Epithelial Cells Are Sensitive Detectors of Bacterial Pore-forming Toxins

Ratner, Adam J.; Hippe, Karen R.; Aguilar, Jorge L.; Bender, Matthew H.; Nelson, Aaron; Weiser, Jeffrey N.

doi:10.1074/jbc.m511431200

Cited by 159 publications

(196 citation statements)

References 32 publications

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“…In contrast, van Rossum et al (44) showed that pneumolysin promotes clearance of colonized S. pneumoniae in a TLR4-independent manner. The pore-forming effect of pneumolysin activates p38, contributing to the production of proinflammatory cytokines independent of both TLR2 and TLR4 (52). It is logical that pneumolysin-activated p38 leads to increased bacterial clearance by inducing proinflammatory responses independent of TLR.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, 500 ng/ml pneumolysin induces pronounced cytotoxicity (60% by LDH assay) but significantly lower MUC5AC expression. Recently, Ratner et al (52) demonstrated that pneumolysin increases cell membrane permeability by forming membrane pores, and the induced osmotic stress activates p38 independent of both TLR2 and TLR4. Implied therein is that activation of p38 is cytotoxicity-mediated and independent of TLR signaling.…”

Section: Discussionmentioning

confidence: 99%

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A Novel Role for IκB Kinase (IKK) α and IKKβ in ERK-Dependent Up-Regulation of MUC5AC Mucin Transcription by Streptococcus pneumoniae

Lim

Jono

et al. 2007

The Journal of Immunology

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Epithelial cells represent the first line of host innate defense against invading microbes by elaborating a range of molecules involved in pathogen clearance. In particular, epithelial mucins facilitate the mucociliary clearance by physically trapping inhaled microbes. Up-regulation of mucin production thus represents an important host innate defense response against invading microbes. How mucin is induced in upper respiratory Streptococcus pneumoniae infections is unknown. In this study, we show that pneumolysin is required for up-regulation of MUC5AC mucin via TLR4-dependent activation of ERK in human epithelial cells in vitro and in mice in vivo. Interestingly, a “second wave” of ERK activation appears to be important in mediating MUC5AC induction. Moreover, IκB kinase (IKK) α and IKKβ are distinctly involved in MUC5AC induction via an ERK1-dependent, but IκBα-p65- and p100-p52-independent, mechanism, thereby revealing novel roles for IKKs in mediating up-regulation of MUC5AC mucin by S. pneumoniae.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Novel Role for IκB Kinase (IKK) α and IKKβ in ERK-Dependent Up-Regulation of MUC5AC Mucin Transcription by Streptococcus pneumoniae

Lim

Jono

et al. 2007

The Journal of Immunology

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“…Specifically, sublytic concentrations of ␣-toxin from S. aureus, streptolysin O from Streptococcus pyogenes, anthrolysin O from Bacillus anthracis, and pneumolysin from Streptococcus pneumoniae, have been shown to stimulate MAP kinase signaling (Ratner et al, 2006). In addition, pneumolysin, as well listeriolysin O from Listeria monocytogenes and perfringolysin from Clostridium perfringes, have been shown to induce histone modifications within target host cells (Hamon et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, generic membrane damage does not seem to be sufficient to induce Akt dephosphorylation, because the treatment of bladder cells with 0.0025 or 0.025% saponin, which forms relatively large pores in host cell membranes, had no effect on Akt (unpublished data). Interestingly, a recent report indicated that sublytic concentrations of pore-forming toxins can trigger osmotic stress in target epithelial cells (Ratner et al, 2006), and osmotic stress has been shown to modulate Akt activation via effects on phosphatases (Meier et al, 1998). These studies suggest a scenario in which osmotic stress induced by small pore-forming toxins may stimulate host protein phosphatase activation and subsequent dephosphorylation of Akt, a possibility that is supported by our results using dextran (M r ϳ 150,000), which blocks HlyA pores and limits osmotic stress.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of Host Akt/Protein Kinase B Signaling by Bacterial Pore-forming Toxins

