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Subversion of autophagy in adherent invasive Escherichia coli-infected neutrophils induces inflammation and cell death.

ABSTRACT: Invading bacteria are recognized, captured and killed by a specialized form of autophagy, called xenophagy. Recently, defects in xenophagy in Crohn's disease (CD) have been implicated in the pathogenesis of human chronic inflammatory diseases of uncertain etiology of the gastrointestinal tract. We show here that pathogenic adherent-invasive Escherichia coli (AIEC) isolated from CD patients are able to adhere and invade neutrophils, which represent the first line of defense against bacteria. Of particular interest, AIEC infection of neutrophil-like PLB-985 cells blocked autophagy at the autolysosomal step, which allowed intracellular survival of bacteria and exacerbated interleukin-8 (IL-8) production. Interestingly, this block in autophagy correlated with the induction of autophagic cell death. Likewise, stimulation of autophagy by nutrient starvation or rapamycin treatment reduced intracellular AIEC survival and IL-8 production. Finally, treatment with an inhibitor of autophagy decreased cell death of AIEC-infected neutrophil-like PLB-985 cells. In conclusion, excessive autophagy in AIEC infection triggered cell death of neutrophils.

SUBMITTER: Chargui A

PROVIDER: S-EPMC3522719 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Subversion of autophagy in adherent invasive Escherichia coli-infected neutrophils induces inflammation and cell death.

Chargui Abderrahman A Cesaro Annabelle A Mimouna Sanda S Fareh Mohamed M Brest Patrick P Naquet Philippe P Darfeuille-Michaud Arlette A Hébuterne Xavier X Mograbi Baharia B Vouret-Craviari Valérie V Hofman Paul P

PloS one 20121214 12

Invading bacteria are recognized, captured and killed by a specialized form of autophagy, called xenophagy. Recently, defects in xenophagy in Crohn's disease (CD) have been implicated in the pathogenesis of human chronic inflammatory diseases of uncertain etiology of the gastrointestinal tract. We show here that pathogenic adherent-invasive Escherichia coli (AIEC) isolated from CD patients are able to adhere and invade neutrophils, which represent the first line of defense against bacteria. Of p ...[more]

PMID: 23272151

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Project description:BackgroundThe predominance of specific bacteria such as adherent-invasive Escherichia coli (AIEC) within the Crohn's disease (CD) intestine remains poorly understood with little evidence uncovered to support a selective pressure underlying their presence. Intestinal ethanolamine is however readily accessible during periods of intestinal inflammation, and enables pathogens to outcompete the host microbiota under such circumstances.MethodsQuantitative RT-PCR (qRT-PCR) to determine expression of genes central to ethanolamine metabolism; transmission electron microscopy to detect presence of bacterial microcompartments (MCPs); in vitro infections of both murine and human macrophage cell lines examining intracellular replication of the AIEC-type strain LF82 and clinical E. coli isolates in the presence of ethanolamine; determination of E. coli ethanolamine utilization (eut) operon transcription in faecal samples from healthy patients, patients with active CD and the same patients in remission following treatment.ResultsGrowth on the intestinal short chain fatty acid propionic acid (PA) stimulates significantly increased transcription of the eut operon (fold change relative to glucose: >16.9; p-value <.01). Additionally ethanolamine was accessible to intra-macrophage AIEC and stimulated significant increases in growth intracellularly when it was added extracellularly at concentrations comparable to those in the human intestine. Finally, qRT-PCR indicated that expression of the E. coli eut operon was increased in children with active CD compared to healthy controls (fold change increase: >4.72; P < .02). After clinical remission post-exclusive enteral nutrition treatment, the same CD patients exhibited significantly reduced eut expression (Pre vs Post fold change decrease: >15.64; P < .01).InterpretationOur data indicates a role for ethanolamine metabolism in selecting for AIEC that are consistently overrepresented in the CD intestine. The increased E. coli metabolism of ethanolamine seen in the intestine during active CD, and its decrease during remission, indicates ethanolamine use may be a key factor in shaping the intestinal microbiome in CD patients, particularly during times of inflammation. FUND: This work was funded by Biotechnology and Biological Sciences Research Council (BBSRC) grants BB/K008005/1 & BB/P003281/1 to DMW; by a Tenovus Scotland grant to MJO; by Glasgow Children's Hospital Charity, Nestle Health Sciences, Engineering and Physical Sciences Research Council (EPSRC) and Catherine McEwan Foundation grants awarded to KG; and by a Natural Environment Research Council (NERC) fellowship (NE/L011956/1) to UZI. The IBD team at the Royal Hospital for Children, Glasgow are supported by the Catherine McEwan Foundation and Yorkhill IBD fund. RKR and RH are supported by NHS Research Scotland Senior fellowship awards.

Dataset Information

Subversion of autophagy in adherent invasive Escherichia coli-infected neutrophils induces inflammation and cell death.

Publications

Subversion of autophagy in adherent invasive Escherichia coli-infected neutrophils induces inflammation and cell death.

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