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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.

Open access

The World Health Organization has rated multidrug-resistant (MDR) Pseudomonas aeruginosa as a critical threat to human health. In the present study, we performed a survey of intestinal colonization, and local and systemic immune responses following peroral association of secondary abiotic mice with either a clinical MDR P. aeruginosa or a commensal murine Escherichia coli isolate. Depletion of the intestinal microbiota following antibiotic treatment facilitated stable intestinal colonization of both P. aeruginosa and E. coli that were neither associated with relevant clinical nor histopathological sequelae. Either stable bacterial colonization, however, resulted in distinct innate and adaptive immune cell responses in the intestines, whereas a pronounced increase in macrophages and monocytes could be observed in the small as well as large intestines upon P. aeruginosa challenge only, which also applied to colonic T lymphocytes. In addition, TNF secretion was exclusively elevated in large intestines of P. aeruginosa-colonized mice. Strikingly, association of secondary abiotic mice with MDR P. aeruginosa, but not commensal E. coli, resulted in pronounced systemic pro-inflammatory responses, whereas anti-inflammatory responses were dampened. Hence, intestinal carriage of MDR P. aeruginosa as compared to a mere commensal Gram-negative strain in otherwise healthy individuals results in distinct local and systemic pro-inflammatory sequelae.

Open access
Authors: Marie E. Alutis, Ursula Grundmann, Ulrike Hagen, André Fischer, Anja A. Kühl, Ulf B. Göbel, Stefan Bereswill and Markus M. Heimesaat

Increased levels of the matrix metalloproteinases (MMPs)-2 and -9 (also referred to gelatinase-A and -B, respectively) can be detected in the inflamed gut. We have recently shown that synthetic gelatinase blockage reduces colonic apoptosis and pro-inflammatory immune responses following murine Campylobacter (C.) jejuni infection. In order to dissect whether MMP-2 and/or MMP-9 is involved in mediating C. jejuni-induced immune responses, infant MMP-2-/-, MMP-9-/-, and wildtype (WT) mice were perorally infected with the C. jejuni strain B2 immediately after weaning. Whereas, at day 2 postinfection (p.i.), fecal C. jejuni B2 loads were comparable in mice of either genotype, mice expelled the pathogen from the intestinal tract until day 4 p.i. Six days p.i., colonic MMP-2 but not MMP-9 mRNA was upregulated in WT mice. Remarkably, infected MMP-2-/- mice exhibited less frequent abundance of blood in feces, less distinct colonic histopathology and apoptosis, lower numbers of effector as well as innate and adaptive immune cells within the colonic mucosa, and higher colonic IL-22 mRNA levels as compared to infected WT mice. In conclusion, these results point towards an important role of MMP-2 in mediating C. jejuni-induced intestinal immunopathogenesis.

Open access
Authors: Marie E. Alutis, Ursula Grundmann, André Fischer, Ulrike Hagen, Anja A. Kühl, Ulf B. Göbel, Stefan Bereswill and Markus M. Heimesaat

Matrix metalloproteinases (MMP)-2 and -9 (also referred to gelatinases-A and -B, respectively) are upregulated in the inflamed gut of mice and men. We recently demonstrated that synthetic gelatinase blockage reduced large intestinal pro-inflammatory immune responses and apoptosis following murine Campylobacter (C.) jejuni infection. In order to address which gelatinase mediates C. jejuni-induced immune responses, gnotobiotic MMP-2−/−, MMP-9−/−, and wildtype (WT) mice were generated by broadspectrum antibiotic treatment and perorally infected with C. jejuni strain 81-176. The pathogen stably colonized the murine intestinal tract irrespective of the genotype but did not translocate to extra-intestinal compartments. At days 8 and 14 postinfection (p.i.), less pronounced colonic histopathological changes were observed in infected MMP-2−/− mice, less distinct epithelial apoptosis, but more epithelial proliferation in both MMP-2−/− and MMP-9−/− mice, as compared to WT controls. Reduced immune responses in gelatinase- deficient mice were characterized by lower numbers of effector as well as innate and adaptive immune cells within the colonic mucosa and lamina propria. The expression of IL-22, IL-18, IL-17A, and IL-1β mRNA was higher in the colon of MMP-2−/− as compared to WT mice. In conclusion, both MMP-2 and MMP-9 are differentially involved in mediating C. jejuni-induced intestinal immunopathology.

