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Bacterial Protein Toxins: Enemies within or Unexpected Friends 2.0
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Bacterial Protein Toxins: Enemies within or Unexpected Friends 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 25662

Special Issue Editors

Prof. Dr. Carla Fiorentini

E-Mail Website
Guest Editor
National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy
Interests: bacterial protein toxins; Rho GTPases; cytoskeleton; mitochondria; cancer; toxins as therapeutics
Special Issues, Collections and Topics in MDPI journals
Dr. Alessia Fabbri

E-Mail Website
Co-Guest Editor
Department of Cardiovascular, Endocrine-Metabolic Diseases and Aging, Istituto Superiore di Sanità, 00161 Rome, Italy
Interests: bacterial protein toxins; Rho GTPases; actin cytoskeleton; mitochondria; cellular microbiology; cancer; toxins as therapeutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a follow-up to our previous Special Issue “Bacterial Protein Toxins: Enemies within or Unexpected Friends” (https://www.mdpi.com/journal/ijms/special_issues/protein_toxins).

Bacterial protein toxins are the principal virulence factors of pathogenic bacteria, and their production represents one of the main bacterial strategies to interact with mammalian cells. Using diverse and sophisticated mechanisms, bacterial toxins manipulate the host cell functions to suit their own needs, favoring the spreading, colonization, and survival of the microbes. However, toxins play a negative role in human health, not only because implicated in infectious diseases but also because potentially involved in harmful situations, such as cancer development. Under all these aspects, bacterial toxins can certainly be considered as “enemies”.

On the other hand, knowledge of the toxins’ modes of action has permitted their beneficial use, not only as highly selective tools in cell biology but also as potential new drugs for medical applications. For example, some toxins can be “engineered” as the cell-killing component of immuno-toxins, while other toxins or their derivatives have been incorporated into human vaccines because of their adjuvant properties. Paradigmatic is the use of botulinum toxin, the most powerful candidate as a biological weapon, which is used to treat human disorders characterized by hyperactivity of nerve terminals of different origins and is today very popular for its ability to reduce wrinkles. Thus, scientific research has permitted to convert these harmful bacterial molecules into “friends”.

In this Special Issue of IJMS, the focus will be on bacterial protein toxins, pointing to both their pathogenetic properties and their therapeutic potentials, thus highlighting the Janus aspect of such virulence factors.

Prof. Carla Fiorentini
Dr. Alessia Fabbri
Guest Editors

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 single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • bacterial protein toxins
  • pathogenesis
  • molecular target
  • drug discovery therapy

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Published Papers (16 papers)

