Abnormally expressed ER stress response chaperone Gp96 in CD favours adherent-invasive Escherichia coli invasion
- Nathalie Rolhion1,
- Nicolas Barnich1,
- Marie-Agnès Bringer2,
- Anne-Lise Glasser1,
- Julien Ranc1,
- Xavier Hébuterne3,
- Paul Hofman3,
- Arlette Darfeuille-Michaud1
- 1Clermont Université, Université d'Auvergne, Clermont-Ferrand, France
- 2INRA, Clermont-Ferrand, France
- 3INSERM ERI-21/EA 4319, Laboratoire de Pathologie Clinique et Expérimentale et CRB INSERM, Hôpital Pasteur, et Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France
- Correspondence to Arlette Darfeuille-Michaud, Pathogénie Bactérienne Intestinale, Université d'Auvergne, CBRV, 28 place Henri Dunant, 63000 Clermont-Ferrand, France;
- Revised 26 April 2010
- Accepted 27 April 2010
- Published Online First 29 June 2010
Background and aims Crohn's disease (CD) ileal lesions are colonised by pathogenic adherent-invasive Escherichia coli (AIEC) producing outer membrane vesicles (OMVs) that contribute to the bacterial invasion process. In addition, increased expression of endoplasmic reticulum (ER)-localised stress response proteins, due to ER stress, is observed in patients with CD. The expression of the ER-localised stress response protein Gp96 in patients with CD and its biological role with regards to the ability of AIEC to invade intestinal epithelial cells were analysed.
Methods and results Immunohistochemistry on tissue arrays showed that, together with CEACAM6 (carcinoembryonic antigen-related cell adhesion molecule 6) or the ER stress protein Grp78, Gp96 is also strongly expressed at the apical plasma membrane of the ileal epithelial cells of 50% of patients with CD. Invasion experiments in the presence of antibodies raised against Gp96, or after transfection of Intestine-407 cells with gp96 small interfering RNA (siRNA), indicated that Gp96 is essential to promote AIEC LF82 invasion, allowing, via the recognition of the outer membrane protein OmpA, OMVs to fuse with intestinal epithelial cells.
Conclusions Gp96 is overexpressed on the apical surface of ileal epithelial cells in patients with CD and acts as a host cell receptor for OMVs, promoting AIEC invasion. From the results shown here, it is speculated that AIEC could take advantage of the abnormal expression of Gp96 in patients with CD to invade the ileal mucosa.
- Crohn's disease
- adherent-invasive E coli
- outer membrane vesicles
- bacterial interactions
- intestinal epithelium
This manuscript is dedicated to our friend and co-author Dr Anne-Lise Glasser who sadly passed away on 7 September 2009.
Funding This study was supported by the Ministère de la Recherche et de la Technologie (JE2526), by the INRA (USC 2018) and by grants from the Association F. Aupetit (AFA), Institut de Recherche des Maladies de l'Appareil Digestif (IRMAD, Laboratoire Astra France) and Project INCa INFLACOL 2008.
Competing interets None
Ethics approval The protocol was approved by the local ethics committee of the University of Nice Sophia Antipolis.
Provenance and peer review Not commissioned; externally peer reviewed.
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