View More View Less
  • 1 Department of Microbiology and Hygiene, Charité — University Medicine Berlin, Berlin, Germany
  • 2 Department of Internal Medicine, Rheumatology and Clinical Immunology / Research Center Immuno-Sciences (RCIS), Charité — University Medicine Berlin, Berlin, Germany
  • 3 Department of Microbiology and Hygiene, Campus Benjamin Franklin, Charité — University Medicine Berlin, CC5, Hindenburgdamm 27, D-12203, Berlin, Germany
Restricted access

Abstract

Campylobacter jejuni is one of the predominant causes for foodborne bacterial infections worldwide. We investigated whether signaling of C. jejuni-lipoproteins and -lipooligosaccharide via Toll-like-receptor (TLR) -2 and -4, respectively, is inducing intestinal and extra-intestinal immune responses following infection of conventional IL-10-/- mice with chronic colitis. At day 3 following oral infection, IL-10-/- mice lacking TLR-2 or TLR-4 harbored comparable C. jejuni strain ATCC 43431 loads in their colon. Interestingly, infected TLR-4-/- IL-10-/- mice displayed less compromized epithelial barrier function as indicated by lower translocation rates of live gut commensals into mesenteric lymphnodes (MLNs), and exhibited less distinct B lymphocyte responses in their colonic mucosa as compared to naïve IL-10-/- controls. Furthermore, in extra-intestinal compartments such as MLNs and spleens, abundance of myeloid cells was less distinct whereas relative percentages of activated T helper cells and cytotoxic T cells were higher in spleens and dendritic cells more abundant in MLNs of infected IL-10-/- animals lacking TLR-4 as compared to IL-10-/- controls. Taken together, in conventionally colonized IL-10-/- mice, TLR-4, but not TLR-2, is involved in mediating extra-intestinal pro-inflammatory immune responses following C. jejuni infection. Thus, conventional IL-10-/- mice are well suited to further dissect mechanisms underlying Campylobacter infections in vivo.

  • 1. R.E. Black M.M. Levine M.L. Clements T.P. Hughes M.J. Blaser 1988 Experimental Campylobacter jejuni infection in humans J Infect Dis 157 472479.

    • Search Google Scholar
    • Export Citation
  • 2. K.T. Young L.M. Davis V.J. Dirita 2007 Campylobacter jejuni: molecular biology and pathogenesis Nat Rev Microbiol 5 665679.

  • 3. R.S. Tsang 2002 The relationship of Campylobacter jejuni infection and the development of Guillain-Barrè syndrome Curr Opin Infect Dis 15 221228.

    • Search Google Scholar
    • Export Citation
  • 4. M. Kist S. Bereswill 2001 Campylobacter jejuni Contrib Microbiol 8 150165.

  • 5. J.P. van Spreeuwel G.C. Duursma C.J. Meijer R. Bax P.C. Rosekrans 1985 Campylobacter colitis: histological immunohistochemical and ultrastructural findings Gut 26 945951.

    • Search Google Scholar
    • Export Citation
  • 6. R.I. Walker M.B. Caldwell E.C. Lee P. Guerry T.J. Trust 1986 Pathophysiology of Campylobacter enteritis Microbiol Rev 50 8194.

  • 7. J.P. Butzler 2004 Campylobacter, from obscurity to celebrity Clin Microbiol Infect 10 868876.

  • 8. T.M. Wassenaar M.J. Blaser 1999 Pathophysiology of Campylobacter jejuni infections of humans Microbes Infect 1 10231033.

  • 9. X. Sun D. Threadgill C. Jobin 2012 Campylobacter jejuni induces colitis through activation of mammalian target of rapamycin signaling Gastroenterology 142 8695 e85.

    • Search Google Scholar
    • Export Citation
  • 10. ÓCróinin T , Backert S: Host epithelial cell invasion by Campylobacter jejuni: trigger or zipper mechanism? Front Cell Inf Microbio 2, 25. doi 10.3389/fcimb.2012.00025 (2012).

