Toxins

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894 KiB

Open AccessArticle

Reduction of Streptolysin O (SLO) Pore-Forming Activity Enhances Inflammasome Activation

by Peter A. Keyel, Robyn Roth, Wayne M. Yokoyama, John E. Heuser and Russell D. Salter

Toxins 2013, 5(6), 1105-1118; https://doi.org/10.3390/toxins5061105 - 6 Jun 2013

Cited by 43 | Viewed by 9587

Abstract

Pore-forming toxins are utilized by bacterial and mammalian cells to exert pathogenic effects and induce cell lysis. In addition to rapid plasma membrane repair, macrophages respond to pore-forming toxins through activation of the NLRP3 inflammasome, leading to IL-1β secretion and pyroptosis. The structural [...] Read more.

Pore-forming toxins are utilized by bacterial and mammalian cells to exert pathogenic effects and induce cell lysis. In addition to rapid plasma membrane repair, macrophages respond to pore-forming toxins through activation of the NLRP3 inflammasome, leading to IL-1β secretion and pyroptosis. The structural determinants of pore-forming toxins required for NLRP3 activation remain unknown. Here, we demonstrate using streptolysin O (SLO) that pore-formation controls IL-1β secretion and direct toxicity. An SLO mutant incapable of pore-formation did not promote direct killing, pyroptosis or IL-1β production. This indicated that pore formation is necessary for inflammasome activation. However, a partially active mutant (SLO N402C) that was less toxic to macrophages than wild-type SLO, even at concentrations that directly lysed an equivalent number of red blood cells, enhanced IL-1β production but did not alter pyroptosis. This suggests that direct lysis may attenuate immune responses by preventing macrophages from successfully repairing their plasma membrane and elaborating more robust cytokine production. We suggest that mutagenesis of pore-forming toxins represents a strategy to enhance adjuvant activity. Full article

(This article belongs to the Special Issue Pore-Forming Toxins)

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Figure 1

Figure 1
Pore formation of streptolysin O (SLO) mutants. Blebbing was induced (A,B,D–G), or not induced (C) in CHO cells by treatment with 25 mM paraformaldehyde and 2 mM DTT. Subsequently, no SLO (A), 10,000 U/mL SLO C530A (B,D,E) or an equivalent mass of SLO N402E (F) or SLO N402C (G,H) were added to the cells, and the cells were prepared for EM. Alternatively, living CHO cells were treated with 125 U/mL SLO for 5 min (C) and prepared for EM. Arrowheads indicate strands formed by SLO N402C. Scale bar = 1 μm (A,B) or 50 nm (C–H). Full article ">Figure 2
SLO N402C shows reduced direct toxicity. LPS-primed bone marrow-derived macrophages (BMDM)from B6 or Casp1−/− mice were treated with the indicated SLO mutants at the indicated concentrations for 5 min (A,B) or 30 min (C,D) and PI uptake analyzed by FACS. The percentage of PIhigh, or dead cells (A,C) or percentage of PIl°w, or transiently permeabilized cells (B,D) are shown. The graphs display the average ± SEM of 3 independent experiments. * indicates p < 0.05, ** indicates p < 0.01 and *** indicates p < 0.001 for comparisons between wild type and N402C SLO (A,B) or comparisons between B6 and Casp1−/− BMDM (C,D). Full article ">Figure 3
SLO C530A/N402C also shows reduced toxicity. LPS-primed BMDM were treated with the indicated SLO mutants at the indicated concentrations (1000 U/mL for C) for 5 min or 30 min in the absence (A–C) or presence (C) of 50 mM KCl and PI uptake analyzed by FACS. The percentage of PIhigh, or dead cells (A,C) or percentage of PIl°w, or transiently permeabilized cells (B,C) are shown. The graphs display the average ± SEM of 3 independent experiments. * indicates p < 0.05, ** indicates p < 0.01 and *** indicates p < 0.001. Full article ">Figure 4
SLO N402C enhances IL-1β release. (A–E) LPS-primed B6 or Casp1−/− BMDM were treated with the indicated inhibitors and concentrations of SLO mutants for 30 min, or the controls nigericin or nothing. Supernatants were harvested and assayed for IL-1β levels by ELISA. (F) LPS-primed BMDM were treated as indicated with controls or 2000 U/mL of each SLO mutant for 30 min. Supernatants were collected and TCA precipitated, while cells were lysed in SDS-sample buffer. Lysates and supernatants were resolved by SDS-PAGE, transferred to PVDF and probed with anti-IL-1β monoclonal antibody 3ZD and anti-actin monoclonal antibody. The graphs display the average of 4 independent experiments ± SEM, while the blot shows one representative experiment of 5. * indicates p < 0.05 and ** indicates p < 0.01. Full article ">

