title: Dissemination of invasive Salmonella via bacterial-induced extrusion of mucosal epithelia.
abstract: Salmonella enterica 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 Salmonella 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 Salmonella hyperreplicating in the cytosol of epithelial cells serves as a reservoir for dissemination. These bacteria are transcriptionally distinct from intravacuolar Salmonella. 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 Salmonella 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 Salmonella for completion of its life cycle, it also provides a mechanistic explanation for the mucosal inflammation that is triggered during Salmonella infection of the gastrointestinal and biliary tracts.
authors.affiliation: Laboratory of Intracellular Parasites and Research Technologies Branch, Microscopy Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA. lknodler@niaid.nih.gov
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Knodler
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Vallance
authors.forename: Jean
authors.initials: J
authors.lastname: Celli
authors.forename: Seth
authors.initials: S
authors.lastname: Winfree
authors.forename: Bryan
authors.initials: B
authors.lastname: Hansen
authors.forename: Marinieve
authors.initials: M
authors.lastname: Montero
authors.forename: Olivia
authors.initials: O
authors.lastname: Steele-Mortimer
mesh_terms: D020170:Caspase 1 / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000382:microbiology*; D005455:Fluorescent Antibody Technique; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology* / Q000502:physiology; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism; D012480:Salmonella Infections / Q000635:transmission*; D019779:Salmonella enterica
chemical_list: D020382:Interleukin-18; D020170:Caspase 1