Dataset Information

Immune responses upon Campylobacter jejuni infection of secondary abiotic mice lacking nucleotide-oligomerization-domain-2.

ABSTRACT:

Background

Campylobacter 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 results

In 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.

Conclusion

In 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.

SUBMITTER: Bereswill S

PROVIDER: S-EPMC5461728 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Immune responses upon <i>Campylobacter jejuni</i> infection of secondary abiotic mice lacking nucleotide-oligomerization-domain-2.

Bereswill Stefan S Grundmann Ursula U Alutis Marie E ME Fischer André A Kühl Anja A AA Heimesaat Markus M MM

Gut pathogens 20170606

<h4>Background</h4><i>Campylobacter jejuni</i> 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.<h4>Methods and results</h4>In order to overcome physiological colonization resistance preventing from <i>C. jejuni</i> infection, we generated secondary abiotic Nod2<sup>-/-</sup> and w ...[more]

PMID: 28592996

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Project description:Human Campylobacter jejuni-infections are progressively increasing worldwide. Despite their high prevalence and socioeconomic impact the underlying mechanisms of pathogen-host-interactions are only incompletely understood. Given that the innate immune receptor nucleotide-oligomerization-domain-2 (Nod2) is involved in clearance of enteropathogens, we here evaluated its role in murine campylobacteriosis. To address this, we applied Nod2-deficient IL-10-/- (Nod2-/- IL-10-/-) mice and IL-10-/- counterparts both with a depleted intestinal microbiota to warrant pathogen-induced enterocolitis. At day 7 following peroral C. jejuni strain 81-176 infection, Nod2 mRNA was down-regulated in the colon of secondary abiotic IL-10-/- and wildtype mice. Nod2-deficiency did neither affect gastrointestinal colonization nor extra-intestinal and systemic translocation properties of C. jejuni. Colonic mucin-2 mRNA was, however, down-regulated upon C. jejuni-infection of both Nod2-/- IL-10-/- and IL-10-/- mice, whereas expression levels were lower in infected, but also naive Nod2-/- IL-10-/- mice as compared to respective IL-10-/- controls. Remarkably, C. jejuni-infected Nod2-/- IL-10-/- mice were less compromised than IL-10-/- counterparts and displayed less distinct apoptotic, but higher regenerative cell responses in colonic epithelia. Conversely, innate as well as adaptive immune cells such as macrophages and monocytes as well as T lymphocytes and regulatory T-cells, respectively, were even more abundant in large intestines of Nod2-/- IL-10-/- as compared to IL-10-/- mice at day 7 post-infection. Furthermore, IFN-? concentrations were higher in ex vivo biopsies derived from intestinal compartments including colon and mesenteric lymph nodes as well as in systemic tissue sites such as the spleen of C. jejuni infected Nod2-/- IL-10-/- as compared to IL10-/- counterparts. Whereas, at day 7 postinfection anti-inflammatory IL-22 mRNA levels were up-regulated, IL-18 mRNA was down-regulated in large intestines of Nod2-/- IL-10-/- vs. IL-10-/- mice. In summary, C. jejuni-infection induced less clinical signs and apoptosis, but more distinct colonic pro- and (of note) anti-inflammatory immune as well as regenerative cell responses in Nod2 deficient IL-10-/- as compared to IL-10-/- control mice. We conclude that, even though colonic Nod2 mRNA was down-regulated upon pathogenic challenge, Nod2-signaling is essentially involved in the well-balanced innate and adaptive immune responses upon C. jejuni-infection of secondary abiotic IL-10-/- mice, but does neither impact pathogenic colonization nor translocation.

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