Our group has been working on the implication of adherent-invasive Escherichia coli (AIEC) in the etiology of Crohn’s disease (CD). We have showed that AIEC abnormally colonize the intestinal mucosa of CD patients, adhere to and invade intestinal epithelial cells (IECs), survive and replicate within macrophages, promote pro-inflammatory cytokine production, and colonize the gut and induce intestinal inflammation in genetically susceptible mouse models. We also showed that upon AIEC infection, autophagy is activated in host cells to restrain AIEC replication and to inhibit AIEC-induced inflammation. We showed recently in vitro and in vivo that activation of the metabolic stress response pathway EIF2AK4-EIF2A-ATF4 upon AIEC infection serves as a host defense mechanism to induce a functional autophagy, independently of mTOR, to control AIEC intracellular replication and to inhibit AIEC-induced inflammation1. Given that most of the current strategies based on modulating autophagy by targeting mTOR can have undesirable effects, targeting the EIF2AK4-EIF2A-ATF4 pathway could be a promising strategy to inhibit specifically AIEC colonization and inflammation. While host cells induce a functional autophagy as a defense mechanism to control AIEC replication, AIEC can subvert autophagy by up-regulating the levels of miR-30c and miR-130a in IECs, thus inhibiting levels of two key autophagy-related proteins ATG5 and ATG16L1. AIEC also inhibit autophagy by impairing host SUMOylation, a eukaryotic-reversible post-translational modification, in which SUMO, an ubiquitin-like polypeptide, is covalently linked to target proteins. Thus, we demonstrated the AIEC-induced impaired autophagy via the modulation of host miRNAs or host SUMOylation consequently leads to increased AIEC intracellular replication and AIEC-induced inflammation. We also showed a role for autophagy in the control of gut microbiota composition and host susceptibility to AIEC infection using genetically manipulated mouse models with a defect in autophagy. This was accompanied with increased AIEC colonization in the gut and enhanced intestinal inflammation. Of interest, upon AIEC infection, IECs and macrophages secrete an increased amount of exosomes, which are extracellular vesicles of 30 to 100 nm playing a role in cell-to-cell communication. Furthermore, the exosomes secreted by AIEC-infected cells can increase pro-inflammatory cytokine production and AIEC replication in exosome-receiving cells. Of interest, exosomes secreted by AIEC-infected IECs inhibit autophagy in exosome-receiving IECs. Mechanistically, this is mediated miR-30c and miR-130a, which are transferred via exosomes from donner cells to recipient cells, in which they directly target and inhibit expression of ATG5 and ATG16L1, respectively (unpublished data). This consequently leads to impaired autophagy response and increased intracellular replication of AIEC in cells that receive exosomes from AIEC-infected cells. These data show that exosomes are an important player in cell-to-cell communication during AIEC infection, which can carry and transfer specific miRNAs, leading to autophagy inhibition and favoring AIEC colonization. Altogether, our researches help to understand better the mechanism underlying the interaction between the host and AIEC strains. In the future, this work could contribute to the development of a personalized therapeutic strategy based on autophagy modulation for patients with abnormal AIEC colonization.
With a PhD degree in 2006 at University of Aix-Marseille III, France and a postdoc training at Department of Medicine, Emory University, USA (2006-2011), H. Nguyen has obtained a tenured position as an assistant professor at the M2iSH (Microbe, intestine, inflammation and Susceptibility of the Host), UMR1071 Inserm, University of Clermont Auvergne since 2012. H. Nguyen has been deeply working on the molecular and cellular mechanisms involved in the etiology of intestinal diseases such as inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Her current researches focus on the infectious etiology of these diseases, and in particular on the interaction between the host and the pathogens involved in these diseases.