Abstract
ABSTRACTCitrobacter rodentium is an attaching and effacing intestinal murine pathogen which shares similar virulence strategies with the human pathogens enteropathogenic- and enterohemorrhagic Escherichia coli to infect their host. C. rodentium is spontaneously cleared by healthy wild-type (WT) mice whereas mice lacking Muc2 or specific immune regulatory genes demonstrate an impaired ability to combat the pathogen. Here we demonstrate that apical formyl peptide receptor 2 (Fpr2) expression increases in colonic epithelial cells during C. rodentium infection. Using a conventional inoculum dose of C. rodentium, both WT and Fpr2−/− mice were infected and displayed similar signs of disease, although Fpr2−/− mice recovered more slowly than WT mice. However, Fpr2−/− mice exhibited increased susceptibility to C. rodentium colonization in response to low dose infection: 100% of the Fpr2−/− and 30% of the WT mice became colonized and Fpr2−/− mice developed more severe colitis and more C. rodentium were in contact with the colonic epithelial cells. In line with the larger amount of C. rodentium detected in the spleen in Fpr2−/− mice, more C. rodentium and enteropathogenic Escherichia coli translocated across an in vitro mucosal surface to the basolateral compartment following FPR2 inhibitor treatment. Fpr2−/− mice also lacked the striated inner mucus layer that was present in WT mice. Fpr2−/− mice had decreased mucus production and different mucin O-glycosylation in the colon compared to WT mice, which may contribute to their defect inner mucus layer. Thus, Fpr2 contributes to protection against infection and influence mucus production, secretion and organization.
Highlights
1.1 The intestinal tractThe intestinal tract is the largest microbial ecosystem in our body, it covers an enormous surface area and is responsible for nutrient uptake and fluid absorption
Mitochondria supply the majority of adenosine triphosphate (ATP) or energy for eukaryotic cells; disturbances in mitochondrial function lead to apoptosis 120
We examined mitochondrial activity in the colon of IFN-γ-/- mice as (Paper III) they possess a different cytokine profile without IFN-γ-/- and more antiinflammatory cytokines that proved beneficial for goblet cell function
Summary
1.1 The intestinal tractThe intestinal tract is the largest microbial ecosystem in our body, it covers an enormous surface area and is responsible for nutrient uptake and fluid absorption. The intestinal tract consists of the small and large intestine or colon and is composed of four concentric tissue layers: serosa, muscularis externa, submucosa, and a single cell layer termed the mucosa. The mucosa or intestinal epithelium facing the lumen consists of a single layer of columnar epithelial cells made up of four differentiated cell types that absorb nutrients, and secrete mucus, hormones and antimicrobial agents that protect the host from noxious luminal substances, including enteric microorganisms 1-3. A protective sheet of secreted mucus covering the colonic epithelium is the first defense barrier. Removal of trapped luminal material coupled with a short mucin half-life requires constant renewal of mucus and is reflected by the fast turnover of MUC2 in surface goblet cells in the colon 5, 10
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