A Reservoir for Fecal Shedding of Salmonella Typhimurium in the Cytosol of Intestinal Epithelial Cells

Persistence and intermittent fecal shedding, hallmarks of Salmonella infections, are critical for fecal-oral transmission. In the intestine, Salmonella enterica serovar Typhimurium (STm) actively invade intestinal epithelial cells and survive in the Salmonella-containing vacuole (SCV) and the cell cytosol. Cytosolic STm replicate rapidly, express invasion factors, and induce extrusion of infected epithelial cells into the intestinal lumen. Here, we engineered STm that self-destruct in the cytosol, but replicate normally in the SCV, to examine the role of cytosolic STm in persistence and shedding. Intestinal expansion of these STm was impaired in an acute enterocolitis infection model, while fecal shedding of STm was eliminated in a mouse model of persistent infection. Thus, the cytosol is a critical reservoir of intestinal STm that maintains the high luminal density required for fecal shedding and transmission. This reveals the requirement of an intracellular niche for pathogen transmission and presents new targets for disease control.