Uncovering host mechanisms underlying Salmonella persistent infection of intestinal epithelial cells
Dr. Antoine-Emmanuel Saliba
During Salmonella persistence, a population of bacteria can maintain its presence in the intestinal lumen and perpetuate fecal-oral transmission. In the intestinal epithelial cells (IECs) lining up the gastrointestinal tract, Salmonella has two lifestyles, one population living in the ‘Salmonella containing vacuole’ (SCV), a phagosome structure that contains bacteria replication, and another population that hyper-replicates within the nutrient rich cytosol milieu and can be released in the intestinal milieu. Why some mucosal cells are able to restrict Salmonella growth while others are permissive to cytosolic escape of the pathogen remains to be determined. Furthermore, most of our knowledge comes from murine models but human intestinal cell responses to pathogens diverge widely from mice. In preliminary work, we have established an experimental system to study the interaction of Salmonella enterica serovar Typhimurium interaction with human IECs at the single-cell level. We observed that bacterial loads vary widely between different host cell subtypes, and uncovered the bacteria tropism using single-cell RNA-seq. Yet, the molecular decision points that drive this heterogeneity are not understood. We hypothesise that some host cell subtypes in the mucosal layer are vulnerable and lack essential restriction factors to control bacterial expansion. In this project, we propose to identify the molecular pathways underlying the host cell mechanisms underlying Salmonella transition from the SCV to the cytosol. For this purpose, we will combine human organoid intestinal epithelial cells and temporal single-cell genomics. If successful, this project will lead to new interception strategies that inhibit bacterial hyper-replication in the intestinal tract and restrict persistent infections.