<i>Salmonella typhimurium</i>transcytoses flagellin via an SPI2-mediated vesicular transport pathway

Lyons, Sean; Wang, Lixin; Casanova, James E.; Sitaraman, Shanthi V.; Merlin, Didier; Gewirtz, Andrew T.

doi:10.1242/jcs.01500

Cited by 54 publications

(46 citation statements)

References 36 publications

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“…Transcytosed flagellin then triggers the production of proinflammatory cytokines via the activation of Toll-like receptor 5, thereby contributing to the intestinal inflammation known to be caused by S. typhimurium. 48 In agreement with what we report here, Lyons et al show that flagellin is incorporated in vesicles and trancytosed across the epithelium without being dependent on bacterial invasion. In addition, several bacterial species are known to interact with b1-integrin 49 and some species, such as Listeria, share some common strategies for cellular uptake.…”

Section: Discussionsupporting

confidence: 93%

Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis

Ragnarsson

Schoultz

Gullberg

et al. 2008

Laboratory Investigation

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Crohn's disease is characterized by a defect in intestinal barrier function, where bacteria are considered the most important inflammation-driving factor. Enteric bacteria, including E. coli and Yersinia spp, affect tight junctions in enterocytes, but little is known about bacterial effects on the transcellular pathway. Our objective was to study the short-term effects of Y. pseudotuberculosis on uptake of nanoparticles across human villus epithelium. Monolayers of human colon epitheliumderived Caco-2 cells and biopsies of normal human ileum were studied after 2 h exposure to Y. pseudotuberculosis expressing (inv þ ) or lacking (invÀ) the bacterial adhesion molecule, invasin. Transepithelial transport of fluorescent nanoparticles (markers of transcytosis) was quantified by flow cytometry, and mechanisms explored by using inhibitors of endocytosis. Epithelial expressions of b1-integrin and particle uptake pathways were studied by confocal microscopy. The paracellular pathway was assessed by electrical resistance (TER), mannitol flux, and expression of tight junction proteins occludin and caludin-4 by confocal microscopy. Inv þ Y. pseudotuberculosis adhered to the apical surface of epithelial cells and induced transcytosis of exogenous nanoparticles across Caco-2 monolayers (30-fold increase, Po0.01) and ileal mucosa (268 ± 47% of control; Po0.01), whereas invÀ bacteria had no effect on transcytosis. The transcytosis was concentration-, particle size-and temperature-dependent, and possibly mediated via macropinocytosis. Y. pseudotuberculosis also induced apical expression of b1-integrin on epithelial cells. A slight drop in TER was seen after exposure to inv þ Y. pseudotuberculosis, whereas mannitol flux and tight junction protein expression was unchanged. In summary, Y. pseudotuberculosis induced apical expression of b1-integrin and stimulated uptake of nanoparticles via invasindependent transcytosis in human intestinal epithelium. Our findings suggest that bacterial factors may initiate transcytosis of luminal exogenous particles across human ileal mucosa, thus presenting a novel mechanism of intestinal barrier dysfunction.

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Section: Discussionsupporting

confidence: 93%

Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis

Ragnarsson

Schoultz

Gullberg

et al. 2008

Laboratory Investigation

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“…The translocation of flagellin into the macrophage cytosol observed by these investigators is mechanistically distinct from the cytosolic translocation of flagellin reported here since in the previous study, flagellin was localized to membrane-bound vacuoles rather then being free in the cytosol. Further, flagellin transcytosis was dependent on a third T3SS, encoded on Salmonella pathogenicity island 2 (SPI-2 T3SS), and was independent of the SPI-1 T3SS (39). Taken together, these results show that flagellin interacts with the innate immune system at multiple levels to induce proinflammatory responses during Salmonella infection.…”

Section: Discussionmentioning

confidence: 78%

“…Gewirtz and colleagues (39) showed that S. Typhimurium colonizing the apical side of epi-thelial monolayers is able to mediate flagellin transcytosis to the basolaterial aspect. The translocation of flagellin into the macrophage cytosol observed by these investigators is mechanistically distinct from the cytosolic translocation of flagellin reported here since in the previous study, flagellin was localized to membrane-bound vacuoles rather then being free in the cytosol.…”

Section: Discussionmentioning

confidence: 99%

Injection of Flagellin into the Host Cell Cytosol by Salmonella enterica Serotype Typhimurium

