https://orcid.org/0000-0003-0531-2137
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ABSTRACT
Citrobacter 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.
Abbreviations
| BSA | = | Bovine serum albumin |
| EDTA | = | Ethylenediaminetetaacetic acid |
| DTT | = | Ditiotreitol |
| TAMRA | = | Tetramethylrhodamine |
| GalNAz | = | N-azidoacetylgalactosamine |
| GlcNAc | = | N-acetylglucosamine |
| NeuAc | = | N-acetylneuraminic acid |
| NeuGc | = | N-glycolylneuraminic acid |
| LC-MS | = | Liquid chromatography-mass spectrometry |
| C. rodentium | = | Citrobacter rodentium |
| E. coli | = | Escherichia coli |
| EPEC | = | Enteropathogenic Escherichia coli |
| EHEC | = | Enterohaemorrhagic Escherichia coli |
| A/E | = | Attaching and effacing |
| CFU | = | Colony forming unit |
| PI | = | Post infection |
| WT | = | Wild-type |
| GI | = | Gastrointestinal |
| DSS | = | Dextran-sulfate sodium |
| FPR | = | Formyl peptide receptor |
| FPR2-/- | = | Formyl peptide receptor 2 knock-out |
| GPCR | = | G-protein coupled receptor |
| IL | = | Interleukin |
| TNF-α | = | Tumor necrosis factor alfa |
| IFN-γ | = | Interferon gamma |
| MCP-1 | = | Macrophage chemotactic protein-1 |
| MIP | = | Macrophage inflammatory protein |
| H/E | = | Hematoxylin/eosin |
| PAS | = | Periodic acid Shiff |
| LB | = | Luria Bertani broth |
| FBS | = | Fetal bovine serum |
Disclosure statement
No potential conflict of interest was reported by the authors.
Author Contributions
SS, HF, and SL conceptualized the study. JW and HF provided material/mice. SS, VV, MP, MW, MG, MS performed the experiments. SS and SL wrote the manuscript. All authors critically reviewed the manuscript.
