Knodler, L. A. et al. Dissemination of invasive Salmonella via bacterial-induced extrusion of mucosal epithelia. Proc. Natl Acad. Sci. USA 107, 17733-17738

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: 9.67). 09/2010; 107(41):17733-8. DOI: 10.1073/pnas.1006098107
Source: PubMed


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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    ABSTRACT: Entry into host cells and intracellular persistence by invasive bacteria are tightly coupled to the ability of the bacterium to disrupt the eukaryotic cytoskeletal machinery. Herein we review the main strategies used by three intracellular pathogens to harness key modulators of the cytoskeleton. Two of these bacteria, namely Listeria monocytogenes and Salmonella enterica serovar Typhimurium, exhibit quite distinct intracellular lifestyles, and therefore, provide a comprehensive panel for the understanding of the intricate bacteria-cytoskeleton interplay during infections. The emerging intracellular pathogen Vibrio parahaemolyticus is depicted as a developing model for the uncovering of novel mechanisms used to hijack the cytoskeleton. This article is protected by copyright. All rights reserved.
    Cellular Microbiology 12/2014; 17(2). DOI:10.1111/cmi.12399 · 4.92 Impact Factor
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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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    ABSTRACT: The gut mucosal epithelium separates the host from the microbiota, but enteropathogens such as Salmonella Typhimurium (S.Tm) can invade and breach this barrier. Defenses against such acute insults remain incompletely understood. Using a murine model of Salmonella enterocolitis, we analyzed mechanisms limiting pathogen loads in the epithelium during early infection. Although the epithelium-invading S.Tm replicate initially, this intraepithelial replicative niche is restricted by expulsion of infected enterocytes into the lumen. This mechanism is compromised if inflammasome components (NAIP1-6, NLRC4, caspase-1/-11) are deleted, or ablated specifically in the epithelium, resulting in ∼100-fold higher intraepithelial loads and accelerated lymph node colonization. Interestingly, the cytokines downstream of inflammasome activation, interleukin (IL)-1α/β and IL-18, appear dispensable for epithelial restriction of early infection. These data establish the role of an epithelium-intrinsic inflammasome, which drives expulsion of infected cells to restrict the pathogen's intraepithelial proliferation. This may represent a general defense mechanism against mucosal infections.
    Cell host & microbe 08/2014; 16(2):237-248. DOI:10.1016/j.chom.2014.07.001 · 12.33 Impact Factor
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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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    ABSTRACT: Inflammasome-mediated host defenses have been extensively studied in innate immune cells. Whether inflammasomes function for innate defense in intestinal epithelial cells, which represent the first line of defense against enteric pathogens, remains unknown. We observed enhanced Salmonella enterica serovar Typhimurium colonization in the intestinal epithelium of caspase-11-deficient mice, but not at systemic sites. In polarized epithelial monolayers, siRNA-mediated depletion of caspase-4, a human ortholog of caspase-11, also led to increased bacterial colonization. Decreased rates of pyroptotic cell death, a host defense mechanism that extrudes S. Typhimurium-infected cells from the polarized epithelium, accounted for increased pathogen burdens. The caspase-4 inflammasome also governs activation of the proinflammatory cytokine, interleukin (IL)-18, in response to intracellular (S. Typhimurium) and extracellular (enteropathogenic Escherichia coli) enteric pathogens, via intracellular LPS sensing. Therefore, an epithelial cell-intrinsic noncanonical inflammasome plays a critical role in antimicrobial defense at the intestinal mucosal surface.
    Cell host & microbe 08/2014; 16(2):249-256. DOI:10.1016/j.chom.2014.07.002 · 12.33 Impact Factor
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