Abstract
Objective To investigate a disease outbreak in a colony of laboratory mice with targeted disruption of the gene for interferon‐γ
Format
A case report based on necropsy, histopathology, serology and immunohistochemistry.
Results
Affected mice exhibited depression and variable ascites. Necropsy revealed a granulomatous peritonitis and pleuritis with extensive adhesions although parenchymal lesions were minimal. Serum samples had high concentrations of antibody to mouse hepatitis virus and immunohistochemical examination revealed the presence of mouse hepatitis virus antigen in granuloma macrophages. Serological testing for other infectious agents and bacterial culture were negative and wild type mice kept in the same facility remained healthy. Despite the association between the disease and mouse hepatitis virus infection, the precise role played by mouse hepatitis virus was not determined. While the disease is superficially similar to feline infectious peritonitis (another coronavirus‐induced serositis), differences exist between the histopathological findings in these two conditions.
Conclusion
This unusual disease process illustrates how new diagnostic challenges can arise in novel mouse genotypes created through molecular genetics. Furthermore, the association between the disease and mouse hepatitis virus illustrates the importance of maintaining laboratory animals under specific‐pathogen free conditions.
Keywords: Mouse, mouse hepatitis virus, interferon‐γ, granuloma, gene knockout, peritonitis, pleuritis, macrophage.
- ELISA
Enzyme‐linked immunosorbent assay
- IFN‐γ
Interferon‐γ
- MHV
Mouse hepatitis virus
- FIP
Feline infectious peritonitis
- SPF
Specific‐pathogen free
References
- 1. Compton SR, Barthold SW, Smith AL. The cellular and molecular pathogenesis of coronaviruses. Lab Anim Sci 1993;43:15–28. [PubMed] [Google Scholar]
- 2. Homberger FR. Enterotropic mouse hepatitis virus. Lab Animals 1996;31:97–115. [DOI] [PubMed] [Google Scholar]
- 3. Jacoby RO, Lindsey JR. Health care for research animals is essential and affordable. FASEB J 1997;11:609–614. [DOI] [PubMed] [Google Scholar]
- 4. Kraft V, Meyer B. Seromonitoring in small laboratory animal colonies. A five year survey:1984ndash;1988. Z Versuchstierkd 1990;33:29–35. [PubMed] [Google Scholar]
- 5. Stevenson R. Annual health report ‐ serology of Australian rodent colonies. Australian and New Zealand Society for Laboratory Animal Science Annual Conference Proceedings, Perth, 1996:71.
- 6. National Research Council. Mouse hepatitis virus In: Infectious diseases of mice and rats. National Academy Press, Washington DC , 1991. [Google Scholar]
- 7. de Souza MS, Smith AL, Bottomly K. Infection of BALB/cByJ mice with the JHM strain of mouse hepatitis virus alters in vitro splenic T cell proliferation and cytokine production. Lab Anim Sci 1991;41:99–105. [PubMed] [Google Scholar]
- 8. Boorman GA, Luster MI, Campbell ML et al. Peritoneal macrophage alterations caused by naturally occurring mouse hepatitis virus. Am J Pathol 1982;106:110–117. [PMC free article] [PubMed] [Google Scholar]
- 9. Cray C, Mateo MO, Altman NH. In vitro and long‐term in vivo immune dysfunction after infection of BALB/c mice with mouse hepatitis virus strain A59. Lab Anim Sci 1993;43:169–174. [PubMed] [Google Scholar]
- 10. Liang S, Lian W, Leu F et al. Epizootic of low‐virulence hepatotropic murine hepatitis virus in a nude mice breeding colony in Taiwan. Lab Anim Sci 1995;45:519–522. [PubMed] [Google Scholar]
- 11. Durbin JE, Hackenmiller R, Simon MC, Levy DE. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 1996;84:443–450. [DOI] [PubMed] [Google Scholar]
- 12. Matthaei KI, Berry JR, France MP et al. Use of polymerase chain reaction to diagnose a natural outbreak of mouse hepatitis virus infection in nude mice. Lab Anim Sci 1998;48:137–144. [PubMed] [Google Scholar]
- 13. Flanagan SP. ‘Nude’, a new hairless gene with pleiotropic effects in the mouse. Genet Res Camb 1966;8:295–309. [DOI] [PubMed] [Google Scholar]