6923 KiB

Open AccessArticle

Multiple Membrane Interactions and Versatile Vesicle Deformations Elicited by Melittin

by Tomoyoshi Takahashi, Fumimasa Nomura, Yasunori Yokoyama, Yohko Tanaka-Takiguchi, Michio Homma and Kingo Takiguchi

Toxins 2013, 5(4), 637-664; https://doi.org/10.3390/toxins5040637 - 17 Apr 2013

Cited by 37 | Viewed by 10115

Abstract

Melittin induces various reactions in membranes and has been widely studied as a model for membrane-interacting peptide; however, the mechanism whereby melittin elicits its effects remains unclear. Here, we observed melittin-induced changes in individual giant liposomes using direct real-time imaging by dark-field optical [...] Read more.

Melittin induces various reactions in membranes and has been widely studied as a model for membrane-interacting peptide; however, the mechanism whereby melittin elicits its effects remains unclear. Here, we observed melittin-induced changes in individual giant liposomes using direct real-time imaging by dark-field optical microscopy, and the mechanisms involved were correlated with results obtained using circular dichroism, cosedimentation, fluorescence quenching of tryptophan residues, and electron microscopy. Depending on the concentration of negatively charged phospholipids in the membrane and the molecular ratio between lipid and melittin, melittin induced the “increasing membrane area”, “phased shrinkage”, or “solubilization” of liposomes. In phased shrinkage, liposomes formed small particles on their surface and rapidly decreased in size. Under conditions in which the increasing membrane area, phased shrinkage, or solubilization were mainly observed, the secondary structure of melittin was primarily estimated as an α-helix, β-like, or disordered structure, respectively. When the increasing membrane area or phased shrinkage occurred, almost all melittin was bound to the membranes and reached more hydrophobic regions of the membranes than when solubilization occurred. These results indicate that the various effects of melittin result from its ability to adopt various structures and membrane-binding states depending on the conditions. Full article

(This article belongs to the Special Issue Pore-Forming Toxins)

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826 KiB

Open AccessArticle

P2X Receptor-Dependent Erythrocyte Damage by α-Hemolysin from Escherichia coli Triggers Phagocytosis by THP-1 Cells

by Steen K. Fagerberg, Marianne Skals, Jens Leipziger and Helle A. Praetorius

Toxins 2013, 5(3), 472-487; https://doi.org/10.3390/toxins5030472 - 5 Mar 2013

Cited by 16 | Viewed by 7471

Abstract

The pore-forming exotoxin α-hemolysin from E. coli causes a significant volume reduction of human erythrocytes that precedes the ultimate swelling and lysis. This shrinkage results from activation of Ca²⁺-sensitive K⁺ (K_Ca3.1) and Cl⁻ channels (TMEM16A) and reduced [...] Read more.

The pore-forming exotoxin α-hemolysin from E. coli causes a significant volume reduction of human erythrocytes that precedes the ultimate swelling and lysis. This shrinkage results from activation of Ca²⁺-sensitive K⁺ (K_Ca3.1) and Cl⁻ channels (TMEM16A) and reduced functions of either of these channels potentiate the HlyA-induced hemolysis. This means that Ca²⁺-dependent activation of K_Ca3.1 and TMEM16A protects the cells against early hemolysis. Simultaneous to the HlyA-induced shrinkage, the erythrocytes show increased exposure of phosphatidylserine (PS) in the outer plasma membrane leaflet, which is known to be a keen trigger for phagocytosis. We hypothesize that exposure to HlyA elicits removal of the damaged erythrocytes by phagocytic cells. Cultured THP-1 cells as a model for erythrocytal phagocytosis was verified by a variety of methods, including live cell imaging. We consistently found the HlyA to very potently trigger phagocytosis of erythrocytes by THP-1 cells. The HlyA-induced phagocytosis was prevented by inhibition of K_Ca3.1, which is known to reduce PS-exposure in human erythrocytes subjected to both ionomycin and HlyA. Moreover, we show that P2X receptor inhibition, which prevents the cell damages caused by HlyA, also reduced that HlyA-induced PS-exposure and phagocytosis. Based on these results, we propose that erythrocytes, damaged by HlyA-insertion, are effectively cleared from the blood stream. This mechanism will potentially reduce the risk of intravascular hemolysis. Full article

