Citrobacter Infection and Wnt Signaling

Abstract

Gut flora generally contributes to a healthy environment while both commensal and pathogenic bacteria that influence the innate and adaptive immune responses, can cause acute and/or chronic mucosal inflammation. Citrobacter rodentium (C. rodentium) is a member of the family of enteropathogens that provide an excellent in vivo model to investigate the host-pathogen interactions in real-time. It is the etiologic agent for transmissible murine colonic hyperplasia (TMCH) while inflammation following C. rodentium infection is dependent upon the genetic background. Ongoing and completed studies in this model have so far established that Wnt/β-catenin, Notch and PI3K pathways regulate colonic crypt hyperplasia while epithelial-stromal cross-talk, mediated by MEK/ERK/NF-κB signaling, regulates inflammation and/or colitis in susceptible strains. The C. rodentium-induced hyperplastic state also increases the susceptibility to either mutagenic insult or in mice heterozygous for Apc gene. The ability to modulate the host response to C. rodentium infection therefore provides an opportunity to delineate the mechanisms that determine mucosal hyperplasia, intestinal inflammation, and/or neoplasia as disease outcomes.

Role of bacterial infection in the epigenetic regulation of Wnt antagonist WIF1 by PRC2 protein EZH2

“…In the current study, we describe a novel mechanism by which Wnt antagonist WIF1 is downregulated in EZH2-overexpressing cells through histone H3K27 trimethylation at the WIF1 promoter which may be directly involved in epigenetic upregulation of β-catenin function in response to CR infection. While these findings are consistent with either targeted overexpression of EZH2 in the mammary gland that causes epithelial hyperplasia 21 or in response to H. pylori CagA-mediated aberrant epigenetic silencing that induces Ras upregulation 15 , CR-induced EZH2 upregulation in a non-transformed colonic epithelium mimics advanced stages of colon carcinogenesis despite TMCH being a self-limiting disease 35 . We have further discovered that blocking EZH2 function in vitro inhibited cell migration and spheroid growth due to decreases in CSC markers CD44, Dclk1 and Lgr5.…”

Citrobacter rodentium -induced colitis: A robust model to study mucosal immune responses in the gut

“…It presents as an elongation of the colonic crypts and thickening of the mucosa which is caused by excessive induction of epithelium regeneration and repair mechanisms (Luperchio and Schauer, 2001;Mundy et al, 2005). TMCH is triggered by the loss of epithelial barrier integrity and the translocation of bacteria into the lamina propria, and is associated with activation of the Wnt/b-catenin, Notch and NF-kB signaling pathways Chandrakesan et al, 2012Chandrakesan et al, , 2014Umar, 2012;Collins et al, 2014). Since the signaling pathways that regulate epithelial proliferation and reparation processes during TMCH are similar to those observed in human IBD (Higgins et al, 1999;Chandrakesan et al, 2014), C. rodentium infection in the mouse can be a useful model to investigate the mechanisms of epithelial injury and regeneration in human disease.…”

Stromal contributions to the carcinogenic process

“…Citrobacter rodentium , a bacterium functionally similar to Escherichia coliEscherichia coli , induces crypt hyperplasia and an increased risk of neoplasia, mimicking the development of colonic adenocarcinoma. The underlying cellular mechanisms include activation of Wnt/β‐catenin and NF‐κB as well as phosphatidylinositol‐3‐kinase (PI3K)/Akt and the Notch pathway . Similarly, H. pylori infection has been found to dysregulate β‐catenin signaling, increasing epithelial cell proliferation and contributing to the formation of gastric cancer .…”