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Toxins
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Bacterial Pore-Forming Toxins
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Bacterial Pore-Forming Toxins

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

Deadline for manuscript submissions: closed (30 September 2018) | Viewed by 30448

Special Issue Editor

Dr. Peter A. Keyel

E-Mail Website
Guest Editor
Department of Biological Sciences, Texas Tech University, Box 43131 Lubbock, TX 79409, USA
Interests: cholesterol-dependent cytolysin; membrane repair; inflammasome; macrophage; Dnase1L3
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pore-forming toxins (PFTs) are the largest family of bacterial toxins. They are extensively involved in the virulence of many lethal Gram positive and Gram negative bacterial infections. In some cases, their impacts appear to be independent of target cell lysis, suggesting that PFTs may affect target cells in multiple ways. Similarly, nonpathogenic bacteria also utilize a range of PFTs, indicating that PFTs provide bacteria with a survival advantage beyond pathogenesis. The evolutionary advantages of PFTs are not limited to bacteria. Bacterial PFTs bear strong structural and three-dimensional similarities to PFTs used by other organisms, and have served effectively as tools for answering broad, fundamental questions about PFT structure and mechanism of action. Three such broad outstanding questions in the field are: How do bacterial PFTs promote bacterial fitness beyond lysis of target cells? What mechanisms do competing bacteria, hosts and other organisms use to react to bacterial PFTs? Which insights and mechanisms from bacterial PFTs are also relevant to PFTs from humans and other organisms?

This Special Issue will focus on the interaction of bacterial pore forming toxins with their targets, the functional outcomes of these interactions, and target responses to these toxins. Nonlethal toxin-target interactions, and novel insights into toxin structure/function are areas of special interest.

Dr. Peter A. Keyel
Guest Editor

Manuscript Submission Information

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. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short 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 thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions 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 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • pore-forming toxin
  • cholesterol-dependent cytolysin
  • hemolysin
  • host-pathogen interaction
  • membrane repair
  • cell death

Published Papers (6 papers)

