"The molecular cross talks occuring at the interface between the intestinal epithelium and bacterial flora will be studied at two levels : (i) how commensals and pathogens affect innate immune signalling, thereby leading to tolerance of the resident microbiota, and inflammatory rejection of the pathogens. The theme of commensals and pathogens regulating this innate response, particularly how they respectively strengthen or weaken the network of humoral and cellular epithelial defense systems will be central here. (ii) How, in molecular and cellular terms, bacteria affect epithelial renewal. The gut of a germ-free mouse and of a conventional mouse show dramatic differences marked by global immaturity and slow epithelial renewal in absence of flora. In front of pathogens, the actual role plaid in the disease in altering the kinetics of epthelial repair is unknown. The aim of this project is to study how commensals and pathogens affect intestinal epithelial renewal, particularly the key steps of the whole developmental process such as lineages decisions, entry in cycle and proliferation, migration and final differentiation, decision to engage in cell death. In order to address these fundamental questions, we will study a commensal microorganism : Lactobacillus casei, and a pathogenic microorganism : Shigella flexneri as model organism, and will develop several novel systems such as reverse genetics of Lactobacilli, development of intestinal crypt models in vitro to study bacterial interactions, and development of a mouse model showing susceptibility to human-specific enteroinvasive pathogens. This project aims at interfacing microbiology, cell biology, and development biology around the concept of microbes manipulating intestinal epithelial homeostaesis. It also includes a strong component of therapeutic development aimed at identifying novel anti-infectious strategies and options to speed up epithelial restitution upon infectious-inflammatory damages."