(This article belongs to the Special Issue Pore-Forming Toxins)

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Figure 1
Phagocytosis of erythrocytes by THP-1 cells. (A) shows the time-course of phagocytosis of a single erythrocyte by a THP-1 cell grown on a coverslip but DIC; (B) shows corresponding pictures obtained by DIC or low light fluorescence of calcein-loaded human erythrocytes phagocytosed by a THP-1 cell grown on a coverslip. Full article ">Figure 2
The effect of HlyA on erythrocyte phagocytosis by THP-1 cells. Differential count of THP-1 cells that have taken up the fluorescent probe calcein from calcein-AM loaded erythrocytes, either exposed to HlyA (10 min) at a concentration that cause 50% hemolysis after 60 min or ionomycin (1 μM) as a positive control. (A) presents images of the phagocytosis of the control erythrocytes (arrows show erythrocytes, lines show boundaries of two THP-1 cells) and erythrocytes exposed to HlyA (arrow show erythrocytes, arrowheads THP-1 cells); (B) shows the summarized data as mean ± SEM, n = 8). Asterisk denominates statistically the significance of the control with a p-value below 0.05. Full article ">Figure 3
The effect of the KCa3.1 inhibitor (TRAM34) on the HlyA-induced phagocytosis of human erythrocytes by THP-1 cells. (A) shows representative images of the HlyA-induced phagocytosis of human erythrocytes by THP-1 cells in the absence or presence of TRAM34 (10 μM). The arrow shows an erythrocyte the arrowheads show THP-1 cells; (B) shows the summarized data as mean ± SEM, n = 8. The asterisk shows a statistical significance from HlyA with a p-value below 0.05. Full article ">Figure 4
The effect of P2 receptor antagonists on HlyA-induced phosphatidylserine exposure of human erythrocytes. Human erythrocytes were exposed to HlyA at a very low concentration that did not cause any detectable lysis after 10 min. The HlyA-induced PS exposure measured as FITC-conjugated annexin V binding was prevented by inhibition of P2 receptor antagonists: MRS2159 (250 μM), PPADS (500 μM), BBG (3 μM) and oxATP (500 μM). The graph shows mean ± SEM, n = 5–7, asterisks illustrate a statistically significant difference from the control with a p-value below 0.05. Full article ">Figure 5
P2X receptor activation modulates HlyA-induced phagocytosis by THP-1 cells The figure shows the effect of oxATP 500 μM on the HlyA-induced erythrocyte phagocytosis by THP-1 cells. Bars show mean ± SEM, n = 6, asterisks indicate p < 0.05. Full article ">

Review

Jump to: Research

917 KiB

Open AccessReview

Earthworm-Derived Pore-Forming Toxin Lysenin and Screening of Its Inhibitors

by Neelanun Sukumwang and Kazuo Umezawa

Toxins 2013, 5(8), 1392-1401; https://doi.org/10.3390/toxins5081392 - 8 Aug 2013

Cited by 17 | Viewed by 9455

Abstract

Lysenin is a pore-forming toxin from the coelomic fluid of earthworm Eisenia foetida. This protein specifically binds to sphingomyelin and induces erythrocyte lysis. Lysenin consists of 297 amino acids with a molecular weight of 41 kDa. We screened for cellular signal transduction [...] Read more.

Lysenin is a pore-forming toxin from the coelomic fluid of earthworm Eisenia foetida. This protein specifically binds to sphingomyelin and induces erythrocyte lysis. Lysenin consists of 297 amino acids with a molecular weight of 41 kDa. We screened for cellular signal transduction inhibitors of low molecular weight from microorganisms and plants. The purpose of the screening was to study the mechanism of diseases using the obtained inhibitors and to develop new chemotherapeutic agents acting in the new mechanism. Therefore, our aim was to screen for inhibitors of Lysenin-induced hemolysis from plant extracts and microbial culture filtrates. As a result, we isolated all-E-lutein from an extract of Dalbergia latifolia leaves. All-E-lutein is likely to inhibit the process of Lysenin-membrane binding and/or oligomer formation rather than pore formation. Additionally, we isolated tyrosylproline anhydride from the culture filtrate of Streptomyces as an inhibitor of Lysenin-induced hemolysis. Full article

(This article belongs to the Special Issue Pore-Forming Toxins)