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Research

Jump to: Review

12 pages, 2596 KiB  
Article
Quantum Calculations of VX Ammonolysis and Hydrolysis Pathways via Hydrated Lithium Nitride
by Calen J. Leverant, Chad W. Priest, Jeffery A. Greathouse, Mark K. Kinnan and Susan B. Rempe
Int. J. Mol. Sci. 2021, 22(16), 8653; https://doi.org/10.3390/ijms22168653 - 11 Aug 2021
Viewed by 2364
Abstract
Recently, lithium nitride (Li3N) has been proposed as a chemical warfare agent (CWA) neutralization reagent for its ability to produce nucleophilic ammonia molecules and hydroxide ions in aqueous solution. Quantum chemical calculations can provide insight into the Li3N neutralization [...] Read more.
Recently, lithium nitride (Li3N) has been proposed as a chemical warfare agent (CWA) neutralization reagent for its ability to produce nucleophilic ammonia molecules and hydroxide ions in aqueous solution. Quantum chemical calculations can provide insight into the Li3N neutralization process that has been studied experimentally. Here, we calculate reaction-free energies associated with the Li3N-based neutralization of the CWA VX using quantum chemical density functional theory and ab initio methods. We find that alkaline hydrolysis is more favorable to either ammonolysis or neutral hydrolysis for initial P-S and P-O bond cleavages. Reaction-free energies of subsequent reactions are calculated to determine the full reaction pathway. Notably, products predicted from favorable reactions have been identified in previous experiments. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends 2.0)
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16 pages, 1616 KiB  
Article
Treatment with the Bacterial Toxin CNF1 Selectively Rescues Cognitive and Brain Mitochondrial Deficits in a Female Mouse Model of Rett Syndrome Carrying a MeCP2-Null Mutation
by Chiara Urbinati, Livia Cosentino, Elena Angela Pia Germinario, Daniela Valenti, Daniele Vigli, Laura Ricceri, Giovanni Laviola, Carla Fiorentini, Rosa Anna Vacca, Alessia Fabbri and Bianca De Filippis
Int. J. Mol. Sci. 2021, 22(13), 6739; https://doi.org/10.3390/ijms22136739 - 23 Jun 2021
Cited by 6 | Viewed by 2352
Abstract
Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene and a major cause of intellectual disability in females. No cure exists for RTT. We previously reported that the behavioural phenotype and brain mitochondria dysfunction are widely [...] Read more.
Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene and a major cause of intellectual disability in females. No cure exists for RTT. We previously reported that the behavioural phenotype and brain mitochondria dysfunction are widely rescued by a single intracerebroventricular injection of the bacterial toxin CNF1 in a RTT mouse model carrying a truncating mutation of the MeCP2 gene (MeCP2-308 mice). Given the heterogeneity of MECP2 mutations in RTT patients, we tested the CNF1 therapeutic efficacy in a mouse model carrying a null mutation (MeCP2-Bird mice). CNF1 selectively rescued cognitive defects, without improving other RTT-related behavioural alterations, and restored brain mitochondrial respiratory chain complex activity in MeCP2-Bird mice. To shed light on the molecular mechanisms underlying the differential CNF1 effects on the behavioural phenotype, we compared treatment effects on relevant signalling cascades in the brain of the two RTT models. CNF1 provided a significant boost of the mTOR activation in MeCP2-308 hippocampus, which was not observed in the MeCP2-Bird model, possibly explaining the differential effects of CNF1. These results demonstrate that CNF1 efficacy depends on the mutation beared by MeCP2-mutated mice, stressing the need of testing potential therapeutic approaches across RTT models. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends 2.0)
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14 pages, 2941 KiB  
Article
SpeS: A Novel Superantigen and Its Potential as a Vaccine Adjuvant against Strangles
by C. Coral Dominguez-Medina, Nicola L. Rash, Sylvain Robillard, Carl Robinson, Androulla Efstratiou, Karen Broughton, Julian Parkhill, Matthew T.G. Holden, Maria R. Lopez-Alvarez, Romain Paillot and Andrew S. Waller
