Dissemination of invasive <i>Salmonella</i> via bacterial-induced extrusion of mucosal epithelia

<jats:p> <jats:italic>Salmonella enterica</jats:italic> is an intracellular bacterial pathogen that resides and proliferates within a membrane-bound vacuole in epithelial cells of the gut and gallbladder. Although essential to disease, how <jats:italic>Salmonella</jats:italic> escapes from its intracellular niche and spreads to secondary cells within the same host, or to a new host, is not known. Here, we demonstrate that a subpopulation of <jats:italic>Salmonella</jats:italic> hyperreplicating in the cytosol of epithelial cells serves as a reservoir for dissemination. These bacteria are transcriptionally distinct from intravacuolar <jats:italic>Salmonella</jats:italic> . They are induced for the invasion-associated type III secretion system and possess flagella; hence, they are primed for invasion. Epithelial cells laden with these cytosolic bacteria are extruded out of the monolayer, releasing invasion-primed and -competent <jats:italic>Salmonella</jats:italic> into the lumen. This extrusion mechanism is morphologically similar to the process of cell shedding required for turnover of the intestinal epithelium. In contrast to the homeostatic mechanism, however, bacterial-induced extrusion is accompanied by an inflammatory cell death characterized by caspase-1 activation and the apical release of IL-18, an important cytokine regulator of gut inflammation. Although epithelial extrusion is obviously beneficial to <jats:italic>Salmonella</jats:italic> for completion of its life cycle, it also provides a mechanistic explanation for the mucosal inflammation that is triggered during <jats:italic>Salmonella</jats:italic> infection of the gastrointestinal and biliary tracts. </jats:p>