Subversion of human intestinal mucosa innate immunity by a Crohn's disease-associated E. coli

Abstract

Adherent-invasive Escherichia coli (AIEC), associated with Crohn's disease, are likely candidate contributory factors in the disease. However, signaling pathways involved in human intestinal mucosa innate host response to AIEC remain unknown. Here we use a 3D model of human intestinal mucosa explant culture to explore the effects of the AIEC strain LF82 on two innate immunity platforms, i.e., the inflammasome through evaluation of caspase-1 status, and NFκB signaling. We showed that LF82 bacteria enter and survive within a few intestinal epithelial cells and macrophages, without altering the mucosa overall architecture. Although 4-h infection with a Salmonella strain caused crypt disorganization, caspase-1 activation, and mature IL-18 production, LF82 bacteria were unable to activate caspase-1 and induce IL-18 production. In parallel, LF82 bacteria activated NFκB signaling in epithelial cells through IκBα phosphorylation, NFκBp65 nuclear translocation, and TNFα secretion. In addition, NFκB activation was crucial for the maintenance of epithelial homeostasis upon LF82 infection. In conclusion, here we decipher at the whole-mucosa level the mechanisms of the LF82-induced subversion of innate immunity that, by maintaining host cell integrity, ensure intracellular bacteria survival.

The Adherent/Invasive Escherichia coli Strain LF82 Invades and Persists in Human Prostate Cell Line RWPE-1, Activating a Strong Inflammatory Response

“…Twenty-four hours postinfection, both strains appeared within vacuoles in the cytoplasm of the prostate cell line. These results are in accordance with a previous study that reported LF82 within membrane-bounded vacuoles in some intestinal epithelial cells ( 30 ).…”

“…Overall, these results indicated that LF82 induces a stronger activation of both MAPKs and NF-κB pathways than EC73. This result is not surprising because it has been recently demonstrated that activation of NF-κB by LF82 is crucial for its intracellular survival ( 30 ).…”

“…Moreover, some UPEC strains are able to persist within infected tissues due to their ability to inhibit NF-κB activation, modulate expression and release of proinflammatory cytokines ( 22 – 24 ), and form intracellular bacterial communities, which allows bacteria to resist the host immune response and antibiotic therapy ( 25 – 28 ). On the other hand, it has been shown that AIEC strains are stronger biofilm producers ( 29 ) and can subvert the innate immune response ( 30 ), allowing them to persistently colonize the intestinal mucosa. Similarly, UPEC strains causing UTIs and prostatitis mainly belong to the B2 phylogenetic group and show a gradient of virulence traits, including a greater tendency to develop biofilm-like structures ( 31 , 32 ).…”

Adherent-invasive Escherichia coli in inflammatory bowel disease

“…LF82 can activate NF-κB signalling in IEC through IκB-α phosphorylation, NF-κB p65 nuclear translocation and TNF-α secretion. Unlike Salmonella , LF82 bacteria were unable to activate caspase-1 and induce IL-18 production 76. In addition, AIEC bacteria modulate the turnover of the ubiquitin proteasome system in infected IECs by downregulating the NF-κB regulator CYLD, leading to IκB-α degradation and NF-κB activation.…”

Adherent‐invasive Escherichia coli (AIEC): Cause or consequence of inflammation, dysbiosis, and rupture of cellular joints in patients with IBD?

“…LF82 and 083:H1 strains induce increased expression of TNF‐α, IFN‐γ, and IL‐8 transcripts on colon biopsies of patients with CD and affect cell cycle distribution on Caco2 cell lines (Mazzarella et al, ). LF82 bacteria were unable to activate caspase‐1 and induce IL‐18 production (Jarry et al, ). In addition, AIEC bacteria modulate the turnover of the ubiquitin‐proteasome system in infected IECs by downregulating the NF‐κB regulator.…”