Skip to main content

Advertisement

Log in

Infection with murine gammaherpesvirus 68 exacerbates inflammatory bowel disease in IL-10-deficient mice

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

We questioned whether infection with murine gammaherpesvirus 68 (HV-68) might exacerbate inflammatory bowel disease using mice deficient in IL-10 (IL-10−/−) as a model of developing colitis.

Methods

Groups of C57BL/6 mice and IL-10−/− mice were mock-treated or infected with HV-68. Two months following infection, mice were euthanized and a variety of parameters were measured to quantify the extent of inflammation and the presence of virus. Measurements included survival, body weight, splenomegaly, colonic disease scores, liver histopathology, viable bacteria in the liver, and splenic viral burden.

Results

IL-10−/− mice infected with HV-68 displayed reduced survival, lower body weights, increased splenomegaly, exacerbated colonic disease scores, increased numbers of viable bacteria in the liver, and increased leukocyte liver infiltration when compared to mock-treated IL-10−/− mice or HV-68 infected C57BL/6 mice. Surprisingly, levels of infectious or latent virus were not significantly different between the groups of mice exposed to HV-68.

Conclusions

The presence of HV-68 in IL-10−/− mice exacerbates the developing clinical disease in this animal model of colitis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Lunemann JD, Munz C. Epstein–Barr virus and multiple sclerosis. Curr Neurol Neurosci Rep. 2007;7(3):253–8.

    Article  PubMed  CAS  Google Scholar 

  2. Niller HH, Wolf H, Minarovits J. Regulation and dysregulation of Epstein–Barr virus latency: implications for the development of autoimmune diseases. Autoimmunity. 2008;41(4):298–328.

    Article  PubMed  CAS  Google Scholar 

  3. Peacock JW, Elsawa SF, Petty CC, Hickey WF, Bost KL. Exacerbation of experimental autoimmune encephalomyelitis in rodents infected with murine gammaherpesvirus-68. Eur J Immunol. 2003;33(7):1849–58.

    Article  PubMed  CAS  Google Scholar 

  4. Harley JB, Harley IT, Guthridge JM, James JA. The curiously suspicious: a role for Epstein–Barr virus in lupus. Lupus. 2006;15(11):768–77.

    Article  PubMed  CAS  Google Scholar 

  5. Costenbader KH, Karlson EW. Epstein–Barr virus and rheumatoid arthritis: is there a link? Arthritis Res Ther. 2006;8(1):204.

    Article  PubMed  CAS  Google Scholar 

  6. Nikolich-Zugich J. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nature Rev. 2008;8(7):512–22.

    Article  CAS  Google Scholar 

  7. Saygun I, Kubar A, Sahin S, Sener K, Slots J. Quantitative analysis of association between herpesviruses and bacterial pathogens in periodontitis. J Periodontal Res. 2008;43(3):352–9.

    Article  PubMed  CAS  Google Scholar 

  8. Slots J. Herpesviruses, the missing link between gingivitis and periodontitis? J Int Acad Periodontol. 2004;6(4):113–9.

    PubMed  Google Scholar 

  9. Slots J. Herpesviral-bacterial synergy in the pathogenesis of human periodontitis. Curr Opin Infect Dis. 2007;20(3):278–83.

    Article  PubMed  Google Scholar 

  10. Brook I. The association of anaerobic bacteria with infectious mononucleosis. Anaerobe. 2005;11(6):308–11.

    Article  PubMed  CAS  Google Scholar 

  11. Stenfors LE, Bye HM, Raisanen S, Myklebust R. Bacterial penetration into tonsillar surface epithelium during infectious mononucleosis. J Laryngol Otol. 2000;114(11):848–52.

    PubMed  CAS  Google Scholar 

  12. Stenfors LE, Bye HM, Raisanen S. Causes for massive bacterial colonization on mucosal membranes during infectious mononucleosis: implications for acute otitis media. Int J Pediatr Otorhinolaryngol. 2002;65(3):233–40.

    Article  PubMed  Google Scholar 

  13. Garimorth K, Kountchev J, Bellmann R, Semenitz B, Weiss G, Joannidis M. Lemierre’s syndrome following infectious mononucleosis. Wien Klin Wochenschr. 2008;120(5–6):181–3.

    Article  PubMed  Google Scholar 

  14. Givner LB. Arcanobacterium haemolyticum sepsis and Epstein–Barr virus infection. Pediatr Infect Dis J. 1992;11(5):417–8.

    PubMed  CAS  Google Scholar 

  15. Yoon TY, Yang TH, Hahn YS, Huh JR, Soo Y. Epstein–Barr virus-associated recurrent necrotic papulovesicles with repeated bacterial infections ending in sepsis and death: consideration of the relationship between Epstein–Barr virus infection and immune defect. J Dermatol. 2001;28(8):442–7.

