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Toxins
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Cholera Toxin
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Cholera Toxin

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

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 4882

Special Issue Editors

Dr. Thandavarayan Ramamurthy

E-Mail Website
Guest Editor
ICMR-National Institute of Cholera and Enteric Diseases, Kolkata 700010, India
Interests: cholera; infectious diseases; molecular epidemiology; antimicrobial resistance; microbial ecology
Prof. Dr. Asoke C. Ghose

E-Mail Website
Guest Editor
Former Professor, Department of Microbiology, Bose Institute, Kolkata 700054, India
Interests: Vibrio cholerae; cholera; immunogenetics; pathophysiology; cholera toxin
Dr. Amit Ghosh

E-Mail Website
Guest Editor
ICMR-National Institute of Cholera and Enteric Diseases, Kolkata 700010, India
Interests: Vibrio cholerae; cholera; cholera toxin; molecular genetics; vaccines
Dr. G. Balakrish Nair

E-Mail Website
Guest Editor
Former Regional Advisor, Communicable Diseases Department, World Health Organization, New Delhi 110002, India
Interests: molecular epidemiology; clinical microbiology; Vibrio cholerae; cholera; cholera toxin

Special Issue Information

Dear Colleagues,

Cholera toxin (CT) has been considered an important protein in several medical research and technology advancements. CT serves as a model for AB type toxins that act by ADP-ribosylation of an intracellular G-protein in the target cell. High-resolution crystal structure studies of CT subunits led to the development of its molecular dynamics and docking simulation models. Several other studies revealed the inter-domain stability of CT, as well as its translocation steps during the internalization process, and also facilitated discovery of its pharmacological properties. The fusogenic lectin-like property of CT has been explored for membrane transport, cell signalling, host cell biology and controlling intracellular machineries. Changes in the CTB sequences play an important role in the global epidemics of cholera.

CT plays an important role in the induction of protective immunity against cholera. CTB-associated mucosal immunity has been further explored in the development of vaccines against several pathogens. CTB is also proven to possess neuroprotective mechanisms, contribute to the maintenance of intestinal homeostasis, induce wound-healing effects, and improve the efficiency of drug delivery and treatment of inflammatory diseases. The immunomodulatory function of CT has been investigated for reducing age-associated obesity, food allergens, detection and treatment of cancer, autoantigen-specific immunotherapy for multiple sclerosis and type-1 diabetes.

The binding ability of CT to ganglioside GM1, fucosylated glycoconjugates/molecules and the other host glycoproteins has been tested to block the CT action and design detoxified enterotoxin-based adjuvants. Several inhibitors of CT have also been discovered and well characterised as potential agents of toxin binding.

Considering the vast information accumulated in the past, we trust that a comprehensive collection of articles from the experts in this Special Issue would be of great value to many researchers.

Dr. Thandavarayan Ramamurthy
Prof. Dr. Asoke C. Ghose
Dr. Amit Ghosh
Dr. G. Balakrish Nair
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 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

  • cholera
  • cholera toxin
  • GM1 ganglioside
  • CT-B subunit
  • diarrhoea
  • vaccines
  • immunity

Published Papers (4 papers)