Wiles

Dhakal

Eto

et al. 2008

MBoC

102

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Uropathogenic Escherichia coli (UPEC) are the major cause of urinary tract infections (UTIs), and they have the capacity to induce the death and exfoliation of target uroepithelial cells. This process can be facilitated by the pore-forming toxin ␣-hemolysin (HlyA), which is expressed and secreted by many UPEC isolates. Here, we demonstrate that HlyA can potently inhibit activation of Akt (protein kinase B), a key regulator of host cell survival, inflammatory responses, proliferation, and metabolism. HlyA ablates Akt activation via an extracellular calcium-dependent, potassium-independent process requiring HlyA insertion into the host plasma membrane and subsequent pore formation. Inhibitor studies indicate that Akt inactivation by HlyA involves aberrant stimulation of host protein phosphatases. We found that two other bacterial pore-forming toxins (aerolysin from Aeromonas species and ␣-toxin from Staphylococcus aureus) can also markedly attenuate Akt activation in a dose-dependent manner. These data suggest a novel mechanism by which sublytic concentrations of HlyA and other pore-forming toxins can modulate host cell survival and inflammatory pathways during the course of a bacterial infection. INTRODUCTIONStrains of uropathogenic Escherichia coli (UPEC) are the leading cause of urinary tract infections (UTIs), which currently rank among the most common of infectious diseases worldwide (Foxman, 2003;Marrs et al., 2005). During the course of an infection, UPEC can stimulate a number of antimicrobial, proinflammatory, prodifferentiation, proliferation, and host cell death pathways (Mulvey, 2002;Mysorekar et al., 2002). In some cases, UPEC can reportedly modulate these signaling events, causing attenuation of host inflammatory responses and potentiating host apoptotic cascades (Klumpp et al., 2001(Klumpp et al., , 2006Hunstad et al., 2005;Billips et al., 2007). These phenomena have been linked in part to the suppression of nuclear factor-B (NF B) activation and downstream signaling by unknown factors associated with UPEC (Klumpp et al., 2001;Hunstad et al., 2005). By hindering host cytokine expression and ensuing inflammatory responses, UPEC may be better able to establish itself and multiply within the cells and tissues of the urinary tract. At the same time, UPEC-induced death of bladder and renal epithelial cells can compromise mucosal barriers, and it may thereby facilitate bacterial dissemination and persistence within the urinary tract (Mulvey et al., 1998Chen et al., 2003a;Bower et al., 2005;Eto et al., 2006;Mansson et al., 2007b).A key regulator of host cell survival pathways is Akt (also known as protein kinase B, PKB; for recent reviews, see Fayard et al., 2005;Song et al., 2005;Manning and Cantley, 2007). This serine/threonine kinase is able to inhibit apoptosis, and it can help control cell cycle and metabolic pathways, endocytosis and vesicular trafficking, and host inflammatory responses, including the activation of NF B. Akt is activated downstream of phosphoinositide 3-kinase (PI3-kinase), which it...

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“…This latter assessment, although well-accepted, does not, however, detect the sub-lytic activity which underpins the potentially harmful pro-inflammatory activity of the toxin with other cell-types such as neutrophils 11 and epithelial cells. 12 In the current study, we have therefore compared the effects of WT/PLY and Δ6 PLY on several Ca 2+ -dependent pro-inflammatory activities of human neutrophils in vitro.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the interactions of the pneumolysoid, Δ6 PLY, with human neutrophils in vitro

Cockeran

Steel

Theron

et al. 2011

Vaccine

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The pneumolysin toxoid, Δ6 PLY, is a prototype pneumococcal protein vaccine candidate. However, its potentially detrimental residual proinflammatory interactions with human neutrophils are unknown. In the current study the effects of the toxoid (8-1000 ng/ml) have been compared with those of wild-type pneumolysin (WT/PLY, 8 ng/ml) on neutrophil cytosolic Ca 2+ fluxes, generation of leukotriene B 4 (LTB 4 ), and release of matrix metalloproteinase-9 (MMP-9), using spectrofluorimetric, and ELISA procedures (LTB 4 and MMP-9) respectively. Exposure of neutrophils to WT/PLY resulted in influx of Ca 2+ and significant (P<0.05) release of MMP-9 and generation of LTB 4 . However, treatment of the cells with Δ6 PLY at concentrations of up to 1000 ng/ml had only trivial effects on Ca 2+ influx and no effects on either release of MMP-9 or LTB 4 production. The observed absence of pro-inflammatory interactions of Δ6 PLY with neutrophils is clearly an important property of this pneumococcal protein vaccine candidate.

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Epithelial Cells Are Sensitive Detectors of Bacterial Pore-forming Toxins

Cited by 159 publications

References 32 publications

A Novel Role for IκB Kinase (IKK) α and IKKβ in ERK-Dependent Up-Regulation of MUC5AC Mucin Transcription by Streptococcus pneumoniae

A Novel Role for IκB Kinase (IKK) α and IKKβ in ERK-Dependent Up-Regulation of MUC5AC Mucin Transcription by Streptococcus pneumoniae

Inactivation of Host Akt/Protein Kinase B Signaling by Bacterial Pore-forming Toxins

Characterization of the interactions of the pneumolysoid, Δ6 PLY, with human neutrophils in vitro

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