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Toxins
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Toxin-Host Interaction of Clostridium Toxins
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Toxin-Host Interaction of Clostridium Toxins

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

Deadline for manuscript submissions: 31 May 2024 | Viewed by 12045

Special Issue Editor

Dr. Jonatan Dorca-Arévalo

E-Mail Website
Guest Editor
Institut d'Investigació Biomedica de Bellvitge, Hospitalet de Llobregat, Spain
Interests: bacterial protein toxins; pore-forming toxins; neurotoxins; microvesicles; exosomes; demyelinating diseases; oli-godendrocytes; glial cells; gut–brain axis; blood–brain barrier crossing; immune system; lipid rafts

Special Issue Information

Dear Colleagues,

There are many toxins produced by Clostridia that are involved in serious disease in a wide range of animals, including humans. Most of these toxins cause gastrointestinal diseases with serious health problems that lead to the death of the host. Well-known clostridial toxins include: binary toxins, such as Clostridioides difficile toxins (TcdA and TcdB) or Clostridium spiriforme toxin (CST), which employ a synergistic binary mechanism for intoxicating eukaryotic cells; large clostridial toxins (LCTs), such as Clostridium perfringens toxin TpeL and Clostridium novyi toxin (TcnA), which infiltrate and destroy eukaryotic cells to promote bacterial infection; and pore-forming toxins (PFTs), such as Clostridium perfringens epsilon toxin (Etx) or perfringolysin O (Pfo), which produce small pores in the plasma membrane of the host cell. Moreover, some clostridial neurotoxins can cross the blood–brain barrier such as Etx, which can produce neuronal damage. Other neurotoxins include botulinum neurotoxins (BoNTs), which inhibit neurotransmission at neuromuscular junctions, and tetanus neurotoxin (TeNT), which targets the inhibitory interneurons of the CNS.

The main goal of this Special Issue is the study of the toxin–host interactions of Clostridium toxins. We welcome expert reviews of clinical aspects of host intoxication, as well as research papers on the following sub-topics:

-Structural studies of the toxin binding to the host cell receptor;

-The effects of the clostridial toxins in the host cells;

-The implication of the clostridial toxins in the gut–brain axis;

-The clostridial toxins effects in the blood and in the immune system;

-New methods of toxin detection and diagnosis in host animals;

-Novel neutralizing toxin molecules;

-New vaccines against clostridial diseases;

-New clostridial toxin mutants.

We look forward to receiving your contributions.

Dr. Jonatan Dorca-Arévalo
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

  • clostridial toxins
  • gut-brain axis
  • clostridial vaccines
  • clostridial diseases
  • clostridial toxin structure
  • clostridial toxin effects

Published Papers (6 papers)

