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 3‐D 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 NFkB signaling. We showed that LF82 bacteria enter and survive within a few intestinal epithelial cells and lamina propria macrophages, without altering the mucosa overall architecture. While 4h 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 NFkB signaling in epithelial cells through IkBα phosphorylation, NFkBp65 nuclear translocation and TNFα secretion. In addition, pharmacological blockade of NFkB activation using the SN50 peptide showed that NFkB 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.