Sun¹,

Rolán²,

Tsolis³

2007

Journal of Biological Chemistry

156

150

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Bacterial flagella are filamentous appendages on the cell surface that mediate bacterial motility. The filament of the flagellum is composed of ϳ20,000 flagellin subunits (1). Flagellin monomers of many bacterial species function as pathogen-associated molecular patterns and can be detected by host cells using both surface-localized toll-like receptor 5 (TLR5) 2 and cytosolic Nod-like receptors (2-6). The interaction of flagellin with TLR5 at the cell surface has been characterized in detail, identifying the structural basis for the TLR5-flagellin interaction (7,8). TLR5 sensing has been shown to be important in Legionnaires disease, a respiratory tract infection caused by the bacterium Legionella pneumophila, since human TLR5 polymorphisms correlated with disease susceptibility (7,8). In the intestine, TLR5 localizes to the basolateral surface of enterocytes and to CD11c ϩ lamina propria dendritic cells (9, 10). In these locations, TLR5 is thought to be involved in sensing a breach of the intestinal mucosa by enteroinvasive pathogens, triggering an inflammatory response that limits systemic spread of the bacteria (11).In addition to sensing by TLRs, flagellin was recently shown to be sensed by two different Nod-like receptors, Ipaf and Birc1e (also known as Naip5) (2, 4 -6, 12). Ipaf transmits a proinflammatory signal in response to flagellin by activating the inflammasome, resulting in caspase 1-dependent activation of Il-1␤, which is accompanied by cell death (pyroptosis) (13-17). Birc1e/Naip5 signals in response to flagellin, restricting intracellular growth of L. pneumophila by antagonizing the ability of the bacterium to avoid fusion with lysosomes and form a replicative phagosome (18). Several lines of evidence suggest that pathogens residing in a membrane-bound compartment of the cell, such as L. pneumophila and S. Typhimurium (Salmonella enterica serotype Typhimurium), may release flagellins from their vacuole into the host cytosol, which triggers signaling via Ipaf and Birc1e. First, S. Typhimurium and L. pneumophila mutants lacking flagellin elicit reduced caspase activation, IL-1␤ secretion, and cytotoxicity in macrophages (2, 4 -6, 19). Second, mutants of S. Typhimurium lacking the SPI-1 T3SS and L. pneumophila mutants lacking a functional Type IV secretion system (T4SS) fail to trigger Ipaf-dependent signaling (4,5,19). Third, introduction of purified flagellins into the cytosol of macrophages using pore-forming toxins or detergents or by heterologous expression in Escherichia coli expressing listeriolysin O triggers caspase-1 activation and IL-1␤ activation by an Ipaf-dependent mechanism (2, 4 -6, 20).Although injection of effector proteins into host cells by the S. Typhimurium SPI-1 T3SS has been visualized microscopically (21, 22), it has not yet been demonstrated that in infected cells, bacteria are able to translocate flagellin from a membrane-bound compartment into the cytosol. In this report, we show that S. Typhimurium translocates flagellin into the cytosol of infected cells by a process t...

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“…SPI-2-encoded proteins appear to play a role in the transcytosis of flagellin subunits across epithelial cells, a process that is proposed to elicit proinflammatory responses by activation of basolateral Toll-like receptor 5 (Lyons et al 2004). Studies in the bovine ileal loop model established a role for the S. Typhimurium flagella master regulator flhD in fluid secretion and neutrophil recruitment (Schmitt et al 2001).…”

Section: Molecular Mechanisms Underlying the Induction Of Enteritis Imentioning

confidence: 99%

Molecular insights into farm animal and zoonoticSalmonellainfections

Stevens

Humphrey

Maskell

2009

Phil. Trans. R. Soc. B

147

102

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Salmonella enterica is a facultative intracellular pathogen of worldwide importance. Infections may present in a variety of ways, from asymptomatic colonization to inflammatory diarrhoea or typhoid fever depending on serovar-and host-specific factors. Human diarrhoeal infections are frequently acquired via the food chain and farm environment by virtue of the ability of selected non-typhoidal serovars to colonize the intestines of food-producing animals and contaminate the avian reproductive tract and egg. Colonization of reservoir hosts often occurs in the absence of clinical symptoms; however, some S. enterica serovars threaten animal health owing to their ability to cause acute enteritis or translocate from the intestines to other organs causing fever, septicaemia and abortion. Despite the availability of complete genome sequences of isolates representing several serovars, the molecular mechanisms underlying Salmonella colonization, pathogenesis and transmission in reservoir hosts remain ill-defined. Here we review current knowledge of the bacterial factors influencing colonization of food-producing animals by Salmonella and the basis of host range, differential virulence and zoonotic potential.

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Salmonella typhimuriumtranscytoses flagellin via an SPI2-mediated vesicular transport pathway

Cited by 54 publications

References 36 publications

Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis

Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis

Injection of Flagellin into the Host Cell Cytosol by Salmonella enterica Serotype Typhimurium

Molecular insights into farm animal and zoonoticSalmonellainfections

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