Host defences to Citrobacter rodentium

doi:10.1078/1438-4221-00247

International Journal of Medical Microbiology

Volume 293, Issue 1, 2003, Pages 87-93

https://doi.org/10.1078/1438-4221-00247 Get rights and content

Abstract

Citrobacter rodentium is a natural non-invasive bacterial pathogen which infects the distal colon of mice. It uses the same molecular mechanisms of type III secretion as human enteropathogenic and enterohemorrhagic Escherichia coli to colonise the epithelial cells of the gut and is therefore an ideal model to study host-bacterial pathogen interactions in vivo. Infection elicits mucosal inflammation with similarities to inflammatory bowel disease, and so it is a readily accessible model to investigate the relationship between inflammation and anti-bacterial immunity in the gut.

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Cr produces attaching and effacing lesions in the colon which are indistinguishable from those produced by pathogenic E. coli in humans. Infection of mice with Cr induces changes to the colon that include crypt hyperplasia, epithelial cell proliferation, an uneven apical enterocyte surface, crypt dilation, increased cellularity, and mucosal thickening [1,5]. Except in susceptible mouse strains such as C3H/He, Cr growth is restricted to the colon with little bacterial translocation to systemic compartments [6].
The pomegranate fruit peel is a rich source of polyphenols including punicalins, punicalagins, and ellagic acids, but is considered an agricultural waste product. Pomegranate derived products have been reported to have a wide variety of health promoting benefits including antibacterial properties in vitro but there is limited evidence of their antibacterial properties in vivo. The purpose of this study was to test the in vivo antibacterial properties of a pomegranate peel extract (PPX) containing punicalin, punicalagin, and ellagic acid. C3H/He mice were orally pre-treated with water or PPX prior to infection with the mouse bacterial pathogen, Citrobacter rodentium (Cr) that mimics many aspects of human enteropathogenic Escherichia coli infections. Fecal excretion of Cr was monitored and mice were euthanized on day 12 post-infection to assess Cr colonization of the colon and spleen, histological changes, and gene expression. PPX-treatment reduced Cr infection induced weight loss and mortality that was observed in water-treated infected mice. However, Cr colonization of the colon and clearance was unaffected by PPX-treatment. Consistent with this, PPX treatment did not alter the potent Th1/Th17 pro-inflammatory response elicited by Cr infection. Significant colonization of the spleen was only seen in water-treated infected mice and was inversely correlated with the dose of PPX administered. PPX treatment decreased the extent of Cr-induced colon damage that correlated with decreased mortality and reduced colonization of the spleen. Thus, a pomegranate peel extract contains bioactive compounds that mitigate the deleterious effects of an in vivo infection with the model enteropathogenic bacteria, Cr.
Prevalence of Citrobacter spp. From Pet Turtles and Their Environment
2017, Journal of Exotic Pet Medicine
Pet turtles are considered a source of bacterial infection to humans when handled in captivity. Turtles purchased from 9 pet shops and 8 online markets in Korea were examined to determine whether the turtles and their environment were contaminated with Citrobacter spp. Biochemical tests and morphology revealed that Citrobacter spp. were isolated from 7 fecal and 76 environmental samples. Among the 7 fecal isolates, 5 bacteria were identified as Citrobacter freundii through 16S rRNA gene sequencing. The isolation rate of Citrobacter spp. from soil and water samples increased over time. Each of the isolate’s antibiotic resistance was characterized with a disk diffusion test. The strains showed susceptibility against amikacin, ceftriaxone, ciprofloxacin, imipenem, sulfamethoxazole/trimethoprim, and tetracycline, but were resistant to cefoxitin, cephalotin, and chloramphenicol. These results indicate that pet turtles are a potential source of Citrobacter infection in humans in Korea.
Novel changes in NF-κB activity during progression and regression phases of hyperplasia: Role of MEK, ERK, and p38
2010, Journal of Biological Chemistry
Citation Excerpt :
These changes correlated with hyperplasia of the colonic crypts wherein sustained Ki-67 immunoreactivity was recorded between days 6 and 27 followed by decline by day 34. Thus, continuous bacterial attachment or colonization per se is not required to keep NF-κB active for an extended period, which corroborates well with the noninvasive nature of C. rodentium (37). Instead, the C. rodentium-induced cytokinetic changes due to intracellular signaling as discussed below may be sufficient to regulate NF-κB activity for an extended period of time.
Utilizing the Citrobacter rodentium-induced transmissible murine colonic hyperplasia (TMCH) model, we measured hyperplasia and NF-κB activation during progression (days 6 and 12 post-infection) and regression (days 20–34 post-infection) phases of TMCH. NF-κB activity increased at progression in conjunction with bacterial attachment and translocation to the colonic crypts and decreased 40% by day 20. NF-κB activity at days 27 and 34, however, remained 2–3-fold higher than uninfected control. Expression of the downstream target gene CXCL-1/KC in the crypts correlated with NF-κB activation kinetics. Phosphorylation of cellular IκBα kinase (IKK)α/β (Ser^176/180) was elevated during progression and regression of TMCH. Phosphorylation (Ser^32/36) and degradation of IκBα, however, contributed to NF-κB activation only from days 6 to 20 but not at later time points. Phosphorylation of MEK1/2 (Ser^217/221), ERK1/2 (Thr²⁰²/Tyr²⁰⁴), and p38 (Thr¹⁸⁰/Tyr¹⁸²) paralleled IKKα/β kinetics at days 6 and 12 without declining with regressing hyperplasia. siRNAs to MEK, ERK, and p38 significantly blocked NF-κB activity in vitro, whereas MEK1/2-inhibitor (PD98059) also blocked increases in MEK1/2, ERK1/2, and IKKα/β thereby inhibiting NF-κB activity in vivo. Cellular and nuclear levels of Ser⁵³⁶-phosphorylated (p65⁵³⁶) and Lys³¹⁰-acetylated p65 subunit accompanied functional NF-κB activation during TMCH. RSK-1 phosphorylation at Thr³⁵⁹/Ser³⁶³ in cellular/nuclear extracts and co-immunoprecipitation with cellular p65-NF-κB overlapped with p65⁵³⁶ kinetics. Dietary pectin (6%) blocked NF-κB activity by blocking increases in p65 abundance and nuclear translocation thereby down-regulating CXCL-1/KC expression in the crypts. Thus, NF-κB activation persisted despite the lack of bacterial attachment to colonic mucosa beyond peak hyperplasia. The MEK/ERK/p38 pathway therefore seems to modulate sustained activation of NF-κB in colonic crypts in response to C. rodentium infection.
Lymphotoxin Beta Receptor Signaling in Intestinal Epithelial Cells Orchestrates Innate Immune Responses against Mucosal Bacterial Infection
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Citation Excerpt :
Both the innate and adaptive immune systems are involved in control of C. rodentium infection. The adaptive immune components, including CD4+ T cells, B cells, and C. rodentiu-specific antibodies, have been shown to play an essential role in containing and eradicating the infection (Bry and Brenner, 2004; Maaser et al., 2004; MacDonald et al., 2003; Uren et al., 2005; Vallance et al., 2003). Accordingly, recombination activating gene 1 deficient (Rag1−/−) mice lacking both T and B cells fail to clear C. rodentium infection and eventually die by 3 weeks after infection (Bry and Brenner, 2004; Vallance et al., 2003).
Epithelial cells provide the first line of defense against mucosal pathogens; however, their coordination with innate and adaptive immune cells is not well understood. Using mice with conditional gene deficiencies, we found that lymphotoxin (LT) from innate cells expressing transcription factor RORγt, but not from adaptive T and B cells, was essential for the control of mucosal C. rodentium infection. We demonstrate that the LTβR signaling was required for the regulation of the early innate response against infection. Furthermore, we have revealed that LTβR signals in gut epithelial cells and hematopoietic-derived cells coordinate to protect the host from infection. We further determined that LTβR signaling in intestinal epithelial cells was required for recruitment of neutrophils to the infection site early during infection via production of CXCL1 and CXCL2 chemokines. These results support a model wherein LT from RORγt⁺ cells orchestrates the innate immune response against mucosal microbial infection.
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Host defences to Citrobacter rodentium