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Research

Jump to: Review

18 pages, 3585 KiB  
Article
PLGA Nanoparticle-Based Dissolving Microneedle Vaccine of Clostridium perfringens ε Toxin
by Wei Wan, Yue Li, Jing Wang, Zhiying Jin, Wenwen Xin, Lin Kang, Junhong Wang, Xiaoyang Li, Yakun Cao, Hao Yang, Jinglin Wang and Shan Gao
Toxins 2023, 15(7), 461; https://doi.org/10.3390/toxins15070461 - 19 Jul 2023
Cited by 1 | Viewed by 1657
Abstract
Epsilon toxin (ETX) is an exotoxin produced by type B and D Clostridium perfringens that causes enterotoxemia or necrotic enteritis in animals such as goats, sheep, and cattle. Vaccination is a key method in preventing such diseases. In this study, we developed a [...] Read more.
Epsilon toxin (ETX) is an exotoxin produced by type B and D Clostridium perfringens that causes enterotoxemia or necrotic enteritis in animals such as goats, sheep, and cattle. Vaccination is a key method in preventing such diseases. In this study, we developed a new type of dissolving microneedle patch (dMN) with a nanoparticle adjuvant for enhanced immune response to deliver the rETXY196E-C protein vaccine. We chose FDA-approved poly(lactic-co-glycolic acid) (PLGA) to prepare nanospheres as the vaccine adjuvant and introduced dimethyldioctadecylammonium bromide (DDAB) to make the surface of PLGA nanoparticles (PLGA NPs) positively charged for antigen adsorption. PLGA NPs with a diameter of 100~200 nm, a surface ZETA potential of approximately +40 mV, and good safety were successfully prepared and could effectively adsorb rETXY196E-C protein. Using non-toxic and antibacterial fish gelatin as the microneedle (MN) matrix, we prepared a PLGA-DDAB dMN vaccine with good mechanical properties that successfully penetrated the skin. After immunization of subcutaneous (SC) and dMN, antibody titers of the PLGA and Al adjuvant groups were similar in both two immune ways. However, in vivo neutralization experiments showed that the dMN vaccines had a better protective effect. When challenged with 100 × LD50 GST-ETX, the survival rate of the MN group was 100%, while that of the SC Al group was 80%. However, a 100% protective effect was achieved in both immunization methods using PLGA NPs. In vitro neutralization experiments showed that the serum antibodies from the dMN and SC PLGA NPs groups both protect naive mice from 10 × LD50 GST-ETX attack after being diluted 20 times and could also protect MDCK cells from 20 × CT50 GST-ETX attack. In conclusion, the PLGA-DDAB dMN vaccine we prepared has good mechanical properties, immunogenicity, and protection, and can effectively prevent ETX poisoning. This provides a better way of delivering protein vaccines. Full article
(This article belongs to the Special Issue Toxin-Host Interaction of Clostridium Toxins)
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19 pages, 2316 KiB  
Article
Clostridium perfringens Epsilon Toxin Binds to and Kills Primary Human Lymphocytes
by Samantha V. Shetty, Michael R. Mazzucco, Paige Winokur, Sylvia V. Haigh, Kareem Rashid Rumah, Vincent A. Fischetti, Timothy Vartanian and Jennifer R. Linden
Toxins 2023, 15(7), 423; https://doi.org/10.3390/toxins15070423 - 29 Jun 2023
Viewed by 1586
Abstract
Clostridium perfringens epsilon toxin (ETX) is the third most lethal bacterial toxin and has been suggested to be an environmental trigger of multiple sclerosis, an immune-mediated disease of the human central nervous system. However, ETX cytotoxicity on primary human cells has not been [...] Read more.
Clostridium perfringens epsilon toxin (ETX) is the third most lethal bacterial toxin and has been suggested to be an environmental trigger of multiple sclerosis, an immune-mediated disease of the human central nervous system. However, ETX cytotoxicity on primary human cells has not been investigated. In this article, we demonstrate that ETX preferentially binds to and kills human lymphocytes expressing increased levels of the myelin and lymphocyte protein MAL. Using flow cytometry, ETX binding was determined to be time and dose dependent and was highest for CD4+ cells, followed by CD8+ and then CD19+ cells. Similar results were seen with ETX-induced cytotoxicity. To determine if ETX preference for CD4+ cells was related to MAL expression, MAL gene expression was determined by RT-qPCR. CD4+ cells had the highest amount of Mal gene expression followed by CD8+ and CD19+ cells. These data indicate that primary human cells are susceptible to ETX and support the hypothesis that MAL is a main receptor for ETX. Interestingly, ETX bindings to human lymphocytes suggest that ETX may influence immune response in multiple sclerosis. Full article
(This article belongs to the Special Issue Toxin-Host Interaction of Clostridium Toxins)