Int. J. Mol. Sci. 2020, 21(12), 4467; https://doi.org/10.3390/ijms21124467 - 23 Jun 2020
Cited by 2 | Viewed by 2720
Abstract
Bacterial superantigens (sAgs) are powerful activators of the immune response that trigger unspecific T cell responses accompanied by the release of proinflammatory cytokines. Streptococcus equi (S. equi) and Streptococcus zooepidemicus (S. zooepidemicus) produce sAgs that play an important role [...] Read more.
Bacterial superantigens (sAgs) are powerful activators of the immune response that trigger unspecific T cell responses accompanied by the release of proinflammatory cytokines. Streptococcus equi (S. equi) and Streptococcus zooepidemicus (S. zooepidemicus) produce sAgs that play an important role in their ability to cause disease. Strangles, caused by S. equi, is one of the most common infectious diseases of horses worldwide. Here, we report the identification of a new sAg of S. zooepidemicus, SpeS, and show that mutation of the putative T cell receptor (TCR)-binding motif (YAY to IAY) abrogated TCR-binding, whilst maintaining interaction with major histocompatibility complex (MHC) class II molecules. The fusion of SpeS and SpeSY39I to six S. equi surface proteins using two different peptide linkers was conducted to determine if MHC class II-binding properties were maintained. Proliferation assays, qPCR and flow cytometry analysis showed that SpeSY39I and its fusion proteins induced less mitogenic activity and interferon gamma expression when compared to SpeS, whilst retaining Antigen-Presenting Cell (APC)-binding properties. Our data suggest that SpeSY39I-surface protein fusions could be used to direct vaccine antigens towards antigen-presenting cells in vivo with the potential to enhance antigen presentation and improve immune responses. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends 2.0)
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16 pages, 3813 KiB  
Article
The Bacterial Toxin CNF1 Protects Human Neuroblastoma SH-SY5Y Cells against 6-Hydroxydopamine-Induced Cell Damage: The Hypothesis of CNF1-Promoted Autophagy as an Antioxidant Strategy
by Sara Travaglione, Stefano Loizzo, Rosa Vona, Giulia Ballan, Roberto Rivabene, Danila Giordani, Marco Guidotti, Maria Luisa Dupuis, Zaira Maroccia, Monica Baiula, Roberto Rimondini, Gabriele Campana and Carla Fiorentini
Int. J. Mol. Sci. 2020, 21(9), 3390; https://doi.org/10.3390/ijms21093390 - 11 May 2020
Cited by 4 | Viewed by 3385
Abstract
Several chronic neuroinflammatory diseases, including Parkinson’s disease (PD), have the so-called ‘redox imbalance’ in common, a dynamic system modulated by various factors. Among them, alteration of the mitochondrial functionality can cause overproduction of reactive oxygen species (ROS) with the consequent induction of oxidative [...] Read more.
Several chronic neuroinflammatory diseases, including Parkinson’s disease (PD), have the so-called ‘redox imbalance’ in common, a dynamic system modulated by various factors. Among them, alteration of the mitochondrial functionality can cause overproduction of reactive oxygen species (ROS) with the consequent induction of oxidative DNA damage and apoptosis. Considering the failure of clinical trials with drugs that eliminate ROS directly, research currently focuses on approaches that counteract redox imbalance, thus restoring normal physiology in a neuroinflammatory condition. Herein, we used SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA), a neurotoxin broadly employed to generate experimental models of PD. Cells were pre-treated with the Rho-modulating Escherichia coli cytotoxic necrotizing factor 1 (CNF1), before the addition of 6-OHDA. Then, cell viability, mitochondrial morphology and dynamics, redox profile as well as autophagic markers expression were assessed. We found that CNF1 preserves cell viability and counteracts oxidative stress induced by 6-OHDA. These effects are accompanied by modulation of the mitochondrial network and an increase in macroautophagic markers. Our results confirm the Rho GTPases as suitable pharmacological targets to counteract neuroinflammatory diseases and evidence the potentiality of CNF1, whose beneficial effects on pathological animal models have been already proven to act against oxidative stress through an autophagic strategy. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends 2.0)
