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Contrasting immune responses mediate Campylobacter jejuni-induced colitis and autoimmunity.

ABSTRACT: Campylobacter jejuni is a leading cause of foodborne enteritis that has been linked to the autoimmune neuropathy, Guillain Barré syndrome (GBS). C57BL/6 interleukin (IL)-10(+/+) and congenic IL-10(-/-) mice serve as C. jejuni colonization and colitis models, respectively, but a mouse model for GBS is lacking. We demonstrate that IL-10(-/-) mice infected with a C. jejuni colitogenic human isolate had significantly upregulated type 1 and 17 but not type 2 cytokines in the colon coincident with infiltration of phagocytes, T cells and innate lymphoid cells (ILCs). Both ILC and T cells participated in interferon-? (IFN-?), IL-17, and IL-22 upregulation but in a time- and organ-specific manner. T cells were, however, necessary for colitis as mice depleted of Thy-1(+) cells were protected while neither Rag1(-/-) nor IL-10R blocked Rag1(-/-) mice developed colitis after infection. Depleting IFN-?, IL-17, or both significantly ameliorated colitis and drove colonic responses toward type 2 cytokine and antibody induction. In contrast, C. jejuni GBS patient strains induced mild colitis associated with blunted type 1/17 but enhanced type 2 responses. Moreover, the type 2 but not type 1/17 antibodies cross-reacted with peripheral nerve gangliosides demonstrating autoimmunity.

SUBMITTER: Malik A

PROVIDER: S-EPMC4112758 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Contrasting immune responses mediate Campylobacter jejuni-induced colitis and autoimmunity.

Malik A A Sharma D D St Charles J J Dybas L A LA Mansfield L S LS

Mucosal immunology 20131113 4

Campylobacter jejuni is a leading cause of foodborne enteritis that has been linked to the autoimmune neuropathy, Guillain Barré syndrome (GBS). C57BL/6 interleukin (IL)-10(+/+) and congenic IL-10(-/-) mice serve as C. jejuni colonization and colitis models, respectively, but a mouse model for GBS is lacking. We demonstrate that IL-10(-/-) mice infected with a C. jejuni colitogenic human isolate had significantly upregulated type 1 and 17 but not type 2 cytokines in the colon coincident with inf ...[more]

PMID: 24220299

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Project description:BackgroundHuman Campylobacter jejuni infections are progressively rising worldwide. Information about the molecular mechanisms underlying campylobacteriosis, however, are limited. In the present study we investigated whether cytokines such as IL-23, IL-22 and IL-18, which share pivotal functions in host immunity, were involved in mediating intestinal and systemic immunopathological responses upon C. jejuni infection.Methodology/principal findingsTo assure stable infection, gnotobiotic (i.e. secondary abiotic) IL-23p19-/-, IL-22-/- and IL-18-/- mice were generated by broad-spectrum antibiotic treatment. Following peroral C. jejuni strain 81-176 infection, mice of all genotypes harbored comparably high pathogenic loads in their intestines. As compared to wildtype controls, however, IL-18-/- mice displayed less distinct C. jejuni induced sequelae as indicated by less pronounced large intestinal shrinkage and lower numbers of apoptotic cells in the colonic epithelial layer at day 8 postinfection (p.i.). Furthermore, lower colonic numbers of adaptive immune cells including regulatory T cells and B lymphocytes were accompanied by less distinct secretion of pro-inflammatory cytokines such as TNF and IFN-γ and lower IL-17A mRNA expression levels in colonic ex vivo biopsies of infected IL-18-/- as compared to wildtype mice. Upon C. jejuni infection, colonic IL-23p19 expression was up-regulated in IL-18-/- mice only, whereas IL-22 mRNA levels were lower in uninfected and infected IL-23p19-/- as well as infected IL-18-/- as compared to respective wildtype control mice. Remarkably, not only intestinal, but also systemic infection-induced immune responses were less pronounced in IL-18-/- mice as indicated by lower TNF, IFN-γ and IL-6 serum levels as compared to wildtype mice.Conclusion/significanceWe here show for the first time that IL-18 is essentially involved in mediating C. jejuni infection in the gnotobiotic mouse model. Future studies need to further unravel the underlying regulatory mechanisms orchestrating pathogen-host interaction.

Project description:BackgroundCampylobacter jejuni infections are of rising importance worldwide. Given that innate immune receptors including nucleotide-oligomerization-domain-2 (Nod2) are essentially involved in combating enteropathogenic infections, we here surveyed the impact of Nod2 in murine campylobacteriosis.Methods and resultsIn order to overcome physiological colonization resistance preventing from C. jejuni infection, we generated secondary abiotic Nod2-/- and wildtype (WT) mice by broad-spectrum antibiotic treatment. Mice were then perorally infected with C. jejuni strain 81-176 on 2 consecutive days and could be stably colonized by the pathogen at high loads. Notably, Nod2 deficiency did not affect gastrointestinal colonization properties of C. jejuni. Despite high intestinal pathogenic burdens mice were virtually uncompromised and exhibited fecal blood in single cases only. At day 7 postinfection (p.i.) similar increases in numbers of colonic epithelial apoptotic cells could be observed in mice of either genotype, whereas C. jejuni infected Nod2-/- mice displayed more distinct regenerative properties in the colon than WT controls. C. jejuni infection was accompanied by increases in distinct immune cell populations such as T lymphocytes and regulatory T cells in mice of either genotype. Increases in T lymphocytes, however, were less pronounced in large intestines of Nod2-/- mice at day 7 p.i. when compared to WT mice, whereas colonic numbers of B lymphocytes were elevated in WT controls only upon C. jejuni infection. At day 7 p.i., colonic pro-inflammatory mediators including nitric oxide, TNF, IFN-? and IL-22 increased more distinctly in Nod2-/- as compared to WT mice, whereas C. jejuni induced IL-23p19 and IL-18 levels were lower in the large intestines of the former. Converse to the colon, however, ileal concentrations of nitric oxide, TNF, IFN-?, IL-6 and IL-10 were lower in Nod2-/- as compared to WT mice at day 7 p.i. Even though MUC2 was down-regulated in C. jejuni infected Nod2-/- mice, this did not result in increased pathogenic translocation from the intestinal tract to extra-intestinal compartments.ConclusionIn secondary abiotic mice, Nod2 signaling is involved in the orchestrated host immune responses upon C. jejuni infection, but does not control pathogen loads in the gastrointestinal tract.

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Contrasting immune responses mediate Campylobacter jejuni-induced colitis and autoimmunity.

Publications

Contrasting immune responses mediate Campylobacter jejuni-induced colitis and autoimmunity.

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