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15 pages, 7662 KiB  
Article
Domperidone Protects Cells from Intoxication with Clostridioides difficile Toxins by Inhibiting Hsp70-Assisted Membrane Translocation
by Maria Braune-Yan, Jinfang Jia, Mary Wahba, Johannes Schmid, Panagiotis Papatheodorou, Holger Barth and Katharina Ernst
Toxins 2023, 15(6), 384; https://doi.org/10.3390/toxins15060384 - 07 Jun 2023
Cited by 1 | Viewed by 1627
Abstract
Clostridioides difficile infections cause severe symptoms ranging from diarrhea to pseudomembranous colitis due to the secretion of AB-toxins, TcdA and TcdB. Both toxins are taken up into cells through receptor-mediated endocytosis, autoproteolytic processing and translocation of their enzyme domains from acidified endosomes into [...] Read more.
Clostridioides difficile infections cause severe symptoms ranging from diarrhea to pseudomembranous colitis due to the secretion of AB-toxins, TcdA and TcdB. Both toxins are taken up into cells through receptor-mediated endocytosis, autoproteolytic processing and translocation of their enzyme domains from acidified endosomes into the cytosol. The enzyme domains glucosylate small GTPases such as Rac1, thereby inhibiting processes such as actin cytoskeleton regulation. Here, we demonstrate that specific pharmacological inhibition of Hsp70 activity protected cells from TcdB intoxication. In particular, the established inhibitor VER-155008 and the antiemetic drug domperidone, which was found to be an Hsp70 inhibitor, reduced the number of cells with TcdB-induced intoxication morphology in HeLa, Vero and intestinal CaCo-2 cells. These drugs also decreased the intracellular glucosylation of Rac1 by TcdB. Domperidone did not inhibit TcdB binding to cells or enzymatic activity but did prevent membrane translocation of TcdB’s glucosyltransferase domain into the cytosol. Domperidone also protected cells from intoxication with TcdA as well as CDT toxin produced by hypervirulent strains of Clostridioides difficile. Our results reveal Hsp70 requirement as a new aspect of the cellular uptake mechanism of TcdB and identified Hsp70 as a novel drug target for potential therapeutic strategies required to combat severe Clostridioides difficile infections. Full article
(This article belongs to the Special Issue Toxin-Host Interaction of Clostridium Toxins)
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13 pages, 2011 KiB  
Article
Genomic Insights into Virulence Factors and Multi-Drug Resistance in Clostridium perfringens IRMC2505A
by Reem AlJindan, Doaa M. AlEraky, Maha Farhat, Noor B. Almandil, Sayed AbdulAzeez and Jesu Francis Borgio
Toxins 2023, 15(6), 359; https://doi.org/10.3390/toxins15060359 - 25 May 2023
Cited by 3 | Viewed by 2223
Abstract
Clostridium perfringens is a spore-forming, Gram-positive anaerobic pathogen that causes several disorders in humans and animals. A multidrug-resistant Clostridium strain was isolated from the fecal sample of a patient who was clinically suspected of gastrointestinal infection and had a recent history of antibiotic [...] Read more.
Clostridium perfringens is a spore-forming, Gram-positive anaerobic pathogen that causes several disorders in humans and animals. A multidrug-resistant Clostridium strain was isolated from the fecal sample of a patient who was clinically suspected of gastrointestinal infection and had a recent history of antibiotic exposure and diarrhea. The strain was identified by 16s rRNA sequencing as Clostridium perfringens. The strain’s pathogenesis was analyzed through its complete genome, specifically antimicrobial resistance-related genes. The Clostridium perfringens IRMC2505A genome contains 19 (Alr, Ddl, dxr, EF-G, EF-Tu, folA, Dfr, folP, gyrA, gyrB, Iso-tRNA, kasA, MurA, rho, rpoB, rpoC, S10p, and S12p) antibiotic-susceptible genetic species according to the k-mer-based detection of antimicrobial resistance genes. Genome mapping using CARD and VFDB databases revealed significant (p-value = 1 × 10−26) genes with aligned reads against antibiotic-resistant genes or virulence factors, including phospholipase C, perfringolysin O, collagenase, hyaluronidase, alpha-clostripain, exo-alpha-sialidase, and sialidase activity. In conclusion, this is the first report on C. perfringens from Saudi Arabia that conducted whole genome sequencing of IRMC2505A and confirmed the strain as an MDR bacterium with several virulence factors. Developing control strategies requires a detailed understanding of the epidemiology of C. perfringens, its virulence factors, and regional antimicrobial resistance patterns. Full article
(This article belongs to the Special Issue Toxin-Host Interaction of Clostridium Toxins)
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Review

