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Special Issue "Cellular Microbiology of Bacterial 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 (15 January 2011)

Special Issue Editor

Guest Editor
Dr. Emmanuel Lemichez

INSERM U895, C3M, Université de Nice, Bâtiment Universitaire ARCHIMED, 151 route Saint Antoine de Ginestière, BP 2 3194, 06204 NICE CEDEX 3, France
Website | E-Mail
Interests: microbial toxins in host pathogen interactions; host epithelium and endothelium barriers; inflammation; cell cytoskeleton; toxin and bacterial entry; cell signaling : Rho GTPases; regulation by ubiquitination; MAP Kinases

Special Issue Information

Dear Colleagues,

Protein toxins secreted by pathogenic bacteria such as Anthrax, Tetanus and Diphtheria toxins are among the most potent poisons, but also valuable targets for developing efficient vaccines. These “molecular syringe” devices are composed of three functional parts sequentially involved in the three steps of the intoxication process: (1) plasma membrane interaction and endocytosis, (2) translocation through host cell membrane compartments and (3) targeting of key cellular signaling pathways. Another family of protein toxins acts directly on host cell plasma membrane by forming pores for corrupting specific signaling pathways.

This special issue on the Cellular Biology of Bacterial Toxins covers recent exciting findings on various aspects of the mode of action of several harmful toxins in relationship to key host cellular functions. Other complementary aspects have been covered in a recent special issue edited by Dr Yasuhiko Horiguchi.

(1) The first step of intoxication consists in the interaction of toxins with the plasma membrane of host cells. (i) Upon interaction, pore forming toxins directly interfere on intracellular signaling for instance via release of intracellular potassium. (ii) Other toxins, upon association with specific host cell surface receptors, are routed into various host cell compartments. Recent findings have elucidated new aspects on the entry and complex retrograde traffic of Shiga toxin and the closely related plant toxin Ricin.

(2) Upon reaching specific intracellular compartments, the translocation-domain of the toxins inserts into the lipid bilayer and drives the transport of the catalytic subunit into the cytosol. Major progress has been made in deciphering the structure of the pore of anthrax toxin and the translocation of the enzymatic components of this toxin through the pore. Evidences also suggest a hijacking of cellular components by diphtheria toxin to efficiently cross endosomal membranes.

(3) Once inside the cytosol the catalytic part of toxins directly corrupts the regulation of master regulators of host cells homeostasis. Deciphering the molecular mechanism of action of toxins thus informed us on the function and regulation of key cellular proteins. Recent findings have unveiled that some bacterial factors modify Rho GTPases by Adenylylation (AMPylation) and can interfere with cell signaling by ubiquitin and ubiquitin-like molecules. This also contributes to define the function of toxin targets in cell biology such as the crosstalk between regulations of actin and microtubule cytoskeleton.

Dr. Emmanuel Lemichez
Guest Editor

Keywords

  • protein toxins
  • pathogenic bacteria
  • signaling
  • endocytosis and vesicle trafficking
  • cell cycle
  • actin cytoskeleton
  • microtubule cytoskeleton
  • ubiquitin
  • ubiquitin-like
  • Rho GTPases

Published Papers (6 papers)

