Caspase-1 Activation of Lipid Metabolic Pathways in Response to Bacterial Pore-Forming Toxins Promotes Cell Survival

Gurcel, Laure; Abrami, Laurence; Girardin, Stephen E.; Tschopp, Jürg; Goot, F. Gisou van der

doi:10.1016/j.cell.2006.07.033

Cited by 461 publications

(448 citation statements)

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“…Infection with A. hydrophila induces caspase-1 activation, IL-1b release and pyroptosis It has been reported that aerolysin produced by A. salmonicida induces caspase-1 activation in CHO cells [20,21]. However, whether whole bacterial infection by A. hydrophila leads to caspase-1 activation in macrophages has not been elucidated.…”

Section: Resultsmentioning

confidence: 99%

“…1). This latter finding further supports our notion that A. hydrophila also induces caspase-1-independent cell death.Caspase-1 activation is mediated by aerolysin, HlyA and multifunctional RtxA Purified aerolysin has been shown to induce caspase-1 activation and an aerolysin-deficient A. trota mutant was incapable of inducing caspase-1 activation in human fibroblasts [21]. However, an A. hydrophila aerolysin mutant (DaerA) remained capable of activating caspase-1 and IL-1b processing/secretion in infected BMM (Fig.…”

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confidence: 96%

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Cytotoxins of the human pathogen Aeromonas hydrophila trigger, via the NLRP3 inflammasome, caspase‐1 activation in macrophages

et al. 2010

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Aeromonas hydrophila is a Gram-negative pathogen that causes serious infectious disease in humans. A. hydrophila induces apoptosis in infected macrophages, but the host proinflammatory responses triggered by macrophage death are largely unknown. Here, we demonstrate that the infection of mouse macrophages with A. hydrophila triggers the activation of caspase-1 and release of IL-1b. Caspase-1 activation was abrogated in macrophages deficient in Nod-like receptor family, pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), but not NLR family, CARD domain containing 4 (NLRC4). The activation of the NLRP3 inflammasome was mediated by three cytotoxins (aerolysin, hemolysin and multifunctional repeat-in-toxin) produced by A. hydrophila. Our results indicated that the NLRP3 inflammasome senses A. hydrophila infection through the action of bacterial cytotoxins.Key words: Aeromonas . Caspase-1 . Nod-like receptor Supporting Information available online IntroductionThe genus Aeromonas is responsible for a significant number of animal and human infections. Aeromonas are opportunistic human pathogens that can cause intestinal and extraintestinal, wound, soft tissue, skin, and blood infections and septicemia. The most common human disease associated with Aeromonas infection is gastroenteritis with diarrhea symptoms. Among the 21 species that have been differentiated based on DNA-DNA hybridization, A. caviae, A. veronii biotype sobria and A. hydrophila are most commonly associated with human infections and account for more than 85% of all clinical isolates [1,2].Recently, it has been reported that infection with A. hydrophila induces apoptosis in macrophages [3,4]. Although the cytotoxicity by the bacteria is believed to enable the bacteria to evade eradication and clearance by the macrophages, the host proinflammatory responses triggered by the death of the macrophages remain unknown.Induction of apoptosis is considered a virulence mechanism of pathogenic bacteria that can cause tissue damage and Here, we investigated the cell death of macrophages infected with A. hydrophila and demonstrate that the bacteria cause pyroptosis with caspase-1 activation via the NLRP3 inflammasome. Aerolysin, hemolysin (HlyA) and multifunctional repeat-intoxin (RtxA) produced by A. hydrophila are required to elicit the NLRP3 inflammasome and necrotic cell death. We identify the essential bacterial and host factors for eliciting caspase-1 activation and proinflammatory responses. SHORT COMMUNICATION Results and discussionInfection with A. hydrophila induces caspase-1 activation, IL-1b release and pyroptosis It has been reported that aerolysin produced by A. salmonicida induces caspase-1 activation in CHO cells [20,21]. However, whether whole bacterial infection by A. hydrophila leads to caspase-1 activation in macrophages has not been elucidated. We examined caspase-1 activation in infected primary mouse BMderived macrophages (BMM) and observed that BMM infected with WT strai...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 96%

Cytotoxins of the human pathogen Aeromonas hydrophila trigger, via the NLRP3 inflammasome, caspase‐1 activation in macrophages

et al. 2010

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“…Our results indicate that pore formation by HlyA in the membrane of target bladder epithelial cells is required to inactivate Akt. Pores formed by HlyA stimulate both Ca 2ϩ fluxes and decreases in cytosolic K ϩ levels, events that can significantly affect cellular signaling processes (Uhlen et al, 2000;Gurcel et al, 2006). However, changes in intracellular Ca 2ϩ or K ϩ concentrations did not seem to affect HlyA-mediated inactivation of Akt.…”

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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“…In addition to the processing of pro-IL-1b/IL-18 and induction of pyroptosis, caspase-1 has been shown to support the survival of cells in response to membrane damage caused by pore-forming toxins derived from invasive bacteria (Gurcel et al 2006). In response to stimulation with aerolysin from Aeromonas hydrophila, caspase-1 is activated by K ?…”

Section: Membrane Stabilizationmentioning

confidence: 99%

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

Uchiyama

Tsutsui

2014

Arch. Immunol. Ther. Exp.

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Caspase-1 Activation of Lipid Metabolic Pathways in Response to Bacterial Pore-Forming Toxins Promotes Cell Survival

Cited by 461 publications

References 57 publications

Cytotoxins of the human pathogen Aeromonas hydrophila trigger, via the NLRP3 inflammasome, caspase‐1 activation in macrophages

Cytotoxins of the human pathogen Aeromonas hydrophila trigger, via the NLRP3 inflammasome, caspase‐1 activation in macrophages

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

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

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