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The Citrobacter rodentium Mouse Model: Studying Pathogen and Host Contributions to Infectious Colitis
Published on: February 19, 2013
Citrobacter rodentium induces rapid and unique metabolic and inflammatory responses in mice suffering from severe
Danielle Carson1, Rachael Barry1, Eve G D Hopkins1
1Centre for Molecular Microbiology and Infection, Department of Life Sciences, Imperial College London, London, UK.
Abstract:
The mouse pathogen Citrobacter rodentium is used to model infections with enterohaemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC). Pathogenesis is commonly modelled in mice developing mild disease (e.g., C57BL/6). However, little is known about host responses in mice exhibiting severe colitis (e.g., C3H/HeN), which arguably provide a more clinically relevant model for human paediatric enteric infection. Infection of C3H/HeN mice with C. rodentium results in rapid colonic colonisation, coinciding with induction of key inflammatory signatures and colonic crypt hyperplasia. Infection also induces dramatic changes to bioenergetics in intestinal epithelial cells, with transition from oxidative phosphorylation (OXPHOS) to aerobic glycolysis and higher abundance of SGLT4, LDHA, and MCT4. Concomitantly, mitochondrial proteins involved in the TCA cycle and OXPHOS were in lower abundance. Similar to observations in C57BL/6 mice, we detected simultaneous activation of cholesterol biogenesis, import, and efflux. Distinctly, however, the pattern recognition receptors NLRP3 and ALPK1 were specifically induced in C3H/HeN. Using cell-based assays revealed that C. rodentium activates the ALPK1/TIFA axis, which is dependent on the ADP-heptose biosynthesis pathway but independent of the Type III secretion system. This study reveals for the first time the unfolding intestinal epithelial cells' responses during severe infectious colitis, which resemble EPEC human infections.
Insights
Citrobacter rodentium infection in C3H/HeN mice causes severe colitis, altering intestinal cell bioenergetics and activating specific immune pathways. This severe colitis model offers insights into human paediatric enteric infections.
Area of Science:
- Microbiology
- Immunology
- Gastroenterology
Background:
- Citrobacter rodentium is a mouse model for enterohaemorrhagic and enteropathogenic E. coli infections.
- Severe colitis models, like in C3H/HeN mice, offer greater clinical relevance for human paediatric enteric infections than mild models.
- Host responses in severe colitis models are less understood compared to mild disease models.
Purpose of the Study:
- To investigate host responses in C3H/HeN mice during severe Citrobacter rodentium-induced colitis.
- To characterize changes in intestinal epithelial cell bioenergetics and immune signaling during severe infection.
- To compare host responses in severe colitis models to those in mild disease models and human infections.
Main Methods:
- Infection of C3H/HeN mice with Citrobacter rodentium.
- Analysis of colonic inflammation, crypt hyperplasia, and epithelial cell bioenergetics.
- Measurement of protein abundance, including metabolic enzymes and pattern recognition receptors.
- Cell-based assays to investigate immune pathway activation (ALPK1/TIFA axis).
Main Results:
- Citrobacter rodentium infection in C3H/HeN mice led to rapid colonic colonization, inflammation, and crypt hyperplasia.
- Intestinal epithelial cells shifted from oxidative phosphorylation to aerobic glycolysis, with altered expression of metabolic genes (SGLT4, LDHA, MCT4).
- NLRP3 and ALPK1 pattern recognition receptors were specifically induced, and the ALPK1/TIFA axis was activated via ADP-heptose biosynthesis.
Conclusions:
- Severe colitis induced by Citrobacter rodentium in C3H/HeN mice involves significant changes in host intestinal epithelial cell bioenergetics and immune responses.
- The study highlights the induction of the ALPK1/TIFA pathway, independent of the Type III secretion system, during severe infection.
- This model provides valuable insights into host-pathogen interactions during severe infectious colitis, resembling human enteropathogenic E. coli infections.