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Research

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Open AccessArticle Arf6-Dependent Intracellular Trafficking of Pasteurella multocida Toxin and pH-Dependent Translocation from Late Endosomes
Toxins 2011, 3(3), 218-241; doi:10.3390/toxins3030218
Received: 20 January 2011 / Revised: 20 February 2011 / Accepted: 8 March 2011 / Published: 16 March 2011
Cited by 12 | PDF Full-text (1086 KB) | HTML Full-text | XML Full-text
Abstract
The potent mitogenic toxin from Pasteurella multocida (PMT) is the major virulence factor associated with a number of epizootic and zoonotic diseases caused by infection with this respiratory pathogen. PMT is a glutamine-specific protein deamidase that acts on its intracellular G-protein targets to
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The potent mitogenic toxin from Pasteurella multocida (PMT) is the major virulence factor associated with a number of epizootic and zoonotic diseases caused by infection with this respiratory pathogen. PMT is a glutamine-specific protein deamidase that acts on its intracellular G-protein targets to increase intracellular calcium, cytoskeletal, and mitogenic signaling. PMT enters cells through receptor-mediated endocytosis and then translocates into the cytosol through a pH-dependent process that is inhibited by NH4Cl or bafilomycin A1. However, the detailed mechanisms that govern cellular entry, trafficking, and translocation of PMT remain unclear. Co-localization studies described herein revealed that while PMT shares an initial entry pathway with transferrin (Tfn) and cholera toxin (CT), the trafficking pathways of Tfn, CT, and PMT subsequently diverge, as Tfn is trafficked to recycling endosomes, CT is trafficked retrograde to the ER, and PMT is trafficked to late endosomes. Our studies implicate the small regulatory GTPase Arf6 in the endocytic trafficking of PMT. Translocation of PMT from the endocytic vesicle occurs through a pH-dependent process that is also dependent on both microtubule and actin dynamics, as evidenced by inhibition of PMT activity in our SRE-based reporter assay, with nocodazole and cytochalasin D, respectively, suggesting that membrane translocation and cytotoxicity of PMT is dependent on its transfer to late endosomal compartments. In contrast, disruption of Golgi-ER trafficking with brefeldin A increased PMT activity, suggesting that inhibiting PMT trafficking to non-productive compartments that do not lead to translocation, while promoting formation of an acidic tubulovesicle system more conducive to translocation, enhances PMT translocation and activity. Full article
(This article belongs to the Special Issue Cellular Microbiology of Bacterial Toxins)
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Open AccessArticle Gangliosides Block Aggregatibacter Actinomycetemcomitans Leukotoxin (LtxA)-Mediated Hemolysis
Toxins 2010, 2(12), 2824-2836; doi:10.3390/toxins2122824
Received: 5 November 2010 / Revised: 24 November 2010 / Accepted: 10 December 2010 / Published: 14 December 2010
Cited by 6 | PDF Full-text (481 KB) | HTML Full-text | XML Full-text
Abstract
Aggregatibacter actinomycetemcomitans is an oral pathogen and etiologic agent of localized aggressive periodontitis. The bacterium is also a cardiovascular pathogen causing infective endocarditis. A. actinomycetemcomitans produces leukotoxin (LtxA), an important virulence factor that targets white blood cells (WBCs) and plays a role in
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Aggregatibacter actinomycetemcomitans is an oral pathogen and etiologic agent of localized aggressive periodontitis. The bacterium is also a cardiovascular pathogen causing infective endocarditis. A. actinomycetemcomitans produces leukotoxin (LtxA), an important virulence factor that targets white blood cells (WBCs) and plays a role in immune evasion during disease. The functional receptor for LtxA on WBCs is leukocyte function antigen-1 (LFA-1), a b-2 integrin that is modified with N-linked carbohydrates. Interaction between toxin and receptor leads to cell death. We recently discovered that LtxA can also lyse red blood cells (RBCs) and hemolysis may be important for pathogenesis of A. actinomycetemcomitans. In this study, we further investigated how LtxA might recognize and lyse RBCs. We found that, in contrast to a related toxin, E. coli a-hemolysin, LtxA does not recognize glycophorin on RBCs. However, gangliosides were able to completely block LtxA-mediated hemolysis. Furthermore, LtxA did not show a preference for any individual ganglioside. LtxA also bound to ganglioside-rich C6 rat glioma cells, but did not kill them. Interaction between LtxA and C6 cells could be blocked by gangliosides with no apparent specificity. Gangliosides were only partially effective at preventing LtxA-mediated cytotoxicity of WBCs, and the effect was only observed when a high ratio of ganglioside:LtxA was used over a short incubation period. Based on the results presented here, we suggest that because of the similarity between N-linked sugars on LFA-1 and the structures of gangliosides, LtxA may have acquired the ability to lyse RBCs. Full article
(This article belongs to the Special Issue Cellular Microbiology of Bacterial Toxins)
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Review

