Host-pathogen interactions have recently received much attention. Yet, a more comprehensive understanding of these interplays should provide fundamental advances in biology and help generating new therapeutics. The intracellular bacterium Listeria monocytogenes has emerged as an exceptional model organism to address key questions in biology such as actin-based motility, phagocytosis and post-transcriptional regulation. We will exploit our deep knowledge of Listeria and use this bacterium as a model to explore new landmarks in biology.In that aim, we will analyze several aspects of the infectious process, in a spatio-temporal fashion, at the bacteria, cell, tissue and host levels. Specifically, we will 1) search and analyze the function of new non-coding RNAs involved in virulence, and of new RNA-mediated regulations; 2) investigate new facets of bacterial entry and cell-to-cell spread in particular the role of uncharacterized cytoskeletal components, septins; 3) address the role of mitochondria and their dynamics in infection; 4) systematically analyze post-translational modifications during infection, starting with SUMOylation, a reversible modification and proteolysis, an irreversible one; 5) investigate chromatin remodeling upon infection; 6) characterize new virulence factors identified by their interaction with known signaling components or cellular sensors, by post genomics or by their effect on cellular responses analyzed herein ; 7) investigate further the intestinal phase of Listeria infection by analyzing in the germ-free transgenic mouse that we generated, the impact of commensals on Listeria (growth and transcription including non-coding RNAs) and on the intestinal tissue (histology and transcription of genes and microRNAs).Our main goal is to improve significantly our understanding of bacterial infections, by discovering important new concepts in microbiology, cell biology and infection biology thereby opening new avenues for further research.