Interleukin-18 Mediates Immune Responses to Campylobacter jejuni Infection in Gnotobiotic Mice

Bereswill, Stefan; Alutis, Marie E.; Grundmann, Ursula; Fischer, André; Göbel, Ulf B.; Heimesaat, Markus M.

doi:10.1371/journal.pone.0158020

Cited by 8 publications

(16 citation statements)

References 41 publications

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“…This is well in line with our previous infection studies in secondary abiotic mice that were deficient in matrix metalloproteinase (MMP) -2 or -9 [24, 36], in cytokines belonging to the IL-23/IL-22/IL-18 axis [32] or in innate immune receptors including Toll-like receptor (TLR) -4 or -9 and respective WT counterparts [8, 32]. Nevertheless, in our present and previous studies [8, 24, 32, 36], distinct C. jejuni induced microscopic changes within the intestinal tract such as accelerated colonic epithelial apoptosis and pronounced influx of immune cells to the site of infection could be observed. Whereas Nod2 deficiency had no impact on C. jejuni induced colonic histopathological changes and apoptosis development, infected Nod2 −/− mice exhibited more distinct regenerative properties counteracting potential cell damage than WT controls.…”

Section: Discussionsupporting

confidence: 87%

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

et al. 2017

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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-γ 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-γ, 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.

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Section: Discussionsupporting

confidence: 87%

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

et al. 2017

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“…We have recently shown that cytokines belonging to the IL-23/IL-22/IL-18 axis are involved in mediating murine campylobacteriosis [35–37] and, therefore, assessed expression levels of the respective cytokines in colonic ex vivo biopsies. As for TNF mRNA, expression of IL-23p19 was upregulated 14 days following C. jejuni infection of NOD2 –/– IL-10 –/– , but not IL-10 –/– mice ( p < 0.05; Fig.…”

Section: Resultsmentioning

confidence: 99%

Microbiota composition and immune responses during Campylobacter jejuni infection in conventionally colonized IL-10−/− mice lacking nucleotide oligomerization domain 2

Heimesaat

Grundmann

Alutis

et al. 2017

EuJMI

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Host immune responses are pivotal for combating enteropathogenic infections. We here assessed the impact of the innate receptor nucleotide oligomerization domain protein 2 (NOD2) in murine Campylobacter jejuni-infection. Conventionally colonized IL-10–/– mice lacking NOD2 and IL-10–/– controls were perorally challenged with C. jejuni strain 81-176 and displayed comparable pathogenic colonization of intestines until day 14 postinfection (p.i.). Whereas overall intestinal microbiota compositions were comparable in naive mice, NOD2–/– IL-10–/– mice exhibited less fecal bifidobacteria and lactobacilli than IL-10–/– counterparts after infection. Interestingly, NOD2–/– IL-10–/– mice were clinically more compromised during the early phase of infection, whereas, conversely, IL-10–/– animals exhibited more frequently bloody feces lateron. While colonic apoptotic cell and T lymphocyte numbers were comparable in either C. jejuni-infected mice, B lymphocytes were lower in the colon of infected NOD2–/– IL-10–/– mice versus controls. At day 14 p.i., colonic TNF and IL-23p19 mRNA levels were upregulated in NOD2–/– IL-10–/– mice only. Translocation rates of intestinal commensals to mesenteric lymphnodes and extra-intestinal compartments including liver and kidney were comparable, whereas viable bacteria were more frequently detected in spleens derived from IL-10–/– as compared to NOD2–/– IL-10–/– mice. In conclusion, NOD2 is involved during C. jejuni infection in conventionally colonized IL-10–/– mice in a time-dependent manner.

