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Special Issue "Pore-Forming Toxins"

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A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (28 February 2013)

Special Issue Editor

Guest Editor
Prof. Dr. Shin-ichi Miyoshi (Website)

Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University 1-1-1, Tsushima-Naka, Kita-Ku, Okayama-City, Okayama 700-8530, Japan
Fax: +81 86 251 7926
Interests: bacterial protein toxins; pore-forming toxins; cell membrane proteins/receptors; proteolytic enzymes

Special Issue Information

Dear Colleagues,

Pore-forming toxins (PFTs) are extracellular proteins that contribute to virulence of a variety of pathogenic bacteria. The PFTs are generally cytotoxic/cytolytic because they create unregulated small pores or channels in the plasma membrane of target cells. In addition, the toxins often disturb the signal pathways of the target cells via the non-lytic membrane damage, which may result in confusion of the cell functions or triggering the apoptotic cascade. Some animal toxins, such as melittin from a honeybee, a-latorotoxin from spider venoms, and cytolysins from sea anemones, are also categorized into this toxin group. The PFTs can be divided into two subgroups based on the type of pore-forming structures, namely, a-pore-forming toxins and b-pore-forming toxins. This special issue deals with various aspects of PFTs, which include biochemical and pathological properties, crystal structures of the pores created, the molecular mechanism of the toxic actions, and the development of inhibitors or antagonists to prevent the toxic actions.

Prof. Dr. Shin-ichi Miyoshi
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on theInstructions for Authors page. Toxins is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 800 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Keywords

  • cytolysin
  • hemolysin
  • leukocidin
  • melittin
  • membrane-damaging
  • pore-forming
  • toxin oligomer
  • pore structure

Published Papers (9 papers)

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Research

Jump to: Review

Open AccessArticle Reduction of Streptolysin O (SLO) Pore-Forming Activity Enhances Inflammasome Activation
Toxins 2013, 5(6), 1105-1118; doi:10.3390/toxins5061105
Received: 1 March 2013 / Revised: 29 May 2013 / Accepted: 3 June 2013 / Published: 6 June 2013
Cited by 7 | PDF Full-text (894 KB) | HTML Full-text | XML Full-text
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 [...] 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)
Open AccessArticle Multiple Membrane Interactions and Versatile Vesicle Deformations Elicited by Melittin
Toxins 2013, 5(4), 637-664; doi:10.3390/toxins5040637
Received: 18 February 2013 / Revised: 2 April 2013 / Accepted: 10 April 2013 / Published: 17 April 2013
Cited by 12 | PDF Full-text (6923 KB) | HTML Full-text | XML Full-text | Supplementary Files
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 [...] 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)
Open AccessArticle P2X Receptor-Dependent Erythrocyte Damage by α-Hemolysin from Escherichia coli Triggers Phagocytosis by THP-1 Cells
Toxins 2013, 5(3), 472-487; doi:10.3390/toxins5030472
Received: 7 January 2013 / Revised: 6 February 2013 / Accepted: 18 February 2013 / Published: 5 March 2013
Cited by 5 | PDF Full-text (826 KB) | HTML Full-text | XML Full-text | Supplementary Files
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+ (KCa3.1) and Cl channels (TMEM16A) and [...] 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+ (KCa3.1) and Cl channels (TMEM16A) and reduced functions of either of these channels potentiate the HlyA-induced hemolysis. This means that Ca2+-dependent activation of KCa3.1 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 KCa3.1, 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)

Review

Jump to: Research

Open AccessReview Earthworm-Derived Pore-Forming Toxin Lysenin and Screening of Its Inhibitors
Toxins 2013, 5(8), 1392-1401; doi:10.3390/toxins5081392
Received: 10 June 2013 / Revised: 8 July 2013 / Accepted: 31 July 2013 / Published: 8 August 2013
Cited by 4 | PDF Full-text (917 KB) | HTML Full-text | XML Full-text
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 [...] 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)
Open AccessReview Mini-Review: Novel Therapeutic Strategies to Blunt Actions of Pneumolysin in the Lungs
Toxins 2013, 5(7), 1244-1260; doi:10.3390/toxins5071244
Received: 31 May 2013 / Revised: 25 June 2013 / Accepted: 27 June 2013 / Published: 15 July 2013
Cited by 10 | PDF Full-text (1135 KB) | HTML Full-text | XML Full-text
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 [...] 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)
Open AccessReview Staphylococcus aureus α-Toxin: Nearly a Century of Intrigue
Toxins 2013, 5(6), 1140-1166; doi:10.3390/toxins5061140
Received: 27 April 2013 / Revised: 28 May 2013 / Accepted: 3 June 2013 / Published: 13 June 2013
Cited by 95 | PDF Full-text (645 KB) | HTML Full-text | XML Full-text
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 [...] 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)
Open AccessReview The Pore-Forming Haemolysins of Bacillus Cereus: A Review
Toxins 2013, 5(6), 1119-1139; doi:10.3390/toxins5061119
Received: 28 February 2013 / Revised: 22 May 2013 / Accepted: 24 May 2013 / Published: 7 June 2013
Cited by 18 | PDF Full-text (855 KB) | HTML Full-text | XML Full-text
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, [...] 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)
Open AccessReview Structure, Function, and Biology of the Enterococcus faecalis Cytolysin
Toxins 2013, 5(5), 895-911; doi:10.3390/toxins5050895
Received: 25 March 2013 / Revised: 22 April 2013 / Accepted: 23 April 2013 / Published: 29 April 2013
Cited by 19 | PDF Full-text (566 KB) | HTML Full-text | XML Full-text
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, [...] 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)
Open AccessReview More Than a Pore: The Cellular Response to Cholesterol-Dependent Cytolysins
Toxins 2013, 5(4), 618-636; doi:10.3390/toxins5040618
Received: 1 March 2013 / Revised: 7 April 2013 / Accepted: 7 April 2013 / Published: 12 April 2013
Cited by 18 | PDF Full-text (333 KB) | HTML Full-text | XML Full-text
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 [...] 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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