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Figure 1
Earthworm Eisenia foetida ejecting coelomic fluid. Full article ">Figure 2
Pore formation by Lysenin. Full article ">Figure 3
(A) All-E-Lutein; (B) All-E-lutein-producing plant Dalbergia latifolia. It belongs to the family of Fabaceae (Leguminosae), and is commonly called East Indian rosewood or black rosewood Full article ">Figure 4
(A) Induction of hemolysis by Lysenin in sheep red blood cells; (B) Inhibition of Lysenin-induced hemolysis by all-E-lutein. PEG 4000 and dextran 4 are known inhibitors of hemolysis; (C) All-E-lutein does not inhibit polyoxypeptin A-induced hemolysis. The Data are mean ± S.D. of experiment performed in triplicate. (* p < 0.05, ** p < 0.01). Full article ">Figure 5
(A) Tyrosylproline anhydride; (B) Inhibition of Lysenin-induced hemolysis by tyrosylproline anhydride; (C) Neither tyrosine nor proline inhibits Lysenin-induced hemolysis. The Data are mean ± S.D. of experiment performed in triplicate. (* p < 0.05, ** p < 0.01) Full article ">

1135 KiB

Open AccessReview

Mini-Review: Novel Therapeutic Strategies to Blunt Actions of Pneumolysin in the Lungs

by Rudolf Lucas, Istvan Czikora, Supriya Sridhar, Evgeny Zemskov, Boris Gorshkov, Umapathy Siddaramappa, Aluya Oseghale, Jonathan Lawson, Alexander Verin, Ferenc G. Rick, Norman L. Block, Helena Pillich, Maritza Romero, Martin Leustik, Andrew V. Schally and Trinad Chakraborty

Toxins 2013, 5(7), 1244-1260; https://doi.org/10.3390/toxins5071244 - 15 Jul 2013

Cited by 27 | Viewed by 8898

Abstract

Severe pneumonia is the main single cause of death worldwide in children under five years of age. The main etiological agent of pneumonia is the G⁺ bacterium Streptococcus pneumoniae, which accounts for up to 45% of all cases. Intriguingly, patients can [...] Read more.

Severe pneumonia is the main single cause of death worldwide in children under five years of age. The main etiological agent of pneumonia is the G⁺ bacterium Streptococcus pneumoniae, which accounts for up to 45% of all cases. Intriguingly, patients can still die days after commencing antibiotic treatment due to the development of permeability edema, although the pathogen was successfully cleared from their lungs. This condition is characterized by a dramatically impaired alveolar epithelial-capillary barrier function and a dysfunction of the sodium transporters required for edema reabsorption, including the apically expressed epithelial sodium channel (ENaC) and the basolaterally expressed sodium potassium pump (Na⁺-K⁺-ATPase). The main agent inducing this edema formation is the virulence factor pneumolysin, a cholesterol-binding pore-forming toxin, released in the alveolar compartment of the lungs when pneumococci are being lysed by antibiotic treatment or upon autolysis. Sub-lytic concentrations of pneumolysin can cause endothelial barrier dysfunction and can impair ENaC-mediated sodium uptake in type II alveolar epithelial cells. These events significantly contribute to the formation of permeability edema, for which currently no standard therapy is available. This review focuses on discussing some recent developments in the search for the novel therapeutic agents able to improve lung function despite the presence of pore-forming toxins. Such treatments could reduce the potentially lethal complications occurring after antibiotic treatment of patients with severe pneumonia. Full article

(This article belongs to the Special Issue Pore-Forming Toxins)

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645 KiB

Open AccessReview

Staphylococcus aureus α-Toxin: Nearly a Century of Intrigue

by Bryan J. Berube and Juliane Bubeck Wardenburg

Toxins 2013, 5(6), 1140-1166; https://doi.org/10.3390/toxins5061140 - 13 Jun 2013

Cited by 497 | Viewed by 27229

Abstract

Staphylococcus aureus secretes a number of host-injurious toxins, among the most prominent of which is the small β-barrel pore-forming toxin α-hemolysin. Initially named based on its properties as a red blood cell lytic toxin, early studies suggested a far greater complexity of α-hemolysin [...] Read more.