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Open AccessReview Cycle Inhibiting Factors (Cifs): Cyclomodulins That Usurp the Ubiquitin-Dependent Degradation Pathway of Host Cells
Toxins 2011, 3(4), 356-368; doi:10.3390/toxins3040356
Received: 18 February 2011 / Revised: 16 March 2011 / Accepted: 16 March 2011 / Published: 29 March 2011
Cited by 10 | PDF Full-text (451 KB) | HTML Full-text | XML Full-text
Abstract
Cycle inhibiting factors (Cifs) are type III secreted effectors produced by diverse pathogenic bacteria. Cifs are “cyclomodulins” that inhibit the eukaryotic host cell cycle and also hijack other key cellular processes such as those controlling the actin network and apoptosis. This review summarizes
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Cycle inhibiting factors (Cifs) are type III secreted effectors produced by diverse pathogenic bacteria. Cifs are “cyclomodulins” that inhibit the eukaryotic host cell cycle and also hijack other key cellular processes such as those controlling the actin network and apoptosis. This review summarizes current knowledge on Cif since its first characterization in enteropathogenic Escherichia coli, the identification of several xenologues in distant pathogenic bacteria, to its structure elucidation and the recent deciphering of its mode of action. Cif impairs the host ubiquitin proteasome system through deamidation of ubiquitin or the ubiquitin-like protein NEDD8 that regulates Cullin-Ring-ubiquitin Ligase (CRL) complexes. The hijacking of the ubiquitin-dependent degradation pathway of host cells results in the modulation of various cellular functions such as epithelium renewal, apoptosis and immune response. Cif is therefore a powerful weapon in the continuous arm race that characterizes host-bacteria interactions. Full article
(This article belongs to the Special Issue Cellular Microbiology of Bacterial Toxins)
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Open AccessReview Aggregatibacter actinomycetemcomitans Leukotoxin: A Powerful Tool with Capacity to Cause Imbalance in the Host Inflammatory Response
Toxins 2011, 3(3), 242-259; doi:10.3390/toxins3030242
Received: 27 January 2011 / Revised: 1 March 2011 / Accepted: 8 March 2011 / Published: 21 March 2011
Cited by 24 | PDF Full-text (475 KB) | HTML Full-text | XML Full-text
Abstract
Aggregatibacter actinomycetemcomitans has been described as a member of the indigenous oral microbiota of humans, and is involved in the pathology of periodontitis and various non-oral infections. This bacterium selectively kills human leukocytes through expression of leukotoxin, a large pore-forming protein that belongs
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Aggregatibacter actinomycetemcomitans has been described as a member of the indigenous oral microbiota of humans, and is involved in the pathology of periodontitis and various non-oral infections. This bacterium selectively kills human leukocytes through expression of leukotoxin, a large pore-forming protein that belongs to the Repeat in Toxin (RTX) family. The specificity of the toxin is related to its prerequisite for a specific target cell receptor, LFA-1, which is solely expressed on leukocytes. The leukotoxin causes death of different leukocyte populations in a variety of ways. It activates a rapid release of lysosomal enzymes and MMPs from neutrophils and causes apoptosis in lymphocytes. In the monocytes/macrophages, the toxin activates caspase-1, a cysteine proteinase, which causes a proinflammatory response by the activation and secretion of IL-1β and IL-18. A specific clone (JP2) of A. actinomycetemcomitans with enhanced leukotoxin expression significantly correlates to disease onset in infected individuals. Taken together, the mechanisms by which this toxin kills leukocytes are closely related to the pathogenic mechanisms of inflammatory disorders, such as periodontitis. Therapeutic strategies targeting the cellular and molecular inflammatory host response in periodontal diseases might be a future treatment alternative. Full article
(This article belongs to the Special Issue Cellular Microbiology of Bacterial Toxins)
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Open AccessReview Mechanism of Diphtheria Toxin Catalytic Domain Delivery to the Eukaryotic Cell Cytosol and the Cellular Factors that Directly Participate in the Process
