Abnormally expressed ER stress response chaperone Gp96 in CD favours adherent-invasive Escherichia coli invasion.
OBJECTIVE
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.


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.
Rolhion
Nathalie
N
Pathogénie Bactérienne Intestinale, Université d'Auvergne, CBRV, 28 place Henri Dunant, Clermont-Ferrand, France.
Barnich
Nicolas
N
Bringer
Marie-Agnès
MA
Glasser
Anne-Lise
AL
Ranc
Julien
J
Hébuterne
Xavier
X
Hofman
Paul
P
Darfeuille-Michaud
Arlette
A
D000328:Adult; D001422:Bacterial Adhesion / Q000502:physiology; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D003424:Crohn Disease / Q000378:metabolism* / Q000382:microbiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D004926:Escherichia coli / Q000378:metabolism / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000150:complications* / Q000378:metabolism; D005260:Female; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014774:Virulence; D055815:Young Adult
D001425:Bacterial Outer Membrane Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; C053387:endoplasmin; C078167:OMPA outer membrane proteins; D007371:Interferon-gamma