    • Search Google Scholar
    • Export Citation
  • 11. N. Dorrell B.W. Wren 2007 The second century of Campylobacter research: recent advances, new opportunities and old problems Curr Opin Infect Dis 20 514518.

    • Search Google Scholar
    • Export Citation
  • 12. J.W. Yrios E. Balish 1986 Immune response of athymic and euthymic germfree mice to Campylobacter spp Infect Immun 54 339346.

  • 13. J.W. Yrios E. Balish 1986 Colonization and infection of athymic and euthymic germfree mice by Campylobacter jejuni and Campylobacter fetus subsp. fetus Infect Immun 53 378383.

    • Search Google Scholar
    • Export Citation
  • 14. J.W. Yrios E. Balish 1986 Pathogenesis of Campylobacter spp. in athymic and euthymic germfree mice Infect Immun 53 384392.

  • 15. M.V. Jesudason D.J. Hentges P. Pongpech 1989 Colonization of mice by Campylobacter jejuni Infect Immun 57 22792282.

  • 16. M. Youssef G. Corthier H. Goossens C. Tancrede M. Henry-Amar 1987 Comparative translocation of enteropathogenic Campylobacter spp. and Escherichia coli from the intestinal tract of gnotobiotic mice Infect Immun 55 10191021.

    • Search Google Scholar
    • Export Citation
  • 17. C. Chang J.F. Miller 2006 Campylobacter jejuni colonization of mice with limited enteric flora Infect Immun 74 52615271.

  • 18. S. Bereswill A. Fischer R. Plickert L.M. Haag B. Otto 2011 Novel murine infection models provide deep insights into the “Menage a Trois” of Campylobacter jejuni, microbiota and host innate immunity PLoS One 6 e20953.

    • Search Google Scholar
    • Export Citation
  • 19. S. Bereswill R. Plickert A. Fischer A.A. Kühl C. Loddenkemper 2011 What you eat is what you get: novel Campylobacter models in the quadrangle relationship between nutrition, obesity, microbiota and susceptibiliy to infection Eur J Microbiol Immunol 1 237248.

    • Search Google Scholar
    • Export Citation
  • 20. L.M. Haag A. Fischer B. Otto U. Grundmann A.A. Kühl 2012 Campylobacter jejuni infection of infant mice: acute enterocolitis is followed by asymptomatic intestinal and extra-intestinal immune response Eur J Microbiol Immunol 2 211.

    • Search Google Scholar
    • Export Citation
  • 21. M.M. Heimesaat S. Bereswill A. Fischer D. Fuchs D. Struck 2006 Gram-negative bacteria aggravate murine small intestinal Th1-type immunopathology following oral infection with Toxoplasma gondii J Immunol 177 87858795.

    • Search Google Scholar
    • Export Citation
  • 22. M.M. Heimesaat A. Fischer H.K. Jahn J. Niebergall M. Freudenberg 2007 Exacerbation of murine ileitis by Toll-like receptor 4 mediated sensing of lipopolysaccharide from commensal Escherichia coli. 4 mediated sensing of lipopolysaccharide from commensal Escherichia coli Gut 56 941948.

    • Search Google Scholar
    • Export Citation
  • 23. M.M. Heimesaat A. Fischer B. Siegmund A. Kupz J. Niebergall 2007 Shift towards pro-inflammatory intestinal bacteria aggravates acute murine colitis via Toll-like receptors 2 and 4. 4 PLoS One 2 e662.

    • Search Google Scholar
    • Export Citation
  • 24. C. Erridge S.H. Duncan S. Bereswill M.M. Heimesaat 2010 The induction of colitis and ileitis in mice is associated with marked increases in intestinal concentrations of stimulants of TLRs 2, 4, and 5 PLoS One 5 e9125.