Open access
Authors: Ulrike Escher, Eliezer Giladi, Ildikò R. Dunay, Stefan Bereswill, Illana Gozes and Markus M. Heimesaat

synthetic NAP alleviated intestinal as well as extra-intestinal pro-inflammatory immune responses upon low-dose T. gondii infection, whereas intestinal and systemic anti-inflammatory IL-10 secretion was reinforced to counteract ileitis

Open access

6 A–C), whereas additionally elevated TNF and NO concentrations could be measured in MLN at day 9 p.i., as compared to naive mice ( p < 0.001; Figure 6 D, E). Hence, low-dose T. gondii infection of hma mice resulted in distinct pro-inflammatory

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gastrointestinal tract, ii.) subsequent gut microbiota changes, and iii.) intestinal, as well as iv) systemic pro-inflammatory immune responses following peroral challenge of conventionally colonized adult wildtype mice with either C. coli or C. jejuni . Both

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aeruginosa Induce Systemic Pro-Inflammatory Immune Responses in Colonized Mice . Eur J Microbiol Immunol . 2017 ; 7 : 200 – 9 . doi: 10.1556/1886.2017.00022 . PubMed PMID: 29034109; PubMed Central PMCID: PMCPMC5632747. 15

Open access
Authors: B. Otto, L.-M. Haag, A. Fischer, R. Plickert, A. A. Kühl, U. B. Göbel, Markus M. Heimesaat and S. Bereswill


Campylobacter jejuni is one of the predominant causes for foodborne bacterial infections worldwide. We investigated whether signaling of C. jejuni-lipoproteins and -lipooligosaccharide via Toll-like-receptor (TLR) -2 and -4, respectively, is inducing intestinal and extra-intestinal immune responses following infection of conventional IL-10-/- mice with chronic colitis. At day 3 following oral infection, IL-10-/- mice lacking TLR-2 or TLR-4 harbored comparable C. jejuni strain ATCC 43431 loads in their colon. Interestingly, infected TLR-4-/- IL-10-/- mice displayed less compromized epithelial barrier function as indicated by lower translocation rates of live gut commensals into mesenteric lymphnodes (MLNs), and exhibited less distinct B lymphocyte responses in their colonic mucosa as compared to naïve IL-10-/- controls. Furthermore, in extra-intestinal compartments such as MLNs and spleens, abundance of myeloid cells was less distinct whereas relative percentages of activated T helper cells and cytotoxic T cells were higher in spleens and dendritic cells more abundant in MLNs of infected IL-10-/- animals lacking TLR-4 as compared to IL-10-/- controls. Taken together, in conventionally colonized IL-10-/- mice, TLR-4, but not TLR-2, is involved in mediating extra-intestinal pro-inflammatory immune responses following C. jejuni infection. Thus, conventional IL-10-/- mice are well suited to further dissect mechanisms underlying Campylobacter infections in vivo.

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The rising incidences of infections with multidrug-resistant (MDR) Gram-negative bacteria including Pseudomonas aeruginosa (PA) have gained increasing attention in medicine, but also in the general public and global health politics. The mechanisms underlying opportunistic pathogen—host interactions are unclear, however. To address this, we challenged secondary abiotic IL10−/− mice deficient for Toll-like receptor-4 (TLR4−/− × IL10−/−), the main receptor of the Gram-negative cell wall constituent lipopolysaccharide, with a clinical MDR PA isolate. Despite higher intestinal colonization densities, apoptotic colonic epithelial cell numbers were lower in TLR4−/− × IL10−/− mice as compared to IL10−/− controls at day 14 postinfection (p.i.), whereas proliferating/regenerating cells had increased in the latter only. Furthermore, PA-colonized TLR4−/− × IL10−/− mice displayed less distinct innate and adaptive immune cell responses in the colon as compared to IL10−/− counterparts that were accompanied by lower nitric oxide concentrations in mesenteric lymph nodes in the former at day 14 p.i. Conversely, splenic NO levels were higher in both naive and PA-colonized TLR4-deficient IL10−/− mice versus IL10−/− controls. Remarkably, intestinal MDR PA was able to translocate to extra-intestinal including systemic compartments of TLR4−/− × IL10−/− mice only. Hence, MDR PA-induced intestinal and systemic immune responses observed in secondary abiotic IL10−/− mice are TLR4-dependent.

Open access