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12 pages, 5351 KiB  
Article
In Vivo Targets of Pasteurella Multocida Toxin
by Arshiya Banu, Alistair J. Lax and Agamemnon E. Grigoriadis
Int. J. Mol. Sci. 2020, 21(8), 2739; https://doi.org/10.3390/ijms21082739 - 15 Apr 2020
Cited by 3 | Viewed by 3229
Abstract
Many Pasteurella multocida strains are carried as commensals, while some cause disease in animals and humans. Some type D strains cause atrophic rhinitis in pigs, where the causative agent is known to be the Pasteurella multocida toxin (PMT). PMT activates three families of [...] Read more.
Many Pasteurella multocida strains are carried as commensals, while some cause disease in animals and humans. Some type D strains cause atrophic rhinitis in pigs, where the causative agent is known to be the Pasteurella multocida toxin (PMT). PMT activates three families of G-proteins—Gq/11, G12/13, and Gi/o—leading to cellular mitogenesis and other sequelae. The effects of PMT on whole animals in vivo have been investigated previously, but only at the level of organ-specific pathogenesis. We report here the first study to screen all the organs targeted by the toxin by using the QE antibody that recognizes only PMT-modified G-proteins. Under our experimental conditions, short-term treatment of PMT is shown to have multiple in vivo targets, demonstrating G-alpha protein modification, stimulation of proliferation markers and expression of active β-catenin in a tissue- and cell-specific manner. This highlights the usefulness of PMT as an important tool for dissecting the specific roles of different G-alpha proteins in vivo. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends 2.0)
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18 pages, 4272 KiB  
Article
Bacillus anthracis Edema Toxin Inhibits Efferocytosis in Human Macrophages and Alters Efferocytic Receptor Signaling
by Zijian Pan, Eric K. Dumas, Christina Lawrence, Lance Pate, Sherri Longobardi, Xiaodong Wang, Judith A. James, Susan Kovats and A. Darise Farris
Int. J. Mol. Sci. 2019, 20(5), 1167; https://doi.org/10.3390/ijms20051167 - 07 Mar 2019
Cited by 11 | Viewed by 5640
Abstract
The Bacillus anthracis Edema Toxin (ET), composed of a Protective Antigen (PA) and the Edema Factor (EF), is a cellular adenylate cyclase that alters host responses by elevating cyclic adenosine monophosphate (cAMP) to supraphysiologic levels. However, the role of ET in systemic anthrax [...] Read more.
The Bacillus anthracis Edema Toxin (ET), composed of a Protective Antigen (PA) and the Edema Factor (EF), is a cellular adenylate cyclase that alters host responses by elevating cyclic adenosine monophosphate (cAMP) to supraphysiologic levels. However, the role of ET in systemic anthrax is unclear. Efferocytosis is a cAMP-sensitive, anti-inflammatory process of apoptotic cell engulfment, the inhibition of which may promote sepsis in systemic anthrax. Here, we tested the hypothesis that ET inhibits efferocytosis by primary human macrophages and evaluated the mechanisms of altered efferocytic signaling. ET, but not PA or EF alone, inhibited the efferocytosis of early apoptotic neutrophils (PMN) by primary human M2 macrophages (polarized with IL-4, IL-10, and/or dexamethasone) at concentrations relevant to those encountered in systemic infection. ET inhibited Protein S- and MFGE8-dependent efferocytosis initiated by signaling through MerTK and αVβ5 receptors, respectively. ET inhibited Rac1 activation as well as the phosphorylation of Rac1 and key activating sites of calcium calmodulin-dependent kinases CamK1α, CamK4, and vasodilator-stimulated phosphoprotein, that were induced by the exposure of M2(Dex) macrophages to Protein S-opsonized apoptotic PMN. These results show that ET impairs macrophage efferocytosis and alters efferocytic receptor signaling. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends)
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10 pages, 1285 KiB  
Communication
The Bacterial Protein CNF1 as a Potential Therapeutic Strategy against Mitochondrial Diseases: A Pilot Study
by Alessia Fabbri, Sara Travaglione, Zaira Maroccia, Marco Guidotti, Ciro Leonardo Pierri, Guido Primiano, Serenella Servidei, Stefano Loizzo and Carla Fiorentini
