View More View Less
  • 1 Charité — University Medicine Berlin, Berlin, Germany
Open access

Host immune responses are crucial for combating enteropathogenic infections including Campylobacter jejuni. Within 1 week following peroral C. jejuni infection, secondary abiotic IL-10−/− mice develop severe immunopathological sequelae affecting the colon (ulcerative enterocolitis). In the present study, we addressed whether pathogen-induced pro-inflammatory immune responses could also be observed in the small intestines dependent on the innate receptor nucleotide-oligomerization-domain-protein 2 (Nod2). Within 7 days following peroral infection, C. jejuni stably colonized the gastrointestinal tract of both IL-10−/− mice lacking Nod2 (Nod2−/− IL-10−/−) and IL-10−/− controls displaying bloody diarrhea with similar frequencies. Numbers of apoptotic and regenerating epithelial cells increased in the small intestines of C. jejuni-infected mice of either genotype that were accompanied by elevated ileal T and B lymphocyte counts. Notably, ileal T cell numbers were higher in C. jejuni-infected Nod2−/− IL-10−/− as compared to IL-10−/− counterparts. Furthermore, multifold increased concentrations of pro-inflammatory cytokines including IFN-γ, TNF, and MCP-1 could be measured in small intestinal ex vivo biopsies derived from C. jejuni-infected mice of either genotype. In conclusion, C. jejuni-induced pro-inflammatory immune responses affected the small intestines of both Nod2−/− IL-10−/− and IL-10−/− mice, whereas ileal T lymphocyte numbers were even higher in the former.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1.

    Shaw MH , Reimer T, Kim YG, Nunez G: NOD-like receptors (NLRs): bona fide intracellular microbial sensors. Curr Opin Immunol 20, 377382 (2008)

    • Search Google Scholar
    • Export Citation
  • 2.

    Ogura Y , Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G: Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 276, 48124818 (2001)

    • Search Google Scholar
    • Export Citation
  • 3.

    Tada H , Aiba S, Shibata K, Ohteki T, Takada H: Synergistic effect of Nod1 and Nod2 agonists with toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper type 1 cells. Infect Immun 73, 79677976 (2005)

    • Search Google Scholar
    • Export Citation
  • 4.

    Inohara N , Nunez G: NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 3, 371382 (2003)

  • 5.

    Girardin SE , Travassos LH, Herve M, Blanot D, Boneca IG, Philpott DJ, Sansonetti PJ, Mengin-Lecreulx D: Peptidoglycan molecular requirements allowing detection by Nod1 and Nod2. J Biol Chem 278(43), 4170241708 (2003)

    • Search Google Scholar
    • Export Citation
  • 6.

    Girardin SE , Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, Philpott DJ, Sansonetti PJ: Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278, 88698872 (2003)

    • Search Google Scholar
    • Export Citation
  • 7.

    Grimes CL , Ariyananda Lde Z, Melnyk JE, O’Shea EK: The innate immune protein Nod2 binds directly to MDP, a bacterial cell wall fragment. J Am Chem Soc 134, 1353513537 (2012)

    • Search Google Scholar
    • Export Citation
  • 8.

    Guerry P , Szymanski CM: Campylobacter sugars sticking out. Trends Microbiol 16, 428435 (2008)

  • 9.

    Lane JA , Mehra RK, Carrington SD, Hickey RM: The food glycome: a source of protection against pathogen colonization in the gastrointestinal tract. Int J Food Microbiol 142, 113 (2010)

    • Search Google Scholar
    • Export Citation
  • 10.

    Kist M , Bereswill S: Campylobacter jejuni. Contrib Microbiol 8, 150165 (2001)

  • 11.

    Backert S , Tegtmeyer N, Crónín , Böhm M, Heimesaat MM (2017): Human Campylobacteriosis. In: Campylobacter — Features, Detection, and Prevention of Foodborne Disease, ed. Klein G, Elsevier, London, pp. 116

    • Search Google Scholar
    • Export Citation
  • 12.

    Haag LM , Fischer A, Otto B, Plickert R, Kühl AA, Göbel UB, Bereswill S, Heimesaat MM: Campylobacter jejuni induces acute enterocolitis in gnotobiotic IL-10–/–mice via Toll-like-receptor-2 and -4 signaling. PLoS One 7, e40761 (2012)

    • Search Google Scholar
    • Export Citation
  • 13.

    Heimesaat MM , Alutis M, Grundmann U, Fischer A, Tegtmeyer N, Böhm M, Kühl AA, Göbel UB, Backert S, Bereswill S: The role of serine protease HtrA in acute ulcerative enterocolitis and extra-intestinal immune responses during Campylobacter jejuni infection of gnotobiotic IL-10 deficient mice. Front Cell Infect Microbiol 4, 77 (2014)

    • Search Google Scholar
    • Export Citation
  • 14.

