Point Mutations in FimH Adhesin of Crohn's Disease-Associated Adherent-Invasive Escherichia coli Enhance Intestinal Inflammatory Response

Abstract

Adherent-invasive Escherichia coli (AIEC) are abnormally predominant on Crohn's disease (CD) ileal mucosa. AIEC reference strain LF82 adheres to ileal enterocytes via the common type 1 pili adhesin FimH and recognizes CEACAM6 receptors abnormally expressed on CD ileal epithelial cells. The fimH genes of 45 AIEC and 47 non-AIEC strains were sequenced. The phylogenetic tree based on fimH DNA sequences indicated that AIEC strains predominantly express FimH with amino acid mutations of a recent evolutionary origin - a typical signature of pathoadaptive changes of bacterial pathogens. Point mutations in FimH, some of a unique AIEC-associated nature, confer AIEC bacteria a significantly higher ability to adhere to CEACAM-expressing T84 intestinal epithelial cells. Moreover, in the LF82 strain, the replacement of fimH LF82 (expressing FimH with an AIEC-associated mutation) with fimH K12 (expressing FimH of commensal E. coli K12) decreased the ability of bacteria to persist and to induce severe colitis and gut inflammation in infected CEABAC10 transgenic mice expressing human CEACAM receptors. Our results highlight a mechanism of AIEC virulence evolution that involves selection of amino acid mutations in the common bacterial traits, such as FimH protein, and leads to the development of chronic inflammatory bowel disease (IBD) in a genetically susceptible host. The analysis of fimH SNPs may be a useful method to predict the potential virulence of E. coli isolated from IBD patients for diagnostic or epidemiological studies and to identify new strategies for therapeutic intervention to block the interaction between AIEC and gut mucosa in the early stages of IBD.

Crohn’s disease specific pancreatic antibodies: clinical and pathophysiological challenges

“…Thus, GP2 expressed on the surface of M cells in the PP appears to be located in the very center of CrD inflammation. Intriguingly, certain pathogenic bacteria such as S. typhimurium bind to and induce the transformation of M cells from normal intestinal epithelial cells [77,78]. Since GP2 expression is elevated in the targeted tissue of patients with CrD compared to patients with UC this would be in line with the previous finding and provide a further hint for the putative role of pathogenic bacteria in triggering CrD inflammatory processes.…”

“…In fact, data demonstrating specific pathogenic species to be linked with CrD have been lacking so far. Notwithstanding, high concentrations of mucosal microbes and especially adhesive bacteria which interact with PP have been found in patients with CrD [76][77][78]. Furthermore, gastrointestinal infections appear to pose a higher risk for triggering CrD inflammation [79].…”

Ribonucleotide Reductase NrdR as a Novel Regulator for Motility and Chemotaxis during Adherent-Invasive Escherichia coli Infection

“…In addition, when more than one RNR class is encoded by the bacterial genome, it is crucial to understand which RNR is important during the adhesion, colonization, and persistence of pathogenic bacteria. Adherent-invasive E. coli (AIEC), especially the reference strain LF82, is of particular interest because AIEC virulence evolution involves the selection of amino acid mutations in common bacterial proteins, such as the FimH protein, and leads to the development of chronic inflammatory bowel disease in a genetically susceptible host (25). The AIEC reference strain LF82 is of great interest among the different E. coli species and Enterobacteriaceae, as it provides an additional RNR class of plasmid origin.…”

“…CD-associated AIEC cells adhere to the brush border of primary ileal enterocytes isolated from CD patients but not to enterocytes isolated from controls without inflammatory bowel disease. This adhesion is involved in the recognition between the variant FimH adhesin motifs located on the top of type 1 pili expressed on the AIEC bacterial surface and the carcinoembryonic antigen-related cell-adhesion molecule 6 (CEACAM6) abnormally expressed in the ileal epithelial cells of CD patients (24,25). AIEC strain LF82 colonizes and induces strong gut inflammation in CEABAC10 transgenic mice, which express human CEACAMs and mimic CD susceptibility (25,26).…”

“…This adhesion is involved in the recognition between the variant FimH adhesin motifs located on the top of type 1 pili expressed on the AIEC bacterial surface and the carcinoembryonic antigen-related cell-adhesion molecule 6 (CEACAM6) abnormally expressed in the ileal epithelial cells of CD patients (24,25). AIEC strain LF82 colonizes and induces strong gut inflammation in CEABAC10 transgenic mice, which express human CEACAMs and mimic CD susceptibility (25,26). In the present study, we gained insight into the roles of the different RNR classes during the course of infection with AIEC LF82 using intestinal cells and an in vivo model of infection.…”