- 14. Durum SK, Muegge K. Preface In: Durum SK, Muegge K, editors. Cytokine knockouts. Humana Press, Totowa , New Jersey , 1998:vii–xvi. [Google Scholar]
- 15. Dalton DK, Pitts‐Meek S, Keshav S et al. Multiple defects of immune cell function in mice with disrupted interferon‐γ genes. Science 1993;259:1739–1742. [DOI] [PubMed] [Google Scholar]
- 16. Brownstein DG, Barthold SW. Mouse hepatitis virus immunofluorescence in formalin‐ or Bouin's‐fixed tissues using trypsin digestion. Lab Anim Sci 1982;32:37–39. [PubMed] [Google Scholar]
- 17. Kusnitz AL, Bray MV, Smith AL. Staining method for detecting concurrent viral infections in animals with Pneumocystis carinii . J Histotechnol 1994;17:349–351. [Google Scholar]
- 18. Gledhill AW, Dick GWA, Niven JSF. Mouse hepatitis virus and its pathogenic action. J Path Bact 1955;69:299–309. [DOI] [PubMed] [Google Scholar]
- 19. Ward JM, Collins MJ, Parker JC. Naturally occurring mouse hepatitis virus infection in the nude mouse. Lab Anim Sci 1977;27:372–376. [PubMed] [Google Scholar]
- 20. Yanagisawa T, Nakanaga K, Kyuwa S, Fujiwara K. Ascitic disease in ICR‐nude mice due to mouse hepatitis virus. Jpn J Vet Sci 1986;48:7–14. [DOI] [PubMed] [Google Scholar]
- 21. Boivin GP, Smith FNL. Idiopathic granulomas in IFN‐γ‐/‐, IL‐10‐/‐ double knockout mice. Lab Anim Sci 1998;48:419. [Google Scholar]
- 22. Kyuwa S, Tagawa Y, Shibata S, Doi K et al. Murine coronavirus‐induced subacute fatal peritonitis in C57BL/6 mice deficient in gamma interferon. J Virol 1998;72:9286–9290. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Schijns VECJ, Wierda CMH, van Hoeij M, Horzinek MC. Exacerbated viral hepatitis in IFN‐γ receptor deficient mice is not suppressed by IL‐12. J Immunol 1996;157:815–821. [PubMed] [Google Scholar]
- 24. Lane TE, Paoletti AD, Buchmeier MJ. Disassociation between the in vitro and in vivo effects of nitric oxide on a neurotropic murine coronavirus. J Virol 1997;71:2202–2210. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Schijns VECJ, Haagmans BL, Wierda CMH et al. Mice lacking IL‐12 develop polarized Th1 cells during viral infection. J Immunol 1998;160:3958–3964. [PubMed] [Google Scholar]
- 26. Smith AL, Barthold SW, de Souza MS, Bottomly K. The role of gamma interferon in infection of susceptible mice with murine coronavirus, MHV‐JHM. Arch Virol 1991;121:89–100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Lucchiari MA, Modolell M, Eichmann K, Pereira CA. In vivo depletion of interferon‐gamma leads to susceptibility of A/J mice to mouse hepatitis virus 3 infection. Immunobiology 1992;185:475–482. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Melnicoff MJ, Horna PK, Breslin EW, Morahan PS. Maintenance of peritoneal macrophages in the steady state. J Leukocyte Biol 1988;44:367–375. [DOI] [PubMed] [Google Scholar]
- 29. Bellingan GJ, Caldwell H, Howie SEM, Dransfield I, Haslett C. In vivo fate of the inflammatory macrophage during the resolution of inflammation. Inflammatory macrophages do not die locally, but emigrate to the draining lymph nodes. J Immunol 1996;157:2577–2585. [PubMed] [Google Scholar]
- 30. Billiau A. Interferon‐γ: biology and role in pathogenesis. Adv Immunol 1996;62:61–130. [DOI] [PubMed] [Google Scholar]
- 31. Dempsey WL, Smith AL, Morahan PS. Effect of inapparent murine hepatitis virus infections on macrophages and host resistance. J Leukocyte Biol 1986;39:559–565. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Puddu P, Fantuzzi L, Borghi P et al. IL‐12 induces IFN‐γ expression and secretion in mouse peritoneal macrophages. J Immunol 1997;159:3490–3497. [PubMed] [Google Scholar]
- 33. Ishida H, Hastings R, Kearney J, Howard M. Continuous anti‐interleukin 10 antibody administration depletes mice of Ly‐1 B cells but not conventional B cells. J Exp Med 1992;175:1213–1220. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Hoskins JD. Coronavirus infection in cats. Vet Clin North Am Small Animal Pract 1993;23:1–16. [DOI] [PMC free article] [PubMed] [Google Scholar]