Study of the recognition of Crohn's disease-associated adherent-invasive Escherichia coli (AIEC) by autophagy : identification of autophagic receptors and virulence factors ; Étude de la reconnaissance des Escherichia coli adhérents et invasifs (AIEC) associés à la maladie de Crohn par l'autophagie : identification des récepteurs autophagiques et des facteurs de virulence

Crohn's disease (CD) is a chronic inflammatory bowel disease, of which the etiology is multifactorial. It results from the complex interaction between genetic predispositions, environmental factors and alterations in the intestinal microbiota composition, inducing a deregulation of the intestinal immune system. To date, CD is incurable, only treatments aimed at alleviating symptoms and preventing recurrences and complications are available. In CD patients, an increase in the prevalence of particular strains of Escherichia coli, called AIEC (adherent-invasive E. coli) strains, has been reported. AIEC are the pathobionts able to adhere to and to invade intestinal epithelial cells as well as replicate inside macrophages without inducing cell death, leading to a dysregulated immune response. Furthermore, it has been shown that several polymorphisms in autophagy-related genes (ATG16L1, IRGM, ULK1, etc.) are associated with an increased risk to develop CD. Autophagy is an essential process for maintaining cellular homeostasis, which allows the degradation and recycling of cytoplasmic components and pathogens via the lysosome. However, some intracellular pathogens develop various strategies to escape autophagy degradation. In this context, the aim of my thesis was to identify the autophagic receptors responsible for AIEC recognition, as well as the genes necessary for AIEC to escape autophagy.The first part of my thesis showed that the depletion of p62 or NDP52 in HeLa cells leads to an increase in the intracellular replication of the AIEC LF82 reference strain and the production of pro-inflammatory cytokines. Confocal microscopy analysis revealed the colocalization of p62 or NDP52 with AIEC LF82 bacteria and LC3 protein, a marker of autophagy. Thus, our results suggest that p62 and NDP52 could act as autophagic receptors to control AIEC intracellular replication. Additionally, we investigated the impact of a polymorphism in the NDP52 gene associated with increased susceptibility to develop CD, called NDP52Val248Ala, ...