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14 pages, 2539 KiB  
Review
The Molecular Architecture and Mode of Action of Clostridium perfringens ε-Toxin
by Richard W. Titball
Toxins 2024, 16(4), 180; https://doi.org/10.3390/toxins16040180 - 07 Apr 2024
Viewed by 561
Abstract
Clostridium perfringens ε-toxin has long been associated with a severe enterotoxaemia of livestock animals, and more recently, was proposed to play a role in the etiology of multiple sclerosis in humans. The remarkable potency of the toxin has intrigued researchers for many decades, [...] Read more.
Clostridium perfringens ε-toxin has long been associated with a severe enterotoxaemia of livestock animals, and more recently, was proposed to play a role in the etiology of multiple sclerosis in humans. The remarkable potency of the toxin has intrigued researchers for many decades, who suggested that this indicated an enzymatic mode of action. Recently, there have been major breakthroughs by finding that it is a pore-forming toxin which shows exquisite specificity for cells bearing the myelin and lymphocyte protein (MAL) receptor. This review details the molecular structures of the toxin, the evidence which identifies MAL as the receptor and the possible roles of other cell membrane components in toxin binding. The information on structure and mode of action has allowed the functions of individual amino acids to be investigated and has led to the creation of mutants with reduced toxicity that could serve as vaccines. In spite of this progress, there are still a number of key questions around the mode of action of the toxin which need to be further investigated. Full article
(This article belongs to the Special Issue Toxin-Host Interaction of Clostridium Toxins)
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27 pages, 3347 KiB  
Review
Recent Developments in Vaccine Design: From Live Vaccines to Recombinant Toxin Vaccines
by Sonal Gupta and Sabine Pellett
Toxins 2023, 15(9), 563; https://doi.org/10.3390/toxins15090563 - 08 Sep 2023
Cited by 3 | Viewed by 3830
Abstract
Vaccines are one of the most effective strategies to prevent pathogen-induced illness in humans. The earliest vaccines were based on live inoculations with low doses of live or related pathogens, which carried a relatively high risk of developing the disease they were meant [...] Read more.
Vaccines are one of the most effective strategies to prevent pathogen-induced illness in humans. The earliest vaccines were based on live inoculations with low doses of live or related pathogens, which carried a relatively high risk of developing the disease they were meant to prevent. The introduction of attenuated and killed pathogens as vaccines dramatically reduced these risks; however, attenuated live vaccines still carry a risk of reversion to a pathogenic strain capable of causing disease. This risk is completely eliminated with recombinant protein or subunit vaccines, which are atoxic and non-infectious. However, these vaccines require adjuvants and often significant optimization to induce robust T-cell responses and long-lasting immune memory. Some pathogens produce protein toxins that cause or contribute to disease. To protect against the effects of such toxins, chemically inactivated toxoid vaccines have been found to be effective. Toxoid vaccines are successfully used today at a global scale to protect against tetanus and diphtheria. Recent developments for toxoid vaccines are investigating the possibilities of utilizing recombinant protein toxins mutated to eliminate biologic activity instead of chemically inactivated toxins. Finally, one of the most contemporary approaches toward vaccine design utilizes messenger RNA (mRNA) as a vaccine candidate. This approach was used globally to protect against coronavirus disease during the COVID-19 pandemic that began in 2019, due to its advantages of quick production and scale-up, and effectiveness in eliciting a neutralizing antibody response. Nonetheless, mRNA vaccines require specialized storage and transport conditions, posing challenges for low- and middle-income countries. Among multiple available technologies for vaccine design and formulation, which technology is most appropriate? This review focuses on the considerable developments that have been made in utilizing diverse vaccine technologies with a focus on vaccines targeting bacterial toxins. We describe how advancements in vaccine technology, combined with a deeper understanding of pathogen–host interactions, offer exciting and promising avenues for the development of new and improved vaccines. Full article
(This article belongs to the Special Issue Toxin-Host Interaction of Clostridium Toxins)
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