Int. J. Mol. Sci. 2018, 19(7), 1825; https://doi.org/10.3390/ijms19071825 - 21 Jun 2018
Cited by 15 | Viewed by 3169
Abstract
The Escherichia coli protein toxin cytotoxic necrotizing factor 1 (CNF1), which acts on the Rho GTPases that are key regulators of the actin cytoskeleton, is emerging as a potential therapeutic tool against certain neurological diseases characterized by cellular energy homeostasis impairment. In this [...] Read more.
The Escherichia coli protein toxin cytotoxic necrotizing factor 1 (CNF1), which acts on the Rho GTPases that are key regulators of the actin cytoskeleton, is emerging as a potential therapeutic tool against certain neurological diseases characterized by cellular energy homeostasis impairment. In this brief communication, we show explorative results on the toxin’s effect on fibroblasts derived from a patient affected by myoclonic epilepsy with ragged-red fibers (MERRF) that carries a mutation in the m.8344A>G gene of mitochondrial DNA. We found that, in the patient’s cells, besides rescuing the wild-type-like mitochondrial morphology, CNF1 administration is able to trigger a significant increase in cellular content of ATP and of the mitochondrial outer membrane marker Tom20. These results were accompanied by a profound F-actin reorganization in MERRF fibroblasts, which is a typical CNF1-induced effect on cell cytoskeleton. These results point at a possible role of the actin organization in preventing or limiting the cell damage due to mitochondrial impairment and at CNF1 treatment as a possible novel strategy against mitochondrial diseases still without cure. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends)
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15 pages, 2824 KiB  
Article
Cell Propagation of Cholera Toxin CTA ADP-Ribosylating Factor by Exosome Mediated Transfer
by Cristiana Zanetti, Angelo Gallina, Alessia Fabbri, Sofia Parisi, Angela Palermo, Katia Fecchi, Zaira Boussadia, Maria Carollo, Mario Falchi, Luca Pasquini, Maria Luisa Fiani and Massimo Sargiacomo
Int. J. Mol. Sci. 2018, 19(5), 1521; https://doi.org/10.3390/ijms19051521 - 19 May 2018
Cited by 3 | Viewed by 4803
Abstract
In this study, we report how the cholera toxin (CT) A subunit (CTA), the enzyme moiety responsible for signaling alteration in host cells, enters the exosomal pathway, secretes extracellularly, transmits itself to a cell population. The first evidence for long-term transmission of CT’s [...] Read more.
In this study, we report how the cholera toxin (CT) A subunit (CTA), the enzyme moiety responsible for signaling alteration in host cells, enters the exosomal pathway, secretes extracellularly, transmits itself to a cell population. The first evidence for long-term transmission of CT’s toxic effect via extracellular vesicles was obtained in Chinese hamster ovary (CHO) cells. To follow the CT intracellular route towards exosome secretion, we used a novel strategy for generating metabolically-labeled fluorescent exosomes that can be counted by flow cytometry assay (FACS) and characterized. Our results clearly show the association of CT with exosomes, together with the heat shock protein 90 (HSP90) and Protein Disulfide Isomerase (PDI) molecules, proteins required for translocation of CTA across the ER membrane into the cytoplasm. Confocal microscopy showed direct internalization of CT containing fluorescent exo into CHO cells coupled with morphological changes in the recipient cells that are characteristic of CT action. Moreover, Me665 cells treated with CT-containing exosomes showed an increase in Adenosine 3’,5’-Cyclic Monophosphate (cAMP) level, reaching levels comparable to those seen in cells exposed directly to CT. Our results prompt the idea that CT can exploit an exosome-mediated cell communication pathway to extend its pathophysiological action beyond an initial host cell, into a multitude of cells. This finding could have implications for cholera disease pathogenesis and epidemiology. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends)
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11 pages, 2241 KiB  
Article
The Bacterial Toxin CNF1 Induces Activation and Maturation of Human Monocyte-Derived Dendritic Cells