Staphylococcus aureus secretes a number of host-injurious toxins, among the most prominent of which is the small β-barrel pore-forming toxin α-hemolysin. Initially named based on its properties as a red blood cell lytic toxin, early studies suggested a far greater complexity of α-hemolysin action as nucleated cells also exhibited distinct responses to intoxication. The hemolysin, most aptly referred to as α-toxin based on its broad range of cellular specificity, has long been recognized as an important cause of injury in the context of both skin necrosis and lethal infection. The recent identification of ADAM10 as a cellular receptor for α-toxin has provided keen insight on the biology of toxin action during disease pathogenesis, demonstrating the molecular mechanisms by which the toxin causes tissue barrier disruption at host interfaces lined by epithelial or endothelial cells. This review highlights both the historical studies that laid the groundwork for nearly a century of research on α-toxin and key findings on the structural and functional biology of the toxin, in addition to discussing emerging observations that have significantly expanded our understanding of this toxin in S. aureus disease. The identification of ADAM10 as a proteinaceous receptor for the toxin not only provides a greater appreciation of truths uncovered by many historic studies, but now affords the opportunity to more extensively probe and understand the role of α-toxin in modulation of the complex interaction of S. aureus with its human host. Full article

(This article belongs to the Special Issue Pore-Forming Toxins)

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855 KiB

Open AccessReview

The Pore-Forming Haemolysins of Bacillus Cereus: A Review

by Nalini Ramarao and Vincent Sanchis

Toxins 2013, 5(6), 1119-1139; https://doi.org/10.3390/toxins5061119 - 7 Jun 2013

Cited by 136 | Viewed by 21092

Abstract

The Bacillus cereus sensu lato group contains diverse Gram-positive spore-forming bacteria that can cause gastrointestinal diseases and severe eye infections in humans. They have also been incriminated in a multitude of other severe, and frequently fatal, clinical infections, such as osteomyelitis, septicaemia, pneumonia, [...] Read more.

The Bacillus cereus sensu lato group contains diverse Gram-positive spore-forming bacteria that can cause gastrointestinal diseases and severe eye infections in humans. They have also been incriminated in a multitude of other severe, and frequently fatal, clinical infections, such as osteomyelitis, septicaemia, pneumonia, liver abscess and meningitis, particularly in immuno-compromised patients and preterm neonates. The pathogenic properties of this organism are mediated by the synergistic effects of a number of virulence products that promote intestinal cell destruction and/or resistance to the host immune system. This review focuses on the pore-forming haemolysins produced by B. cereus: haemolysin I (cereolysin O), haemolysin II, haemolysin III and haemolysin IV (CytK). Haemolysin I belongs to the cholesterol-dependent cytolysin (CDC) family whose best known members are listeriolysin O and perfringolysin O, produced by L. monocytogenes and C. perfringens respectively. HlyII and CytK are oligomeric ß-barrel pore-forming toxins related to the α-toxin of S. aureus or the ß-toxin of C. perfringens. The structure of haemolysin III, the least characterized haemolytic toxin from the B. cereus, group has not yet been determined. Full article

(This article belongs to the Special Issue Pore-Forming Toxins)

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Haemolytic types (HT) for B. cereus and B. thuringiensis strains isolated from small soil samples. Haemolytic activity was determined at 30 °C on sheep blood agar plates. All 198 strains were plated on blood agar at the same time and compared after 15 h. The haemolytic activity of each strain was estimated twice, and each replicate was classified “blind” with respect to the previous one. Nine different haemolytic types (A to I) were identified among the 198 strains [<a href="#B31-toxins-05-01119" class="html-bibr">31</a>]. Full article ">Figure 2
Structure of the Perfringolysin O molecule shown in ribbon representation. Reproduced with permission from [<a href="#B40-toxins-05-01119" class="html-bibr">40</a>]. Full article ">Figure 3
Schematic representation of the transcriptional regulator PlcR and its cognate cell-cell signalling peptide PapR. The activity of PlcR depends on PapR, a secreted signalling peptide re-imported into the bacterial cell through the Opp system [<a href="#B51-toxins-05-01119" class="html-bibr">51</a>]. After its export, PapR is cleaved to a C-terminal heptapeptide active fragment that accumulates in the medium [<a href="#B52-toxins-05-01119" class="html-bibr">52</a>]. When high bacterial densities are reached, PapR concentration increases inside the bacterial cells, promoting its interaction with PlcR. The PapR-PlcR complex then binds to its DNA recognition site, the palindromic PlcR box, triggering a positive feedback loop that upregulates the expression of a regulon of 45 genes encoding proteins that are essentially secreted or bound or attached to cell wall structures at the interface between the bacterial cell and its environment [<a href="#B55-toxins-05-01119" class="html-bibr">55</a>]. These proteins are likely to be involved in host tissue degradation or in protecting the bacterial cell from host immune defenses, and may act together to provide food supply. Ultimately, when the bacteria enter the sporulation process, plcR transcription, and consequently PlcR-regulated gene expression, is repressed by the sporulation key-regulator Spo0A. Full article ">Figure 4
Molecular model of the B. cereus haemolysin II heptameric pore. Molecular modeling was performed using the 3D structure of α-hemolysin from S. aureus [<a href="#B60-toxins-05-01119" class="html-bibr">60</a>]. Full article ">Figure 5
Model of the role and expression of hlyII during infection (A) As long as iron and glucose are abundant in the bacterial environment, glucose enters the bacteria as glucose 6P (blue rectangles) and binds HlyIIR (plain orange cross). Iron (purple circles) binds Fur (red ovals). These binding events promote the repressor activities of HlyIIR and Fur, leading to the HlyIIR- and Fur-based transcriptional repression of hlyII gene expression (B) By contrast, when glucose and iron become scarce, hlyII expression is activated. HlyII is then released into the environment and induces macrophage and erythrocyte lysis. The dead cells release their intracellular content, providing access to metabolites that are essential for bacterial growth [<a href="#B75-toxins-05-01119" class="html-bibr">75</a>]. Full article ">