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Research

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19 pages, 2274 KiB  
Article
Multiple Parameters Beyond Lipid Binding Affinity Drive Cytotoxicity of Cholesterol-Dependent Cytolysins
by Sucharit Ray, Roshan Thapa and Peter A. Keyel
Toxins 2019, 11(1), 1; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11010001 - 21 Dec 2018
Cited by 11 | Viewed by 4093
Abstract
The largest superfamily of bacterial virulence factors is pore-forming toxins (PFTs). PFTs are secreted by both pathogenic and non-pathogenic bacteria. PFTs sometimes kill or induce pro-pathogen signaling in mammalian cells, all primarily through plasma membrane perforation, though the parameters that determine these outcomes [...] Read more.
The largest superfamily of bacterial virulence factors is pore-forming toxins (PFTs). PFTs are secreted by both pathogenic and non-pathogenic bacteria. PFTs sometimes kill or induce pro-pathogen signaling in mammalian cells, all primarily through plasma membrane perforation, though the parameters that determine these outcomes are unclear. Membrane binding, calcium influx, pore size, and membrane repair are factors that influence PFT cytotoxicity. To test the contribution of membrane binding to cytotoxicity and repair, we compared the closely related, similarly-sized PFTs Perfringolysin O (PFO) from Clostridium perfringens and Streptolysin O (SLO) from Streptococcus pyogenes. Cell death kinetics for PFO and SLO were different because PFO increased in cytotoxicity over time. We introduced known L3 loop mutations that swap binding affinity between toxins and measured hemolytic activity, nucleated cell death kinetics and membrane repair using viability assays, and live cell imaging. Altered hemolytic activity was directly proportional to toxin binding affinity. In contrast, L3 loop alterations reduced nucleated cell death, and they had limited effects on cytotoxicity kinetics and membrane repair. This suggests other toxin structural features, like oligomerization, drives these parameters. Overall, these findings suggest that repair mechanisms and toxin oligomerization add constraints beyond membrane binding on toxin evolution and activity against nucleated cells. Full article
(This article belongs to the Special Issue Bacterial Pore-Forming Toxins)
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13 pages, 1599 KiB  
Article
Arcanobacterium haemolyticum Phospholipase D Enzymatic Activity Promotes the Hemolytic Activity of the Cholesterol-Dependent Cytolysin Arcanolysin
by Patrick S. Gellings and David J. McGee
Toxins 2018, 10(6), 213; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10060213 - 23 May 2018
Cited by 5 | Viewed by 3516
Abstract
Arcanolysin, produced by the human pathogen Arcanobacterium haemolyticum, is a cholesterol-dependent cytolysin. To mediate the pore-formation process, arcanolysin is secreted by A. haemolyticum and then must interact with cholesterol embedded within a host membrane. However, arcanolysin must compete with membrane components, such [...] Read more.
Arcanolysin, produced by the human pathogen Arcanobacterium haemolyticum, is a cholesterol-dependent cytolysin. To mediate the pore-formation process, arcanolysin is secreted by A. haemolyticum and then must interact with cholesterol embedded within a host membrane. However, arcanolysin must compete with membrane components, such as the phospholipid sphingomyelin, to interact with cholesterol and form pores. Cholesterol forms transient hydrogen bonds with the extracellular portion of sphingomyelin, shielding cholesterol from extracellular factors, including arcanolysin. A. haemolyticum also produces a sphingomyelin-specific phospholipase D, which removes the choline head from sphingomyelin, leaving cyclic-ceramide phosphate and eliminating the potential for cholesterol sequestration. We hypothesized that the enzymatic activity of phospholipase D decreases sphingomyelin-mediated cholesterol sequestration and increases cholesterol accessibility for arcanolysin. Using purified arcanolysin and phospholipase D, we demonstrate that the enzymatic activity of phospholipase D is necessary to promote arcanolysin-mediated hemolysis in both time- and concentration-dependent manners. Phospholipase D promotion of arcanolysin-mediated cytotoxicity was confirmed in Detroit 562 epithelial cells. Furthermore, we determined that incubating phospholipase D with erythrocytes corresponds with an increase in the amount of arcanolysin bound to host membranes. This observation suggests that phospholipase D promotes arcanolysin-mediated cytotoxicity by increasing the ability of arcanolysin to bind to a host membrane. Full article
(This article belongs to the Special Issue Bacterial Pore-Forming Toxins)
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11 pages, 1676 KiB  
Article
Acid Sphingomyelinase Promotes Cellular Internalization of Clostridium perfringens Iota-Toxin
by Masahiro Nagahama, Masaya Takehara, Kazuaki Miyamoto, Kazumi Ishidoh and Keiko Kobayashi
Toxins 2018, 10(5), 209; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10050209 - 20 May 2018
Cited by 5 | Viewed by 3832
Abstract
Clostridium perfringens iota-toxin is a binary actin-ADP-ribosylating toxin composed of the enzymatic component Ia and receptor binding component Ib. Ib binds to a cell surface receptor, forms Ib oligomer in lipid rafts, and associates with Ia. The Ia-Ib complex then internalizes by endocytosis. [...] Read more.
Clostridium perfringens iota-toxin is a binary actin-ADP-ribosylating toxin composed of the enzymatic component Ia and receptor binding component Ib. Ib binds to a cell surface receptor, forms Ib oligomer in lipid rafts, and associates with Ia. The Ia-Ib complex then internalizes by endocytosis. Here, we showed that acid sphingomyelinase (ASMase) facilitates the cellular uptake of iota-toxin. Inhibitions of ASMase and lysosomal exocytosis by respective blockers depressed cell rounding induced by iota-toxin. The cytotoxicity of the toxin increased in the presence of Ca2+ in extracellular fluids. Ib entered target cells in the presence but not the absence of Ca2+. Ib induced the extracellular release of ASMase in the presence of Ca2+. ASMase siRNA prevented the cell rounding induced by iota-toxin. Furthermore, treatment of the cells with Ib resulted in the production of ceramide in cytoplasmic vesicles. These observations showed that ASMase promotes the internalization of iota-toxin into target cells. Full article
(This article belongs to the Special Issue Bacterial Pore-Forming Toxins)
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Review