by Laura Gall-Mas, Alessia Fabbri, Martin R. J. Namini, Michael Givskov, Carla Fiorentini and Thorbjørn Krejsgaard
Int. J. Mol. Sci. 2018, 19(5), 1408; https://doi.org/10.3390/ijms19051408 - 08 May 2018
Cited by 7 | Viewed by 4669
Abstract
Cytotoxic necrotizing factor 1 (CNF1) is a bacterial protein toxin primarily expressed by pathogenic Escherichia coli strains, causing extraintestinal infections. The toxin is believed to enhance the invasiveness of E. coli by modulating the activity of Rho GTPases in host cells, but it [...] Read more.
Cytotoxic necrotizing factor 1 (CNF1) is a bacterial protein toxin primarily expressed by pathogenic Escherichia coli strains, causing extraintestinal infections. The toxin is believed to enhance the invasiveness of E. coli by modulating the activity of Rho GTPases in host cells, but it has interestingly also been shown to promote inflammation, stimulate host immunity and function as a potent immunoadjuvant. The mechanisms underlying the immunostimulatory properties of CNF1 are, however, poorly characterized, and little is known about the direct effects of the toxin on immune cells. Here, we show that CNF1 induces expression of maturation markers on human immature monocyte-derived dendritic cells (moDCs) without compromising cell viability. Consistent with the phenotypic maturation, CNF1 further triggered secretion of proinflammatory cytokines and increased the capacity of moDCs to stimulate proliferation of allogenic naïve CD4+ T cells. A catalytically inactive form of the toxin did not induce moDC maturation, indicating that the enzymatic activity of CNF1 triggers immature moDCs to undergo phenotypic and functional maturation. As the maturation of dendritic cells plays a central role in initiating inflammation and activating the adaptive immune response, the present findings shed new light on the immunostimulatory properties of CNF1 and may explain why the toxin functions as an immunoadjuvant. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends)
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14 pages, 2104 KiB  
Article
Commensal Staphylococcus aureus Provokes Immunity to Protect against Skin Infection of Methicillin-Resistant Staphylococcus aureus
by John-Jackson Yang, Ting-Wei Chang, Yong Jiang, Hsin-Jou Kao, Bin-Hao Chiou, Ming-Shan Kao and Chun-Ming Huang
Int. J. Mol. Sci. 2018, 19(5), 1290; https://doi.org/10.3390/ijms19051290 - 25 Apr 2018
Cited by 22 | Viewed by 6671
Abstract
Unlike USA300, a strain of community-acquired methicillin-resistant Staphylococcus aureus (MRSA), commensal Staphylococcus aureus (S. aureus) bacteria isolated from human skin demonstrated the ability to mediate the glycerol fermentation to produce short-chain fatty acids (SCFAs). Quantitative proteomic analysis of enzymes involved in [...] Read more.
Unlike USA300, a strain of community-acquired methicillin-resistant Staphylococcus aureus (MRSA), commensal Staphylococcus aureus (S. aureus) bacteria isolated from human skin demonstrated the ability to mediate the glycerol fermentation to produce short-chain fatty acids (SCFAs). Quantitative proteomic analysis of enzymes involved in glycerol fermentation demonstrated that the expression levels of six enzymes, including glycerol-3-phosphate dehydrogenase (GPDH) and phosphoglycerate mutase (PGM), in commensal S. aureus are more than three-fold higher than those in USA300. Western blotting validated the low expression levels of GPDH in USA300, MRSA252 (a strain of hospital-acquired MRSA), and invasive methicillin-susceptible S. aureus (MSSA). In the presence of glycerol, commensal S. aureus effectively suppressed the growth of USA300 in vitro and in vivo. Active immunization of mice with lysates or recombinant α-hemolysin of commensal S. aureus or passive immunization with neutralizing sera provided immune protection against the skin infection of USA300. Our data illustrate for the first time that commensal S. aureus elicits both innate and adaptive immunity via glycerol fermentation and systemic antibody production, respectively, to fight off the skin infection of pathogenic MRSA. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends)
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Review

