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Citrobacter rodentium: infection, inflammation and the microbiota

Key Points

  • The mouse pathogen Citrobacter rodentium is a useful model to investigate important human intestinal diseases, including enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC) infections, Crohn's disease, ulcerative colitis and colon tumorigenesis.

  • Whole-genome sequencing of multiple pathogenic attaching and effacing (A/E) bacteria has led to the identification of many genes that are involved in pathogenesis, including gene families that encode effector proteins of the type III secretion system (T3SS). The functions of many putative virulence genes have been evaluated in the C. rodentium model, which has improved our understanding of pathogenesis and the corresponding host responses.

  • C. rodentium elicits robust inflammasome-dependent responses in a caspase 1- and caspase 11-dependent manner. Type I interferon signalling is a key factor that regulates inflammasome activation in C. rodentium infection.

  • The intestinal microbiota is crucial for coordinating mucosal immune responses to C. rodentium infection, including the development of IgA+ plasma cells, group 3 innate lymphoid cells (ILC3s; also known as inducible T helper (iTH) cells), TH17 cells and TH22 cells.

  • Defined dietary components, such as vitamin D, vitamin E, selenium, ligands from cruciferous vegetables and polyunsaturated fatty acids (PUFAs), as well as the intestinal microbiota, directly modify mucosal immune responses and epithelial barrier function in response to C. rodentium infection.

  • Future research using the C. rodentium model will focus on quantitative proteomics, metabolomics and four-dimensional (4D) imaging studies to unravel pathogen–host–microbiota interactions in unprecedented detail.

Abstract

Citrobacter rodentium is a mucosal pathogen of mice that shares several pathogenic mechanisms with enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC), which are two clinically important human gastrointestinal pathogens. Thus, C. rodentium has long been used as a model to understand the molecular basis of EPEC and EHEC infection in vivo. In this Review, we discuss recent studies in which C. rodentium has been used to study mucosal immunology, including the deregulation of intestinal inflammatory responses during bacteria-induced colitis and the role of the intestinal microbiota in mediating resistance to colonization by enteric pathogens. These insights should help to elucidate the roles of mucosal inflammatory responses and the microbiota in the virulence of enteric pathogens.

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Figure 1: The role of Tir signalling pathways in the formation of attaching and effacing lesions.
Figure 2: Mucosal immune responses to Citrobacter rodentium.
Figure 3: The role of the microbiota and nutrition in modulating resistance to Citrobacter rodentium colonization.

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Acknowledgements

The authors are supported by the Canadian Institutes for Health (CIHR) operating grants (to K.M.K. and B.B.F.), US National Institutes of Health (NIH) grant AI083713 (to K.A.F.), NIH grant AI085761 (to K.M.K.), the Wellcome Trust and the UK Medical Research Council (MRC) (to G.F.).

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A chronic inflammatory disease of the gastrointestinal tract; it primarily affects the ileum and colon and causes recurrent abdominal pain, fatigue, weight loss, blood and mucus in the faeces, and diarrhoea.

Ulcerative colitis

A chronic inflammatory disease of the colon and rectum that is characterized by recurrent abdominal pain, chills, fever, colitis and diarrhoea.

Sterilizing immunity

An immune response that completely prevents an infection.

Coprophagy

The consumption of faeces.

H-NS family

(Histone-like nucleoid-structuring family). A family of DNA-binding proteins that bind to AT-rich double-stranded DNA and are involved in transcriptional silencing and bacterial chromosome organization.

Integration host factor

(IHF). A histone-like DNA-binding protein that binds to consensus sites and bends the DNA to form a nucleoprotein complex that promotes transcription.

AHL-type quorum sensing system

(N-Acyl-homoserine lactone quorum sensing system). A dedicated communication system that is present in Gram-negative bacteria and is used to regulate specific genes in response to population density via the production of autoinducer 1.

LuxS quorum sensing system

A communication system that is found in both Gram-positive and Gram-negative bacteria; it controls the expression of virulence genes in a cell density-dependent manner via the production of the signalling molecule autoinducer 2 by luxS.

C3H/HeJ mice

A substrain of the widely used laboratory mouse strain C3H; they carry a mutation in Tlr4 and are resistant to endotoxin exposure.

BarA–SirA two-component regulatory system

A two-component system that is present in Salmonella enterica subsp. enterica serovar Typhimurium. BarA encodes a histidine kinase and SirA encodes the response regulator. Following activation, the system triggers a signalling cascade that results in increased expression of virulence genes and decreased expression of motility genes.

iNOS

(Inducible nitric oxide synthase). A cytosolic enzyme that is found in multiple cell types and that produces nitrous oxide (NO) from L-arginine, following induction by lipopolysaccharide and pro-inflammatory cytokines. It is presumed that the production of NO, in conjunction with superoxide radicals, leads to the formation of antimicrobial reactive nitrogen intermediates, such as peroxynitrite and nitrosothiols, which restrict the growth of invading pathogens.

Inflammasomes

Macromolecular complexes that are found in the cytosol of haematopoietic cells and are assembled in response to a range of microbial and endogenous danger signals, which leads to the proteolytic activation of the effector protein caspase 1. Inflammasomes typically consist of a receptor, an adaptor molecule (apoptosis-associated speck-like protein containing caspase activation and recruitment domain), and the effector caspase 1.

Specific pathogen-free mice

Mice that are provided by laboratory animal vendors or are generated in a home laboratory, that have a guaranteed health status and are free of particular pathogens.

Faecal microbiota transplantation

(FMT). A transplantation process in which the faecal material (including the faecal microbiota) from a healthy donor is transferred into a recipient. Patients are often treated by enema infusion or the consumption of capsules containing donor faeces.

Intestinal lymphoid follicles

A type of lymphoid tissue that consists of aggregates of B cells, CD4+ T cells and IgA-producing plasma cells, which are found directly underneath the associated epithelium. These follicles are induced following environmental cues from the intestinal microbiota and dietary components.

RegIII antimicrobial peptides

Secreted antimicrobial peptides that are produced in the gastrointestinal tract and pancreas and consist of a signal peptide and a single C-type lectin domain; they bind to peptidoglycan and are bactericidal for Gram-positive bacteria.

Trefoil factor

A secretory protein that contains a trefoil motif and is produced by goblet cells in the gastrointestinal mucosa; it is thought to protect against mucosal damage by stabilizing the mucus layer.

Resistin-like molecule B

A protein that is produced by intestinal goblet cells and is induced by microorganisms; it is thought to regulate innate mucosal immune responses, such as macrophage activation and antimicrobial lectin expression.

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Monocolonized mice

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Humanized microbiota

A term used to describe human microbiota colonizing the mouse gastrointestinal tract.

Metabolome

The complete profile of small-molecule metabolites, such as amino acids, nucleotides, antioxidants, organic acids, vitamins, hormones, drugs and food components that are found within a cell, tissue, organ or entire organism.

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Collins, J., Keeney, K., Crepin, V. et al. Citrobacter rodentium: infection, inflammation and the microbiota. Nat Rev Microbiol 12, 612–623 (2014). https://doi.org/10.1038/nrmicro3315

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