In Europe acute food-borne diseases are a frequent cause of morbidity, but are not usually a source of high mortality, with one exception listeriosis, which is a leading cause of deaths due to food-transmitted bacterial pathogens. When premature mortality i.e., the number of potential life years lost to infections, is used as a measure of public health, listeriosis prevention ranks as the area with the highest priority for health improvement and prevention, followed by Norovirus and Shiga-toxin producing E. coli. Listeriosis can present clinically as septicemia, meningitis, with infections leading to abortion, neonatal infection and fetal death. The causative organism, Listeria monocytogenes (Lm), is a Gram-positive, ubiquitous bacterium that can breach intestinal, blood-brain and placental barriers. It accounts for > 10% of all community-acquired bacterial meningitis and is now a common occurrence in patients receiving biotherapies and immunosuppressive drugs. The clinical course of listeriosis is usually sub-acute with few, if any, specific symptoms observed until Lm reaches the central nervous system and/or the fetal-placental barrier. Thus Lm induces little inflammation in the host, both at the intestinal level and systemically, unlike other invasive foodborne pathogens such as Salmonella. Here we propose that anti-inflammatory responses mediated by bacterial factors are an essential component of its pathogenic potential and wish to identify and characterize those bacterial factors involved in subversion of host processes that enable infectious “stealth”. We will use time-resolved chemi-genomic approaches to study post-translational modifications (PTMs) of the host cell. Quantitative mass spectroscopy (iTRAQ/UPLC-Orbitrap-MS) will be used to analyze changes in bacterial and host cell proteins. Metal-tagging electron microscopy will be used to map the position of cell wall, membrane and cytosolic proteins in bacteria. Whole genome sequencing and RNAseq will be used to examine and characterize bacterial mutants. We will use in vivo dynamic tissue imaging, fluorescence-activated cell sorting, mouse genetics, and transcriptomics to identify host cell proteins involved in anti-inflammatory activities. The results of this proposal will shed light on the pathophysiology of one of the deadliest foodborne pathogen. These insights will promote translation into clinically relevant results in the field of mucosal immunology, vaccinology and inflammatory diseases.