Jump to: Research

12 pages, 306 KiB  
Review
Botulinum Toxin: From Poison to Possible Treatment for Spasticity in Spinal Cord Injury
by Ramiro Palazón-García and Ana María Benavente-Valdepeñas
Int. J. Mol. Sci. 2021, 22(9), 4886; https://doi.org/10.3390/ijms22094886 - 05 May 2021
Cited by 8 | Viewed by 3199
Abstract
Botulism has been known for about three centuries, and since its discovery, botulinum toxin has been considered one of the most powerful toxins. However, throughout the 20th century, several medical applications have been discovered, among which the treatment of spasticity stands out. Botulinum [...] Read more.
Botulism has been known for about three centuries, and since its discovery, botulinum toxin has been considered one of the most powerful toxins. However, throughout the 20th century, several medical applications have been discovered, among which the treatment of spasticity stands out. Botulinum toxin is the only pharmacological treatment recommended for spasticity of strokes and cerebral palsy. Although its use as an adjuvant treatment against spasticity in spinal cord injuries is not even approved, botulinum toxin is being used against such injuries. This article describes the advances that have been made throughout history leading to the therapeutic use of botulinum toxin and, in particular, its application to the treatment of spasticity in spinal cord injury. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends 2.0)
12 pages, 1918 KiB  
Review
The Importance of Therapeutically Targeting the Binary Toxin from Clostridioides difficile
by Dinendra L. Abeyawardhane, Raquel Godoy-Ruiz, Kaylin A. Adipietro, Kristen M. Varney, Richard R. Rustandi, Edwin Pozharski and David J. Weber
Int. J. Mol. Sci. 2021, 22(6), 2926; https://doi.org/10.3390/ijms22062926 - 13 Mar 2021
Cited by 9 | Viewed by 2716
Abstract
Novel therapeutics are needed to treat pathologies associated with the Clostridioides difficile binary toxin (CDT), particularly when C. difficile infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to [...] Read more.
Novel therapeutics are needed to treat pathologies associated with the Clostridioides difficile binary toxin (CDT), particularly when C. difficile infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the large clostridial toxins (TcdA and TcdB) in this nosocomial disease, nothing is available yet to treat toxicities arising from strains of CDI having the binary toxin. Like other binary toxins, the active CDTa catalytic subunit of CDT is delivered into host cells together with an oligomeric assembly of CDTb subunits via host cell receptor-mediated endocytosis. Once CDT arrives in the host cell’s cytoplasm, CDTa catalyzes the ADP-ribosylation of G-actin leading to degradation of the cytoskeleton and rapid cell death. Although a detailed molecular mechanism for CDT entry and host cell toxicity is not yet fully established, structural and functional resemblances to other binary toxins are described. Additionally, unique conformational assemblies of individual CDT components are highlighted herein to refine our mechanistic understanding of this deadly toxin as is needed to develop effective new therapeutic strategies for treating some of the most hypervirulent and lethal strains of CDT-containing strains of CDI. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends 2.0)
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21 pages, 1531 KiB  
Review
Gut Microbiota and Colon Cancer: A Role for Bacterial Protein Toxins?
by Carla Fiorentini, Francesca Carlini, Elena Angela Pia Germinario, Zaira Maroccia, Sara Travaglione and Alessia Fabbri
Int. J. Mol. Sci. 2020, 21(17), 6201; https://doi.org/10.3390/ijms21176201 - 27 Aug 2020
Cited by 29 | Viewed by 4846
Abstract
Accumulating evidence indicates that the human intestinal microbiota can contribute to the etiology of colorectal cancer. Triggering factors, including inflammation and bacterial infections, may favor the shift of the gut microbiota from a mutualistic to a pro-carcinogenic configuration. In this context, certain bacterial [...] Read more.
Accumulating evidence indicates that the human intestinal microbiota can contribute to the etiology of colorectal cancer. Triggering factors, including inflammation and bacterial infections, may favor the shift of the gut microbiota from a mutualistic to a pro-carcinogenic configuration. In this context, certain bacterial pathogens can exert a pro-tumoral activity by producing enzymatically-active protein toxins that either directly induce host cell DNA damage or interfere with essential host cell signaling pathways involved in cell proliferation, apoptosis, and inflammation. This review is focused on those toxins that, by mimicking carcinogens and cancer promoters, could represent a paradigm for bacterially induced carcinogenesis. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends 2.0)
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13 pages, 1510 KiB  
Review
Bacterial Toxins and Targeted Brain Therapy: New Insights from Cytotoxic Necrotizing Factor 1 (CNF1)
by Elena Tantillo, Antonella Colistra, Eleonora Vannini, Chiara Cerri, Laura Pancrazi, Laura Baroncelli, Mario Costa and Matteo Caleo
Int. J. Mol. Sci. 2018, 19(6), 1632; https://doi.org/10.3390/ijms19061632 - 31 May 2018
Cited by 10 | Viewed by 3887
Abstract
Pathogenic bacteria produce toxins to promote host invasion and, therefore, their survival. The extreme potency and specificity of these toxins confer to this category of proteins an exceptionally strong potential for therapeutic exploitation. In this review, we deal with cytotoxic necrotizing factor (CNF1), [...] Read more.