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“…In the present study we investigated the impact of the bacterial MDP sensor NOD2 during C. jejuni infection of conventionally colonized mice. Despite peroral challenge with high pathogenic loads even on three consecutive days, both WT and NOD2 −/− could be colonized only sporadically until day 14 p.i., which is due to the physiological colonization resistance mediated by the distinct murine microbiota composition [7, 9, 12, 13, 34, 39, 40]. During the entire time course following infection pathogenic positivity rates of fecal samples were slightly higher in NOD2 −/− as compared to WT mice.…”

Section: Discussionmentioning

confidence: 99%

“…During the entire time course following infection pathogenic positivity rates of fecal samples were slightly higher in NOD2 −/− as compared to WT mice. This might be explained by concomitant slightly higher loads of commensal E. coli (between one and two orders of magnitude) within the gastrointestinal lumen known to facilitate C. jejuni colonization [7, 8, 10, 12, 13, 34, 39, 40]. In addition, NOD2 deficiency is associated with defective expression of antimicrobial peptides resulting in compromized pathogenic clearance by the host [41, 42].…”

Section: Discussionmentioning

confidence: 99%

“…Very recently our group has highlighted the importance of the IL-23/IL-22/IL-18 axis in campylobacteriosis [30, 32, 34, 36]. In infected secondary abiotic WT mice, for instance, colonic IL-23p19, IL-22 and IL-18 were all upregulated [36], whereas large intestinal IL-22 mRNA levels were shown to be increased in infected IL-10 −/− mice [46].…”

Section: Discussionmentioning

confidence: 99%

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Campylobacter jejuni infection of conventionally colonized mice lacking nucleotide-oligomerization-domain-2

et al. 2017

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BackgroundThe nucleotide-binding oligomerisaton protein 2 (NOD2) constitutes a pivotal sensor of bacterial muramyl dipeptide and assures expression of distinct antimicrobial peptides and mediators produced by enterocytes and immune cells directed against pathogens including Campylobacter jejuni. We here elucidated the role of NOD2 during murine C. jejuni infection in more detail.ResultsConventionally colonized NOD2 deficient (NOD2−/−) mice and corresponding wildtype (WT) counterparts were perorally infected with C. jejuni strain 81–176 on three consecutive days. The pathogen colonized both WT and NOD2−/− mice only sporadically until day 14 post infection (p.i.). However, the slightly higher prevalence of C. jejuni in NOD2−/− mice was accompanied by higher intestinal Escherichia coli loads known to facilitate C. jejuni colonization. Neither overt macroscopic (clinical) nor microscopic sequelae (such as colonic epithelial apoptosis) could be observed upon murine C. jejuni infection of either genotype. Innate immune responses were less distinctly induced in C. jejuni infected NOD2−/− versus WT mice as indicated by lower colonic numbers of neutrophils in the former. Conversely, adaptive immune cell counts including T lymphocytes were higher in large intestines of NOD2−/− as compared to WT mice that were paralleled by increased colonic IL-6 secretion and higher TNF and IL-18 mRNA expression levels in large intestines of the former. Only in NOD2−/− mice, however, colonic IL-22 mRNA expression was down-regulated at day 14 p.i. Whereas viable commensal intestinal bacteria could exclusively be detected in mesenteric lymph nodes and livers of NOD2−/− mice, bacterial translocation rates to kidneys and spleen were NOD2 independent. Notably, large intestinal mRNA expression levels of mucin-2, constituting a pivotal factor involved in epithelial barrier integrity, were comparable in naive and C. jejuni infected mice of either genotype.ConclusionNOD2 is involved in the well-balanced regulation of innate and adaptive pro-inflammatory immune responses of conventional mice upon C. jejuni infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s13099-017-0155-3) contains supplementary material, which is available to authorized users.

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Interleukin-18 Mediates Immune Responses to Campylobacter jejuni Infection in Gnotobiotic Mice

Cited by 8 publications

References 41 publications

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

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

Microbiota composition and immune responses during Campylobacter jejuni infection in conventionally colonized IL-10−/− mice lacking nucleotide oligomerization domain 2

Campylobacter jejuni infection of conventionally colonized mice lacking nucleotide-oligomerization-domain-2

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