    • Search Google Scholar
    • Export Citation
  • 25. L.M. Haag A. Fischer B. Otto R. Plickert A.A. Kuhl 2012 Intestinal microbiota shifts towards elevated commensal Esche richia coli loads abrogate colonization resistance against Campylobacter jejuni in mice PLoS One 7 e35988.

    • Search Google Scholar
    • Export Citation
  • 26. S. Akira S. Uematsu O. Takeuchi 2006 Pathogen recognition and innate immunity Cell 124 783801.

  • 27. W. Strober P.J. Murray A. Kitani T. Watanabe 2006 Signalling pathways and molecular interactions of NOD1 and NOD2 Nat Rev Immunol 6 920.

    • Search Google Scholar
    • Export Citation
  • 28. L.M. Haag A. Fischer B. Otto R. Plickert A.A. Kuhl 2012 Campylobacter jejuni induces acute enterocolitis in gnotobiotic IL-10-/- mice via Toll-like-receptor-2 and -4 signaling PLoS ONE 7 e40761.

    • Search Google Scholar
    • Export Citation
  • 29. L.M. Friis M. Keelan D.E. Taylor 2009 Campylobacter jejuni drives MyD 88-independent interleukin-6 secretion via Toll-like receptor 2. 2 Infect Immun 77 15531560.

    • Search Google Scholar
    • Export Citation
  • 30. L. Hu T.E. Hickey 2005 Campylobacter jejuni induces secretion of proinflammatory chemokines from human intestinal epithelial cells Infect Immun 73 44374440.

    • Search Google Scholar
    • Export Citation
  • 31. V.A. Rathinam K.A. Hoag L.S. Mansfield 2008 Dendritic cells from C57BL/6 mice undergo activation and induce Th1-effector cell responses against Campylobacter jejuni Microbes Infect 10 13161324.

    • Search Google Scholar
    • Export Citation
  • 32. L.S. Mansfield J.A. Bell D.L. Wilson A.J. Murphy H.M. Elsheikha 2007 C57BL/6 and congenic interleukin-10-deficient mice can serve as models of Campylobacter jejuni colonization and enteritis Infect Immun 75 10991115.

    • Search Google Scholar
    • Export Citation
  • 33. I.R. Dunay R.A. Damatta B. Fux R. Presti S. Greco 2008 Gr1(+) inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii Immunity 29 306317.

    • Search Google Scholar
    • Export Citation
  • 34. I.R. Dunay A. Fuchs L.D. Sibley 2010 Inflammatory monocytes but not neutrophils are necessary to control infection with Toxoplasma gondii in mice Infect Immun 78 15641570.

    • Search Google Scholar
    • Export Citation
  • 35. I.R. Dunay L.D. Sibley 2010 Monocytes mediate mucosal immunity to Toxoplasma gondii Curr Opin Immunol 22 461466.

  • 36. K.R. Karlmark F. Tacke I.R. Dunay 2012 Monocytes in health and disease Eur J Microbiol Immunol 2 97102.

  • 37. M. Van der Sluis B.A. De Koning A.C. De Bruijn A. Velcich J.P. Meijerink 2006 Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection Gastroenterology 131 117129.

    • Search Google Scholar
    • Export Citation
  • 38. M.B. Hugdahl J.T. Beery M.P. Doyle 1988 Chemotactic behavior of Campylobacter jejuni Infect Immun 56 15601566.

  • 39. Q.V. Tu M.A. McGuckin G.L. Mendz 2008 Campylobacter jejuni response to human mucin MUC2: modulation of colonization and pathogenicity determinants J Med Microbiol 57 795802.

    • Search Google Scholar
    • Export Citation
  • 40. J.L. McAuley S.K. Linden C.W. Png R.M. King H.L. Pennington 2007 MUC1 cell surface mucin is a critical element of the mucosal barrier to infection J Clin Invest 117 23132324.

    • Search Google Scholar
    • Export Citation
  • 41. M.A. McGuckin S.K. Linden P. Sutton T.H. Florin 2011 Mucin dynamics and enteric pathogens Nat Rev Microbiol 9 265278.

