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Dissemination of invasive Salmonella via bacterial-induced extrusion of mucosal epithelia

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.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 09/2010; 107(41):17733-8. DOI: 10.1073/pnas.1006098107
Source: PubMed

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.

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    • "Typhimurium can escape the SCV and hyper-replicate in the cytosol (Knodler et al., 2010). Cytosolic Salmonella is also motile but its motility is mediated by flagellar structures (Knodler et al., 2010) and therefore will not be reviewed here. "
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    • "Intraepithelial NAIP/NLRC4 Restricts S.Tm Load gallbladder (Knodler et al., 2010; Laughlin et al., 2014), and indicate that expulsion of infected epithelial cells may restrict the intraepithelial S.Tm load. Quantitative analysis showed that S.Tm-G + levels within expelled epithelial cells (Figure 2A, black symbols) already at $12 hr p.i. reached comparable levels to those within the mucosal tissue (Figure 2A, red dashed lines). "
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    • "Typhimurium occupies two distinct niches within human epithelial cells (Knodler et al., 2010; Malik-Kale et al., 2012). Epithelial cells containing cytosolic bacteria die by pyroptosis, ultimately being shed from the monolayer (Knodler et al., 2010). Does caspase-4 promote pyroptotic death of infected IECs? "
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