Pathogenic bacteria produce toxins to promote host invasion and, therefore, their survival. The extreme potency and specificity of these toxins confer to this category of proteins an exceptionally strong potential for therapeutic exploitation. In this review, we deal with cytotoxic necrotizing factor (CNF1), a cytotoxin produced by Escherichia coli affecting fundamental cellular processes, including cytoskeletal dynamics, cell cycle progression, transcriptional regulation, cell survival and migration. First, we provide an overview of the mechanisms of action of CNF1 in target cells. Next, we focus on the potential use of CNF1 as a pharmacological treatment in central nervous system’s diseases. CNF1 appears to impact neuronal morphology, physiology, and plasticity and displays an antineoplastic activity on brain tumors. The ability to preserve neural functionality and, at the same time, to trigger senescence and death of proliferating glioma cells, makes CNF1 an encouraging new strategy for the treatment of brain tumors. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends)
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20 pages, 7304 KiB  
Review
Experimental Intrastriatal Applications of Botulinum Neurotoxin-A: A Review
by Alexander Hawlitschka and Andreas Wree
Int. J. Mol. Sci. 2018, 19(5), 1392; https://doi.org/10.3390/ijms19051392 - 07 May 2018
Cited by 11 | Viewed by 3815
Abstract
Parkinson’s disease (PD) is one of the most frequent neurodegenerative disorders. Its main pathophysiological characteristic is the loss of dopaminergic neurons in the substantia nigra pars compacta followed by a lack of striatal dopaminergic input and a consequent disinhibition of tonically active cholinergic [...] Read more.
Parkinson’s disease (PD) is one of the most frequent neurodegenerative disorders. Its main pathophysiological characteristic is the loss of dopaminergic neurons in the substantia nigra pars compacta followed by a lack of striatal dopaminergic input and a consequent disinhibition of tonically active cholinergic interneurons. The resulting striatal hypercholinism causes major motor symptoms in PD. Anticholinergic pharmacotherapies have antiparkinsonian effects on motor symptoms, but, due to systemic actions, also numerous severe side effects occur on a regular basis. To circumvent these side effects, a local anticholinergic therapy acting exclusively in the striatum would be reasonable. Botulinum neurotoxin-A (BoNT-A) is synthesized by Clostridium botulinum and blocks the release of acetylcholine from the presynaptic bouton. For several decades, BoNT-A has been used successfully for medical and cosmetic purposes to induce controlled paralyses of single muscles. Our group and others investigated the experimental treatment of striatal hypercholinism by the direct injection of BoNT-A into the striatum of rats and mice as well as of hemiparkinsonian animal models. This review gives an overview of the most important results of the experimental intrastriatal BoNT-A application, with a focus on hemiparkinsonian rats. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends)
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Review
Multifaceted Role of Pneumolysin in the Pathogenesis of Myocardial Injury in Community-Acquired Pneumonia
by Ronald Anderson, Jan G. Nel and Charles Feldman
Int. J. Mol. Sci. 2018, 19(4), 1147; https://doi.org/10.3390/ijms19041147 - 11 Apr 2018
Cited by 34 | Viewed by 6554
Abstract
Pneumolysin (PLY), a member of the family of Gram-positive bacterial, cholesterol-dependent, β-barrel pore-forming cytolysins, is the major protein virulence factor of the dangerous respiratory pathogen, Streptococcus pneumoniae (pneumococcus). PLY plays a major role in the pathogenesis of community-acquired pneumonia (CAP), promoting colonization and [...] Read more.
Pneumolysin (PLY), a member of the family of Gram-positive bacterial, cholesterol-dependent, β-barrel pore-forming cytolysins, is the major protein virulence factor of the dangerous respiratory pathogen, Streptococcus pneumoniae (pneumococcus). PLY plays a major role in the pathogenesis of community-acquired pneumonia (CAP), promoting colonization and invasion of the upper and lower respiratory tracts respectively, as well as extra-pulmonary dissemination of the pneumococcus. Notwithstanding its role in causing acute lung injury in severe CAP, PLY has also been implicated in the development of potentially fatal acute and delayed-onset cardiovascular events, which are now recognized as being fairly common complications of this condition. This review is focused firstly on updating mechanisms involved in the immunopathogenesis of PLY-mediated myocardial damage, specifically the direct cardiotoxic and immunosuppressive activities, as well as the indirect pro-inflammatory/pro-thrombotic activities of the toxin. Secondly, on PLY-targeted therapeutic strategies including, among others, macrolide antibiotics, natural product antagonists, cholesterol-containing liposomes, and fully humanized monoclonal antibodies, as well as on vaccine-based preventive strategies. These sections are preceded by overviews of CAP in general, the role of the pneumococcus as the causative pathogen, the occurrence and types of CAP-associated cardiac complication, and the structure and biological activities of PLY. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends)
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