    PubMed  CAS  Google Scholar 

  16. Bertalot G, Villanacci V, Gramegna M, Orvieto E, Negrini R, Saleri A, et al. Evidence of Epstein–Barr virus infection in ulcerative colitis. Dig Liver Dis. 2001;33(7):551–8.

    Article  PubMed  CAS  Google Scholar 

  17. Kangro HO, Chong SK, Hardiman A, Heath RB, Walker-Smith JA. A prospective study of viral and mycoplasma infections in chronic inflammatory bowel disease. Gastroenterology. 1990;98(3):549–53.

    PubMed  CAS  Google Scholar 

  18. Spieker T, Herbst H. Distribution and phenotype of Epstein–Barr virus-infected cells in inflammatory bowel disease. Am J Pathol. 2000;157(1):51–7.

    PubMed  CAS  Google Scholar 

  19. Takeda Y, Takada K, Togashi H, Takeda H, Sakano M, Osada Y, et al. Demonstration of Epstein–Barr virus localized in the colonic and ileal mucosa of a patient with ulcerative colitis. Gastrointest Endosc. 2000;51(2):205–9.

    Article  PubMed  CAS  Google Scholar 

  20. Van Kruiningen HJ, Poulin M, Garmendia AE, Desreumaux P, Colombel JF, De Hertogh G, et al. Search for evidence of recurring or persistent viruses in Crohn’s disease. Apmis. 2007;115(8):962–8.

    Article  PubMed  Google Scholar 

  21. Wakefield AJ, Fox JD, Sawyerr AM, Taylor JE, Sweenie CH, Smith M, et al. Detection of herpesvirus DNA in the large intestine of patients with ulcerative colitis and Crohn’s disease using the nested polymerase chain reaction. J Med Virol. 1992;38(3):183–90.

    Article  PubMed  CAS  Google Scholar 

  22. Yanai H, Shimizu N, Nagasaki S, Mitani N, Okita K. Epstein–Barr virus infection of the colon with inflammatory bowel disease. Am J Gastroenterol. 1999;94(6):1582–6.

    Article  PubMed  CAS  Google Scholar 

  23. Cohen JI. Epstein–Barr virus infection. N Engl J Med. 2000;343(7):481–92.

    Article  PubMed  CAS  Google Scholar 

  24. Compston LI, Sarkobie F, Li C, Candotti D, Opare-Sem O, Allain JP. Multiplex real-time PCR for the detection and quantification of latent and persistent viral genomes in cellular or plasma blood fractions. J Virol Methods. 2008;151(1):47–54.

    Article  PubMed  CAS  Google Scholar 

  25. Cameron B, Bharadwaj M, Burrows J, Fazou C, Wakefield D, Hickie I, et al. Prolonged illness after infectious mononucleosis is associated with altered immunity but not with increased viral load. J Infect Dis. 2006;193(5):664–71.

    Article  PubMed  CAS  Google Scholar 

  26. Hislop AD, Taylor GS, Sauce D, Rickinson AB. Cellular responses to viral infection in humans: lessons from Epstein–Barr virus. Annu Rev Immunol. 2007;25:587–617.

    Article  PubMed  CAS  Google Scholar 

  27. Doherty PC, Tripp RA, Hamilton-Easton AM, Cardin RD, Woodland DL, Blackman MA. Tuning into immunological dissonance: an experimental model for infectious mononucleosis [see comments]. Curr Opin Immunol. 1997;9(4):477–83.

    Article  PubMed  CAS  Google Scholar 

  28. Flano E, Woodland DL, Blackman MA. A mouse model for infectious mononucleosis. Immunol Res. 2002;25(3):201–17.

    Article  PubMed  CAS  Google Scholar 

  29. Mistrikova J, Raslova H, Mrmusova M, Kudelova M. A murine gammaherpesvirus. Acta Virol. 2000;44(3):211–26.

    PubMed  CAS  Google Scholar 

  30. Simas JP, Efstathiou S. Murine gammaherpesvirus 68: a model for the study of gammaherpesvirus pathogenesis. Trends Microbiol. 1998;6(7):276–82.

    Article  PubMed  CAS  Google Scholar 

  31. Elsawa SF, Bost KL. Murine gamma-herpesvirus-68-induced IL-12 contributes to the control of latent viral burden, but also contributes to viral-mediated leukocytosis. J Immunol. 2004;172(1):516–24.

    PubMed  CAS  Google Scholar 

  32. Elsawa SF, Taylor W, Petty CC, Marriott I, Weinstock JV, Bost KL. Reduced CTL response and increased viral burden in substance P receptor-deficient mice infected with murine gamma-herpesvirus 68. J Immunol. 2003;170(5):2605–12.

    PubMed  CAS  Google Scholar 

  33. Gasper-Smith N, Marriott I, Bost KL. Murine gamma-herpesvirus 68 limits naturally occurring CD4+CD25+T regulatory cell activity following infection. J Immunol. 2006;177(7):4670–8.