  • 42. L.D. Kalischuk G.D. Inglis A.G. Buret 2009 Campylobacter jejuni induces transcellular translocation of commensal bacteria via lipid rafts Gut Pathog 1 2.

    • Search Google Scholar
    • Export Citation
  • 43. A.J. Macpherson T. Uhr 2004 Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria Science 303 16621665.

    • Search Google Scholar
    • Export Citation
  • 44. L.V. Hooper A.J. Macpherson 2010 Immune adaptations that maintain homeostasis with the intestinal microbiota Nat Rev Immunol 10 159169.

    • Search Google Scholar
    • Export Citation
  • 45. J. Kaldor H. Pritchard A. Serpell W. Metcalf 1983 Serum antibodies in Campylobacter enteritis J Clin Microbiol 18 14.

  • 46. V.A. Rathinam D.M. Appledorn K.A. Hoag A. Amalfitano L.S. Mansfield 2009 Campylobacter jejuni-induced activation of dendritic cells involves cooperative signaling through Tolllike receptor 4 (TLR4)-MyD88 and TLR4-TRIF axes Infect Immun 77 24992507.

    • Search Google Scholar
    • Export Citation
  • 47. A.P. Moran 1997 Structure and conserved characteristics of Campylobacter jejuni lipopolysaccharides J Infect Dis 176 Suppl2 S115121.

    • Search Google Scholar
    • Export Citation
  • 48. A. Rose E. Kay B.W. Wren M.J. Dallman 2012 The Campylobacter jejuni NCTC11168 capsule prevents excessive cytokine production by dendritic cells Med Microbiol Immunol 201 137144.

    • Search Google Scholar
    • Export Citation
  • 49. D.L. Wilson V.A. Rathinam W. Qi L.M. Wick J. Landgraf 2010 Genetic diversity in Campylobacter jejuni is associated with differential colonization of broiler chickens and C57BL/6J IL10-deficient mice Microbiology 156 20462057.

    • Search Google Scholar
    • Export Citation
  • 50. A. van Mourik L. Steeghs J. van Laar H.D. Meiring H.J. Hamstra 2010 Altered linkage of hydroxyacyl chains in lipid A of Campylobacter jejuni reduces TLR4 activation and antimicrobial resistance J Biol Chem 285 1582815836.

    • Search Google Scholar
    • Export Citation
  • 51. X. Li C.L. Swaggerty M.H. Kogut H.I. Chiang Y. Wang 2012 Systemic response to Campylobacter jejuni infection by profiling gene transcription in the spleens of two genetic lines of chickens Immunogenetics 64 5969.

    • Search Google Scholar
    • Export Citation
  • 52. D. Vuckovic M. Abram M. Bubonja B. Wraber M. Doric 2006 Host resistance to primary and secondary Campylobacter jejuni infections in C57Bl/6 mice Microb Pathog 40 3539.

    • Search Google Scholar
    • Export Citation
  • 53. I.N. Crispe 2009 The liver as a lymphoid organ Annu Rev Immunol 27 147163.

  • 54. A. Hakansson G. Molin 2011 Gut microbiota and inflammation Nutrients 3 637682.

  • 55. Siegmund B , Fantuzzi G, Rieder F, Gamboni-Robertson F, Lehr HA et al.: Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNFalpha production. Am J Physiol Regul Integr Comp Physiol 281, R12641273 (2001).

    • Search Google Scholar
    • Export Citation
  • 56. M.M. Heimesaat A. Nogai S. Bereswill R. Plickert A. Fischer 2010 MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease Gut 59 10791087.

    • Search Google Scholar
    • Export Citation
  • 57. M. Munoz M.M. Heimesaat K. Danker D. Struck U. Lohmann 2009 Interleukin (IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17 J Exp Med 206 30473059.

    • Search Google Scholar
    • Export Citation