    Heimesaat MM , Lugert R, Fischer A, Alutis M, Kühl AA, Zautner AE, Tareen AM, Göbel UB, Bereswill S: Impact of Campylobacter jejuni cj0268c knockout mutation on intestinal colonization, translocation, and induction of immunopathology in gnotobiotic IL-10 deficient mice. PLoS One 9, e90148 (2014)

    • Search Google Scholar
    • Export Citation
  • 15.

    Fiebiger U , Bereswill S, Heimesaat MM: Dissecting the interplay between intestinal microbiota and host immunity in health and disease: lessons learned from germfree and gnotobiotic animal models. Eur J Microbiol Immunol (Bp) 6, 253271 (2016)

    • Search Google Scholar
    • Export Citation
  • 16.

    Golz G , Alter T, Bereswill S, Heimesaat MM: The immunopathogenic potential of Arcobacter butzleri — lessons from a meta-analysis of murine infection studies. PLoS One 11, e0159685 (2016)

    • Search Google Scholar
    • Export Citation
  • 17.

    Otto B , Haag LM, Fischer A, Plickert R, Kühl AA, Göbel UB, Heimesaat MM, Bereswill S: Campylobacter jejuni induces extra-intestinal immune responses via Toll-likereceptor-4 signaling in conventional IL-10 deficient mice with chronic colitis. Eur J Microbiol Immunol (Bp) 2, 210219 (2012)

    • Search Google Scholar
    • Export Citation
  • 18.

    Bereswill S , Fischer A, Plickert R, Haag LM, Otto B, Kühl AA, Dasti JI, Zautner AE, Muñoz M, Loddenkemper C, Gross U, Göbel UB, Heimesaat MM: Novel murine infection models provide deep insights into the “ménage à trois” of Campylobacter jejuni, microbiota and host innate immunity. PLoS One 6, e20953 (2011)

    • Search Google Scholar
    • Export Citation
  • 19.

    Heimesaat MM , Bereswill S, Fischer A, Fuchs D, Struck D, Niebergall J, Jahn HK, Dunay IR, Moter A, Gescher DM, Schumann RR, Göbel UB, Liesenfeld O: Gram-negative bacteria aggravate murine small intestinal Th1-type immunopathology following oral infection with Toxoplasma gondii. J Immunol 177, 87858795 (2006)

    • Search Google Scholar
    • Export Citation
  • 20.

    Alutis ME , Grundmann U, Fischer A, Hagen U, Kühl AA, Göbel UB, Bereswill S, Heimesaat MM: The role of gelatinases in Campylobacter jejuni infection of gnotobiotic mice. Eur J Microbiol Immunol (Bp) 5, 256267 (2015)

    • Search Google Scholar
    • Export Citation
  • 21.

    Alutis ME , Grundmann U, Hagen U, Fischer A, Kühl AA, Göbel UB, Bereswill S, Heimesaat MM: Matrix metalloproteinase-2 mediates intestinal immunopathogenesis in Campylobacter jejuni-infected infant mice. Eur J Microbiol Immunol (Bp) 5, 188198 (2015)

    • Search Google Scholar
    • Export Citation
  • 22.

    Heimesaat MM , Nogai A, Bereswill S, Plickert R, Fischer A, Loddenkemper C, Steinhoff U, Tchaptchet S, Thiel E, Freudenberg MA, Göbel UB, Uharek L: MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease. Gut 59, 10791087 (2010)

    • Search Google Scholar
    • Export Citation
  • 23.

    Mansfield LS , Bell JA, Wilson DL, Murphy AJ, Elsheikha HM, Rathinam VA, Fierro BR, Linz JE, Young VB.: C57BL/6 and congenic interleukin-10-deficient mice can serve as models of Campylobacter jejuni colonization and enteritis. Infect Immun 75, 10991115 (2007)

    • Search Google Scholar
    • Export Citation
  • 24.

    Bell JA , St Charles JL, Murphy AJ, Rathinam VA, Plovanich-Jones AE, Stanley EL, Wolf JE, Gettings JR, Whittam TS, Mansfield LS: Multiple factors interact to produce responses resembling spectrum of human disease in Campylobacter jejuni infected C57BL/6 IL-10–/–mice. BMC Microbiol 9, 57 (2009)

    • Search Google Scholar
    • Export Citation
  • 25.

    Bell JA , Jerome JP, Plovanich-Jones AE, Smith EJ, Gettings JR, Kim HY, Landgraf JR, Lefébure T, Kopper JJ, Rathinam VA, St Charles JL, Buffa BA, Brooks AP, Poe SA, Eaton KA, Stanhope MJ, Mansfield LS: Outcome of infection of C57BL/6 IL-10(–/–) mice with Campylobacter jejuni strains is correlated with genome content of open reading frames up-and down-regulated in vivo. Microb Pathog 54, 119 (2013)

    • Search Google Scholar
    • Export Citation