y., Hoshikawa, Y., Katsumoto, T., Kurata, T. & Sairenji, T. (1998). Productive infection of Epstein–Barr virus (EBV) in EBV-genome-positive epithelial cell lines (GT38 and GT39) derived from gastric tissues. Virology 247, 152-159.[CrossRef] [Google Scholar]
  43. Tokunaga, M., Land, C. E., Uemura, Y., Tokudome, T., Tanaka, S. & Sato, E. (1993). Epstein–Barr virus in gastric carcinoma. American Journal of Pathology 143, 1250-1254. [Google Scholar]
  44. Tripp, R. A., Hamilton-Easton, A. M., Cardin, R. D., Nguyen, P., Behm, F. G., Woodland, D. L., Doherty, P. C. & Blackman, M. A. (1997). Pathogenesis of an infectious mononucleosis-like disease induced by a murine gamma-herpesvirus: role for a viral superantigen? Journal of Experimental Medicine 185, 1641-1650.[CrossRef] [Google Scholar]
  45. Usherwood, E. J., Ross, A. J., Allen, D. J. & Nash, A. A. (1996a). Murine gammaherpesvirus-induced splenomegaly: a critical role for CD4 T cells. Journal of General Virology 77, 627-630.[CrossRef] [Google Scholar]
  46. Usherwood, E. J., Stewart, J. P., Robertson, K., Allen, D. J. & Nash, A. A. (1996b). Absence of splenic latency in murine gammaherpesvirus 68-infected B cell-deficient mice. Journal of General Virology 77, 2819-2825.[CrossRef] [Google Scholar]
  47. Virgin, H. W. & Speck, S. H. (1999). Unraveling immunity to gamma-herpesviruses: a new model for understanding the role of immunity in chronic virus infection. Current Opinion in Immunology 11, 371-379.[CrossRef] [Google Scholar]
  48. Virgin, H. W. T., Presti, R. M., Li, X. Y., Liu, C. & Speck, S. H. (1999). Three distinct regions of the murine gammaherpesvirus 68 genome are transcriptionally active in latently infected mice. Journal of Virology 73, 2321-2332. [Google Scholar]
  49. Wakefield, A. J., Fox, J. D., Sawyerr, A. M., Taylor, J. E., Sweenie, C. H., Smith, M., Emery, V. C., Hudson, M., Tedder, R. S. & Pounder, R. E. (1992). Detection of herpesvirus DNA in the large intestine of patients with ulcerative colitis and Crohn’s disease using the nested polymerase chain reaction. Journal of Medical Virology 38, 183-190.[CrossRef] [Google Scholar]
  50. Weck, K. E., Kim, S. S., Virgin, H. I. & Speck, S. H. (1999). Macrophages are the major reservoir of latent murine gammaherpesvirus 68 in peritoneal cells. Journal of Virology 73, 3273-3283. [Google Scholar]
  51. Wolf, H., zur Hausen, H. & Becker, V. (1973). EB viral genomes in epithelial nasopharyngeal carcinoma cells. Nature New Biology 244, 245-247. [Google Scholar]
  52. Yamamoto, M., Fujihashi, K., Beagley, K. W., McGhee, J. R. & Kiyono, H. (1993). Cytokine synthesis by intestinal intraepithelial lymphocytes. Both gamma/delta T cell receptor-positive and alpha/beta T cell receptor-positive T cells in the G1 phase of cell cycle produce IFN-gamma and IL-5. Journal of Immunology 150, 106-114. [Google Scholar]
  53. Yanai, H., Takada, K., Shimizu, N., Mizugaki, Y., Tada, M. & Okita, K. (1997). Epstein–Barr virus infection in non-carcinomatous gastric epithelium. Journal of Pathology 183, 293-298.[CrossRef] [Google Scholar]
  54. Young, L., Alfieri, C., Hennessy, K., Evans, H., O’Hara, C., Anderson, K. C., Ritz, J., Shapiro, R. S., Rickinson, A., Kieff, E. and others (1989). Expression of Epstein–Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease. New England Journal of Medicine 321, 1080–1085.[CrossRef] [Google Scholar]
/content/journal/jgv/10.1099/0022-1317-81-2-421
Loading
/content/journal/jgv/10.1099/0022-1317-81-2-421
Loading

Data & Media loading...

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