Abstract

Gastroenterology

J. Biol. Chem.

Cell

Curr. Opin. Immunol.

J. Biol. Chem.

Detection of intimins alpha, beta, gamma, and delta, four intimin derivatives expressed by attaching and effacing microbial pathogens

J. Clin. Microbiol.

Induction of cell death in Tlymphocytes by invasin via β1-integrin

Eur. J. Immunol.

The etiology of transmissible murine colonic hyperplasia

Lab. Anim. Sci.

Transmissible murine colonic hyperplasia

Vet. Pathol.

The invasin protein of Yersinia spp. provides co-stimulatory activity to human Tcells through interaction with β1 integrins

Eur. J. Immunol.

A second chromosomal gene necessary for intimate attachment of enteropathogenic Escherichia coli to epithelial cells

J. Bacteriol.

The role of T cell subsets and cytokines in the pathogenesis of Helicobacter pylori gastritis in mice

J. Immunol.

The complete sequence of the locus of enterocyte effacement (LEE) from enteropathogenic Escherichia coli E2348/69

Mol. Microbiol.

Very late antigen 4- dependent adhesion and costimulation of resting human Tcells by the bacterial beta 1 integrin ligand invasin

J. Exp. Med.

Characterization of the C-terminal domains of intimin-like proteins of enteropathogenic and enterohemorrhagic Escherichia coli, Citrobacter freundii, and Hafnia alvei

Infect. Immun.

Molecular characterization of a carboxy-terminal eukaryotic-cell-binding domain of intimin from enteropathogenic Escherichia coli

Infect. Immun.

Intimin from enteropathogenic Escherichia coli restores murine virulence to a Citrobacter rodentium eaeA mutant: induction of an immunoglobulin A response to intimin and EspB

Infect. Immun.

Intiminspecific immune responses prevent bacterial colonisation by the attaching-effacing pathogen Citrobacter rodentium

Infect. Immun.