Abstract
A novel mechanism is revealed by which clinical isolates of adherent-invasive Escherichia coli (AIEC) penetrate into the epithelial cell layer, replicate, and establish biofilms in Crohn's disease. AIEC uses the FimH fimbrial adhesin to bind to oligomannose glycans on the surface of host cells. Oligomannose glycans exposed on early apoptotic cells are the preferred binding targets of AIEC, so apoptotic cells serve as potential entry points for bacteria into the epithelial cell layer. Thereafter, the bacteria propagate laterally in the epithelial intercellular spaces. We demonstrate oligomannosylation at two distinct sites of a glycoprotein receptor for AIEC, carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6 or CD66c), on human intestinal epithelia. After bacterial binding, FimH interacts with CEACAM6, which then clusters. The presence of the highest-affinity epitope for FimH, oligomannose-5, on CEACAM6 is demonstrated using LC-MS/MS. As mannose-dependent infections are abundant, this mechanism might also be used by other adherent-invasive pathogens.
Highlights
Microbes express an arsenal of virulence factors with which they highjack the normal functions of the host
The binding of E. coli to epithelial cells is mediated by the type-1 fimbrial adhesin FimH (Hultgren et al, 1991; Martinez et al, 2000)
FimH is involved in the induction of apoptosis (Klumpp et al, 2006; Thumbikat et al, 2009) and we asked whether FimH-induced apoptosis coincides with the occurrence of oligomannosidic glycans
Summary
Microbes express an arsenal of virulence factors with which they highjack the normal functions of the host. Innate immune responses are not pathogen-specific, and rely notably on complement proteins to evoke signaling aimed at eliminating the invaders. Adherent-invasive E. coli (AIEC) strains, which are associated with microbial dysbiosis in 37% of Crohn’s disease (CD) patients (Darfeuille-Michaud et al, 1998, 2004), share a phylogenetic link with UPEC (Miquel et al, 2010). Both AIEC and UPEC strains can adhere to and interact with receptors on the epithelial linings of the gastrointestinal tract. For the fimH gene, the prototypic E. coli strains LF82 and UTI89 are classified in the same phylogenetic group (Miquel et al, 2010; Conte et al, 2016) known as AIEC, which was used in this work
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