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19 pages, 693 KiB  
Review
Pharmacological Targeting of Pore-Forming Toxins as Adjunctive Therapy for Invasive Bacterial Infection
by Tamara Escajadillo and Victor Nizet
Toxins 2018, 10(12), 542; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10120542 - 17 Dec 2018
Cited by 33 | Viewed by 7041
Abstract
For many of the most important human bacterial infections, invasive disease severity is fueled by the cell damaging and pro-inflammatory effects of secreted pore-forming toxins (PFTs). Isogenic PFT-knockout mutants, e.g., Staphylococcus aureus lacking α-toxin or Streptococcus pneumoniae deficient in pneumolysin, show attenuation in [...] Read more.
For many of the most important human bacterial infections, invasive disease severity is fueled by the cell damaging and pro-inflammatory effects of secreted pore-forming toxins (PFTs). Isogenic PFT-knockout mutants, e.g., Staphylococcus aureus lacking α-toxin or Streptococcus pneumoniae deficient in pneumolysin, show attenuation in animal infection models. This knowledge has inspired multi-model investigations of strategies to neutralize PFTs or counteract their toxicity as a novel pharmacological approach to ameliorate disease pathogenesis in clinical disease. Promising examples of small molecule, antibody or nanotherapeutic drug candidates that directly bind and neutralize PFTs, block their oligomerization or membrane receptor interactions, plug establishment membrane pores, or boost host cell resiliency to withstand PFT action have emerged. The present review highlights these new concepts, with a special focus on β-PFTs produced by leading invasive human Gram-positive bacterial pathogens. Such anti-virulence therapies could be applied as an adjunctive therapy to antibiotic-sensitive and -resistant strains alike, and further could be free of deleterious effects that deplete the normal microflora. Full article
(This article belongs to the Special Issue Bacterial Pore-Forming Toxins)
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14 pages, 581 KiB  
Review
Functional Consequences of Calcium Influx Promoted by Bacterial Pore-Forming Toxins
by Stéphanie Bouillot, Emeline Reboud and Philippe Huber
Toxins 2018, 10(10), 387; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10100387 - 25 Sep 2018
Cited by 36 | Viewed by 5528
Abstract
Bacterial pore-forming toxins induce a rapid and massive increase in cytosolic Ca2+ concentration due to the formation of pores in the plasma membrane and/or activation of Ca2+-channels. As Ca2+ is an essential messenger in cellular signaling, a sustained increase [...] Read more.
Bacterial pore-forming toxins induce a rapid and massive increase in cytosolic Ca2+ concentration due to the formation of pores in the plasma membrane and/or activation of Ca2+-channels. As Ca2+ is an essential messenger in cellular signaling, a sustained increase in Ca2+ concentration has dramatic consequences on cellular behavior, eventually leading to cell death. However, host cells have adapted mechanisms to protect against Ca2+ intoxication, such as Ca2+ efflux and membrane repair. The final outcome depends upon the nature and concentration of the toxin and on the cell type. This review highlights the repercussions of Ca2+ overload on the induction of cell death, repair mechanisms, cellular adhesive properties, and the inflammatory response. Full article
(This article belongs to the Special Issue Bacterial Pore-Forming Toxins)
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13 pages, 1706 KiB  
Review
Membrane Repair Mechanisms against Permeabilization by Pore-Forming Toxins
by Asier Etxaniz, David González-Bullón, César Martín and Helena Ostolaza
Toxins 2018, 10(6), 234; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10060234 - 09 Jun 2018
Cited by 37 | Viewed by 5770
Abstract
Permeabilization of the plasma membrane represents an important threat for any cell, since it compromises its viability by disrupting cell homeostasis. Numerous pathogenic bacteria produce pore-forming toxins that break plasma membrane integrity and cause cell death by colloid-osmotic lysis. Eukaryotic cells, in turn, [...] Read more.
Permeabilization of the plasma membrane represents an important threat for any cell, since it compromises its viability by disrupting cell homeostasis. Numerous pathogenic bacteria produce pore-forming toxins that break plasma membrane integrity and cause cell death by colloid-osmotic lysis. Eukaryotic cells, in turn, have developed different ways to cope with the effects of such membrane piercing. Here, we provide a short overview of the general mechanisms currently proposed for plasma membrane repair, focusing more specifically on the cellular responses to membrane permeabilization by pore-forming toxins and presenting new data on the effects and cellular responses to the permeabilization by an RTX (repeats in toxin) toxin, the adenylate cyclase toxin-hemolysin secreted by the whooping cough bacterium Bordetella pertussis, which we have studied in the laboratory. Full article
(This article belongs to the Special Issue Bacterial Pore-Forming Toxins)
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