575 research outputs found
Absence of Nucleotide-Oligomerization-Domain-2 Is Associated with Less Distinct Disease in Campylobacter jejuni Infected Secondary Abiotic IL-10 Deficient Mice
No full textHuman 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-γ 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
Microbiota composition and immune responses during Campylobacter jejuni infection in conventionally colonized IL-10−/− mice lacking nucleotide oligomerization domain 2
No full textHost 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
Small intestinal pro-inflammatory immune responses following <i>Campylobacter jejuni</i> infection of secondary abiotic IL-10<sup>−/−</sup> mice lacking nucleotide-oligomerization-domain-2
No full textHost 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
MOESM2 of Campylobacter jejuni infection of conventionally colonized mice lacking nucleotide-oligomerization-domain-2
No full textAdditional file 2: Figure S2. Colonic mucin-2 mRNA expression levels in C. jejuni infected conventionally colonized NOD2-/- mice. Wildtype (WT; white circles) and NOD2-/- mice (black circles) were perorally infected with C. jejuni strain 81-176 on three consecutive days (d0, 1 and 2). Mucin-2 (MUC-2) mRNA expression levels were determined in colonic ex vivo biopsies at day 14 post infection by Real Time PCR and expressed in Arbitrary Units (fold expression). Naive (N) mice served as uninfected controls. Medians (black bars) and numbers of analyzed animals (in parentheses) are indicated. Data were pooled from four independent experiments
Ly6Chi Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis
No full textSummaryAntibiotics, though remarkably useful, can also cause certain adverse effects. We detected that treatment of adult mice with antibiotics decreases hippocampal neurogenesis and memory retention. Reconstitution with normal gut flora (SPF) did not completely reverse the deficits in neurogenesis unless the mice also had access to a running wheel or received probiotics. In parallel to an increase in neurogenesis and memory retention, both SPF-reconstituted mice that ran and mice supplemented with probiotics exhibited higher numbers of Ly6Chi monocytes in the brain than antibiotic-treated mice. Elimination of Ly6Chi monocytes by antibody depletion or the use of knockout mice resulted in decreased neurogenesis, whereas adoptive transfer of Ly6Chi monocytes rescued neurogenesis after antibiotic treatment. We propose that the rescue of neurogenesis and behavior deficits in antibiotic-treated mice by exercise and probiotics is partially mediated by Ly6Chi monocytes
Immune responses upon Campylobacter jejuni infection of secondary abiotic mice lacking nucleotide-oligomerization-domain-2
No full textBackground 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
The IL-23/IL-22/IL-18 axis in murine Campylobacter jejuni infection
No full textBackground Human Campylobacter jejuni infections are worldwide on the rise. Information about the distinct molecular mechanisms underlying campylobacteriosis, however, are scarce. In the present study we investigated whether cytokines including IL-23, IL-22 and IL-18 sharing pivotal functions in host immunity were involved in mediating immunopathological responses upon C. jejuni infection. Results To address this, conventionally colonized IL-23p19−/−, IL-22−/− and IL-18−/− mice were perorally infected with C. jejuni strain ATCC 43431. Respective gene-deficient, but not wildtype mice were susceptible to C. jejuni infection and could be readily colonized with highest pathogenic loads in the terminal ileum and colon at day 14 postinfection (p.i.). In IL-23p19−/−, IL-22−/− and IL-18−/− mice viable C. jejuni were detected in MLNs, but did not translocate to spleen, liver, kidney and blood in the majority of cases. Susceptible IL-22−/−, but neither IL-23p19−/−, nor IL-18−/− mice harbored higher intestinal commensal E. coli loads when compared to resistant wildtype mice. Alike C. jejuni, commensal E. coli did not translocate from the intestinal to extra-intestinal tissue sites. Despite C. jejuni infection, mice lacking IL-23p19, IL-22 or IL-18 exhibited less apoptotic cells, but higher numbers