566 KiB

Open AccessReview

Structure, Function, and Biology of the Enterococcus faecalis Cytolysin

by Daria Van Tyne, Melissa J. Martin and Michael S. Gilmore

Toxins 2013, 5(5), 895-911; https://doi.org/10.3390/toxins5050895 - 29 Apr 2013

Cited by 140 | Viewed by 25411

Abstract

Enterococcus faecalis is a Gram-positive commensal member of the gut microbiota of a wide range of organisms. With the advent of antibiotic therapy, it has emerged as a multidrug resistant, hospital-acquired pathogen. Highly virulent strains of E. faecalis express a pore-forming exotoxin, called [...] Read more.

Enterococcus faecalis is a Gram-positive commensal member of the gut microbiota of a wide range of organisms. With the advent of antibiotic therapy, it has emerged as a multidrug resistant, hospital-acquired pathogen. Highly virulent strains of E. faecalis express a pore-forming exotoxin, called cytolysin, which lyses both bacterial and eukaryotic cells in response to quorum signals. Originally described in the 1930s, the cytolysin is a member of a large class of lanthionine-containing bacteriocins produced by Gram-positive bacteria. While the cytolysin shares some core features with other lantibiotics, it possesses unique characteristics as well. The current understanding of cytolysin biosynthesis, structure/function relationships, and contribution to the biology of E. faecalis are reviewed, and opportunities for using emerging technologies to advance this understanding are discussed. Full article

(This article belongs to the Special Issue Pore-Forming Toxins)

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333 KiB

Open AccessReview

More Than a Pore: The Cellular Response to Cholesterol-Dependent Cytolysins

by Sara K. B. Cassidy and Mary X. D. O'Riordan

Toxins 2013, 5(4), 618-636; https://doi.org/10.3390/toxins5040618 - 12 Apr 2013

Cited by 65 | Viewed by 11307

Abstract

Targeted disruption of the plasma membrane is a ubiquitous form of attack used in all three domains of life. Many bacteria secrete pore-forming proteins during infection with broad implications for pathogenesis. The cholesterol-dependent cytolysins (CDC) are a family of pore-forming toxins expressed predominately [...] Read more.

Targeted disruption of the plasma membrane is a ubiquitous form of attack used in all three domains of life. Many bacteria secrete pore-forming proteins during infection with broad implications for pathogenesis. The cholesterol-dependent cytolysins (CDC) are a family of pore-forming toxins expressed predominately by Gram-positive bacterial pathogens. The structure and assembly of some of these oligomeric toxins on the host membrane have been described, but how the targeted cell responds to intoxication by the CDCs is not as clearly understood. Many CDCs induce lysis of their target cell and can activate apoptotic cascades to promote cell death. However, the extent to which intoxication causes cell death is both CDC- and host cell-dependent, and at lower concentrations of toxin, survival of intoxicated host cells is well documented. Additionally, the effect of CDCs can be seen beyond the plasma membrane, and it is becoming increasingly clear that these toxins are potent regulators of signaling and immunity, beyond their role in intoxication. In this review, we discuss the cellular response to CDC intoxication with emphasis on the effects of pore formation on the host cell plasma membrane and subcellular organelles and whether subsequent cellular responses contribute to the survival of the affected cell. Full article

(This article belongs to the Special Issue Pore-Forming Toxins)

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