Toxins 2011, 3(3), 294-308; doi:10.3390/toxins3030294
Received: 27 January 2011 / Revised: 3 March 2011 / Accepted: 10 March 2011 / Published: 21 March 2011
Cited by 45 | PDF Full-text (366 KB) | HTML Full-text | XML Full-text
Abstract
Research on diphtheria and anthrax toxins over the past three decades has culminated in a detailed understanding of their structure function relationships (e.g., catalytic (C), transmembrane (T), and receptor binding (R) domains), as well as the identification of their eukaryotic cell surface receptor,
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Research on diphtheria and anthrax toxins over the past three decades has culminated in a detailed understanding of their structure function relationships (e.g., catalytic (C), transmembrane (T), and receptor binding (R) domains), as well as the identification of their eukaryotic cell surface receptor, an understanding of the molecular events leading to the receptor-mediated internalization of the toxin into an endosomal compartment, and the pH triggered conformational changes required for pore formation in the vesicle membrane. Recently, a major research effort has been focused on the development of a detailed understanding of the molecular interactions between each of these toxins and eukaryotic cell factors that play an essential role in the efficient translocation of their respective catalytic domains through the trans-endosomal vesicle membrane pore and delivery into the cell cytosol. In this review, I shall focus on recent findings that have led to a more detailed understanding of the mechanism by which the diphtheria toxin catalytic domain is delivered to the eukaryotic cell cytosol. While much work remains, it is becoming increasingly clear that the entry process is facilitated by specific interactions with a number of cellular factors in an ordered sequential fashion. In addition,since diphtheria, anthrax lethal factor and anthrax edema factor all carry multiple coatomer I complex binding motifs and COPI complex has been shown to play an essential role in entry process, it is likely that the initial steps in catalytic domain entry of these divergent toxins follow a common mechanism. Full article
(This article belongs to the Special Issue Cellular Microbiology of Bacterial Toxins)
Open AccessReview The Biology of the Cytolethal Distending Toxins
Toxins 2011, 3(3), 172-190; doi:10.3390/toxins3030172
Received: 17 January 2011 / Revised: 14 February 2011 / Accepted: 22 February 2011 / Published: 7 March 2011
Cited by 33 | PDF Full-text (457 KB) | HTML Full-text | XML Full-text
Abstract
The cytolethal distending toxins (CDTs), produced by a variety of Gram-negative pathogenic bacteria, are the first bacterial genotoxins described, since they cause DNA damage in the target cells. CDT is an A-B2 toxin, where the CdtA and CdtC subunits are required to
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The cytolethal distending toxins (CDTs), produced by a variety of Gram-negative pathogenic bacteria, are the first bacterial genotoxins described, since they cause DNA damage in the target cells. CDT is an A-B2 toxin, where the CdtA and CdtC subunits are required to mediate the binding on the surface of the target cells, allowing internalization of the active CdtB subunit, which is functionally homologous to the mammalian deoxyribonuclease I. The nature of the surface receptor is still poorly characterized, however binding of CDT requires intact lipid rafts, and its internalization occurs via dynamin-dependent endocytosis. The toxin is retrograde transported through the Golgi complex and the endoplasmic reticulum, and subsequently translocated into the nuclear compartment, where it exerts the toxic activity. Cellular intoxication induces DNA damage and activation of the DNA damage responses, which results in arrest of the target cells in the G1 and/or G2 phases of the cell cycle and activation of DNA repair mechanisms. Cells that fail to repair the damage will senesce or undergo apoptosis. This review will focus on the well-characterized aspects of the CDT biology and discuss the questions that still remain unanswered. Full article
(This article belongs to the Special Issue Cellular Microbiology of Bacterial Toxins)

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