of proliferating cells in their colonic epithelium as compared to wildtype mice at day 14 p.i. Less pronounced apoptosis was parallelled by lower abundance of neutrophils within the colonic mucosa and lamina propria of infected IL-23p19−/− and IL-22−/− as compared to wildtype control mice, whereas less distinct colonic TNF secretion could be measured in IL-22−/− and IL-18−/− than in wildtype mice at day 14 p.i. Notably, in infected IL-22−/− mice, colonic IL-23p19 mRNA levels were lower, whereas the other way round, colonic IL-22 expression rates were lower in IL-23p19−/− mice as compared to wildtype controls. Moreover, IL-18 mRNA was less distinctly expressed in large intestines of naive and infected IL-22−/− mice, but not vice versa, given that IL-22 mRNA levels did not differ between in IL-18−/− and wildtype mice. Conclusion Cytokines belonging to the IL-23/IL-22/IL-18 axis mediate immunopathological responses upon murine C. jejuni infection in a differentially orchestrated manner. Future studies need to further unravel the underlying regulatory mechanisms orchestrating pathogenic-host interaction
The Role of IL-23, IL-22, and IL-18 in Campylobacter Jejuni Infection of Conventional Infant Mice
No full textWe have recently shown that, within 1 week following peroral Campylobacter jejuni infection, conventional infant mice develop self-limiting enteritis. We here investigated the role of IL-23, IL-22, and IL-18 during C. jejuni strain 81-176 infection of infant mice. The pathogen efficiently colonized the intestines of IL-18−/− mice only, but did not translocate to extra-intestinal compartments. At day 13 postinfection (p.i.), IL-22−/− mice displayed lower colonic epithelial apoptotic cell numbers as compared to wildtype mice, whereas, conversely, colonic proliferating cells increased in infected IL-22−/− and IL-18−/− mice. At day 6 p.i., increases in neutrophils, T and B lymphocytes were less pronounced in gene-deficient mice, whereas regulatory T cell numbers were lower in IL-23p19−/− and IL-22−/− as compared to wildtype mice, which was accompanied by increased colonic IL-10 levels in the latter. Until then, colonic pro-inflammatory cytokines including TNF, IFN-γ, IL-6, and MCP-1 increased in IL-23p19−/− mice, whereas IL-18−/− mice exhibited decreased cytokine levels and lower colonic numbers of T and B cell as well as of neutrophils, macrophages, and monocytes as compared to wildtype controls. In conclusion, IL-23, IL-22, and IL-18 are differentially involved in mediating C. jejuni-induced immunopathology of conventional infant mice
Interleukin-18 Mediates Immune Responses to Campylobacter jejuni Infection in Gnotobiotic Mice.
No full textBackgroundHuman 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
Colonic Expression of Genes Encoding Inflammatory Mediators and Gelatinases During Campylobacter Jejuni Infection of Conventional Infant Mice
No full textWithin 1 week following peroral Campylobacter jejuni infection, infant mice develop acute enteritis resolving thereafter. We here assessed colonic expression profiles of mediators belonging to the IL-23/IL-22/IL-18 axis and of matrix-degrading gelatinases MMP-2 and MMP-9 at day 6 post C. jejuni strain 81-176 infection. Whereas the pathogen readily colonized the intestines of infant IL-18−/− mice only, colonic mucin-2 mRNA, a pivotal mucus constituent, was downregulated in IL-22−/− mice and accompanied by increased expression of pro-inflammatory cytokines including IFN-γ, TNF, IL-17A, and IL-1β. Furthermore, in both naive and infected IL-22−/− mice, colonic expression of IL-23p19 and IL-18 was lower as compared to wildtype mice, whereas, conversely, colonic IL-22 mRNA levels were lower in IL-18−/− and colonic IL-18 expression lower in IL-23p19−/− as compared to wildtype mice. Moreover, colonic expression of MMP-2 and MMP-9 and their endogenous inhibitor TIMP-1 were lower in IL-22−/− as compared to wildtype mice at day 6 postinfection. In conclusion, mediators belonging of the IL-23/IL-22/IL-18 axis as well as the gelatinases MMP-2 and MMP-9 are involved in mediating campylobacteriosis of infant mice in a differentially regulated fashion
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