    PubMed  CAS  Google Scholar 

  34. Gasper-Smith N, Singh S, Bost KL. Limited IL-6 production following infection with murine gammaherpesvirus 68. Arch Virol. 2006;151(7):1423–9.

    Article  PubMed  CAS  Google Scholar 

  35. Peacock JW, Bost KL. Infection of intestinal epithelial cells and development of systemic disease following gastric instillation of murine gammaherpesvirus-68. J Gen Virol. 2000;81(Pt 2):421–9.

    PubMed  CAS  Google Scholar 

  36. Peacock JW, Bost KL. Murine gammaherpesvirus-68-induced interleukin-10 increases viral burden, but limits virus-induced splenomegaly and leukocytosis. Immunology. 2001;104(1):109–17.

    Article  PubMed  CAS  Google Scholar 

  37. Bhan AK, Mizoguchi E, Smith RN, Mizoguchi A. Colitis in transgenic and knockout animals as models of human inflammatory bowel disease. Immunol Rev. 1999;169:195–207.

    Article  PubMed  CAS  Google Scholar 

  38. Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75(2):263–74.

    Article  PubMed  CAS  Google Scholar 

  39. Powrie F, Uhlig H. Animal models of intestinal inflammation: clues to the pathogenesis of inflammatory bowel disease. Novartis Found Symp. 2004;263:164–74. discussion 74-8, 211-8.

    Article  PubMed  CAS  Google Scholar 

  40. Berg DJ, Davidson N, Kuhn R, Muller W, Menon S, Holland G, et al. Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest. 1996;98(4):1010–20.

    Article  PubMed  CAS  Google Scholar 

  41. Dutia BM, Allen DJ, Dyson H, Nash AA. Type I interferons and IRF-1 play a critical role in the control of a gammaherpesvirus infection. Virology. 1999;261(2):173–9.

    Article  PubMed  CAS  Google Scholar 

  42. DeMeo MT, Mutlu EA, Keshavarzian A, Tobin MC. Intestinal permeation and gastrointestinal disease. J Clin Gastroenterol. 2002;34(4):385–96.

    Article  PubMed  Google Scholar 

  43. Karlinger K, Gyorke T, Mako E, Mester A, Tarjan Z. The epidemiology and the pathogenesis of inflammatory bowel disease. Eur J Radiol. 2000;35(3):154–67.

    Article  PubMed  CAS  Google Scholar 

  44. Swidsinski A, Lee SP. The role of bacteria in gallstone pathogenesis. Front Biosci. 2001;6:E93–103.

    Article  PubMed  CAS  Google Scholar 

  45. Zeuzem S. Gut-liver axis. Int J Colorectal Dis. 2000;15(2):59–82.

    Article  PubMed  CAS  Google Scholar 

  46. Kennedy RJ, Hoper M, Deodhar K, Erwin PJ, Kirk SJ, Gardiner KR. Interleukin 10-deficient colitis: new similarities to human inflammatory bowel disease. Br J Surg. 2000;87(10):1346–51.

    Article  PubMed  CAS  Google Scholar 

  47. Madsen KL. Inflammatory bowel disease: lessons from the IL-10 gene-deficient mouse. Clin Invest Med. 2001;24(5):250–7.

    PubMed  CAS  Google Scholar 

  48. Rennick DM, Fort MM. Lessons from genetically engineered animal models. XII. IL-10-deficient (IL-10(−/−) mice and intestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2000;278(6):G829–33.

    PubMed  CAS  Google Scholar 

  49. Brimnes J, Reimann J, Nissen M, Claesson M. Enteric bacterial antigens activate CD4(+) T cells from scid mice with inflammatory bowel disease. Eur J Immunol. 2001;31(1):23–31.

    Article  PubMed  CAS  Google Scholar 

  50. Madsen KL, Doyle JS, Tavernini MM, Jewell LD, Rennie RP, Fedorak RN. Antibiotic therapy attenuates colitis in interleukin 10 gene-deficient mice. Gastroenterology. 2000;118(6):1094–105.

    Article  PubMed  CAS  Google Scholar 

  51. Sellon RK, Tonkonogy S, Schultz M, Dieleman LA, Grenther W, Balish E, et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect Immun. 1998;66(11):5224–31.

    PubMed  CAS  Google Scholar 

  52. Takahashi I, Matsuda J, Gapin L, DeWinter H, Kai Y, Tamagawa H, et al. Colitis-related public T cells are selected in the colonic lamina propria of IL-10-deficient mice. Clin Immunol. 2002;102(3):237–48.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kenneth L. Bost.

Additional information

Responsible Editor: S. Stimpson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nelson, D.A., Petty, C.C. & Bost, K.L. Infection with murine gammaherpesvirus 68 exacerbates inflammatory bowel disease in IL-10-deficient mice. Inflamm. Res. 58, 881–889 (2009). https://doi.org/10.1007/s00011-009-0059-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-009-0059-x

Keywords

Navigation