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Research

13 pages, 4791 KiB  
Article
Sortase-Modified Cholera Toxoids Show Specific Golgi Localization
by Darren C. Machin, Daniel J. Williamson, Peter Fisher, Victoria J. Miller, Zoe L. P. Arnott, Charlotte M. E. Stevenson, Gemma C. Wildsmith, James F. Ross, Christopher W. Wasson, Andrew Macdonald, Benjamin I. Andrews, Daniel Ungar, W. Bruce Turnbull and Michael E. Webb
Toxins 2024, 16(4), 194; https://doi.org/10.3390/toxins16040194 - 16 Apr 2024
Viewed by 436
Abstract
Cholera toxoid is an established tool for use in cellular tracing in neuroscience and cell biology. We use a sortase labeling approach to generate site-specific N-terminally modified variants of both the A2-B5 heterohexamer and B5 pentamer forms of the toxoid. Both [...] Read more.
Cholera toxoid is an established tool for use in cellular tracing in neuroscience and cell biology. We use a sortase labeling approach to generate site-specific N-terminally modified variants of both the A2-B5 heterohexamer and B5 pentamer forms of the toxoid. Both forms of the toxoid are endocytosed by GM1-positive mammalian cells, and while the heterohexameric toxoid was principally localized in the ER, the B5 pentamer showed an unexpectedly specific localization in the medial/trans-Golgi. This study suggests a future role for specifically labeled cholera toxoids in live-cell imaging beyond their current applications in neuronal tracing and labeling of lipid rafts in fixed cells. Full article
(This article belongs to the Special Issue Cholera Toxin)
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16 pages, 6769 KiB  
Article
The Mutagenic Plasticity of the Cholera Toxin B-Subunit Surface Residues: Stability and Affinity
by Cheuk W. Au, Iain Manfield, Michael E. Webb, Emanuele Paci, W. Bruce Turnbull and James F. Ross
Toxins 2024, 16(3), 133; https://doi.org/10.3390/toxins16030133 - 04 Mar 2024
Viewed by 1258
Abstract
Mastering selective molecule trafficking across human cell membranes poses a formidable challenge in healthcare biotechnology while offering the prospect of breakthroughs in drug delivery, gene therapy, and diagnostic imaging. The cholera toxin B-subunit (CTB) has the potential to be a useful cargo transporter [...] Read more.
Mastering selective molecule trafficking across human cell membranes poses a formidable challenge in healthcare biotechnology while offering the prospect of breakthroughs in drug delivery, gene therapy, and diagnostic imaging. The cholera toxin B-subunit (CTB) has the potential to be a useful cargo transporter for these applications. CTB is a robust protein that is amenable to reengineering for diverse applications; however, protein redesign has mostly focused on modifications of the N- and C-termini of the protein. Exploiting the full power of rational redesign requires a detailed understanding of the contributions of the surface residues to protein stability and binding activity. Here, we employed Rosetta-based computational saturation scans on 58 surface residues of CTB, including the GM1 binding site, to analyze both ligand-bound and ligand-free structures to decipher mutational effects on protein stability and GM1 affinity. Complimentary experimental results from differential scanning fluorimetry and isothermal titration calorimetry provided melting temperatures and GM1 binding affinities for 40 alanine mutants among these positions. The results showed that CTB can accommodate diverse mutations while maintaining its stability and ligand binding affinity. These mutations could potentially allow modification of the oligosaccharide binding specificity to change its cellular targeting, alter the B-subunit intracellular routing, or impact its shelf-life and in vivo half-life through changes to protein stability. We anticipate that the mutational space maps presented here will serve as a cornerstone for future CTB redesigns, paving the way for the development of innovative biotechnological tools. Full article
(This article belongs to the Special Issue Cholera Toxin)
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14 pages, 1389 KiB  
Article
Expression of Cholera Toxin (CT) and the Toxin Co-Regulated Pilus (TCP) by Variants of ToxT in Vibrio cholerae Strains
by Donghyun Lee, Hunseok Choi, Seonghyeon Son, Jonghyun Bae, Jayun Joo, Dong Wook Kim and Eun Jin Kim
Toxins 2023, 15(8), 507; https://doi.org/10.3390/toxins15080507 - 17 Aug 2023
Cited by 1 | Viewed by 1320
Abstract
The expression of the two major virulence genes of Vibrio cholerae—tcpA (the major subunit of the toxin co-regulated pilus) and ctxAB (cholera toxin)—is regulated by the ToxR regulon, which is triggered by environmental stimuli during infection within the human small intestine. [...] Read more.
The expression of the two major virulence genes of Vibrio cholerae—tcpA (the major subunit of the toxin co-regulated pilus) and ctxAB (cholera toxin)—is regulated by the ToxR regulon, which is triggered by environmental stimuli during infection within the human small intestine. Special culture methods are required to induce the expression of virulence genes in V. cholerae in the laboratory setting. In the present study, induction of the expression of virulence genes by two point mutations (65th and 139th amino acids) in toxT, which is produced by the ToxR regulon and activates the transcription of the virulence genes in V. cholerae, under laboratory culture conditions has been investigated. Each of the four toxT alleles assessed displayed different transcriptional activator functions in a given V. cholerae strain. Although the ToxR regulon has been known to not be expressed by El Tor biotype V. cholerae strains cultured under standard laboratory conditions, the variant toxT alleles that we assessed in this study enabled the expression virulence genes in El Tor biotype strains grown under simple culture conditions comprising shake culture in LB medium, suggesting that the regulation of virulence gene expression may be regulated more complexly than previously thought and may involve additional factors beyond the production of ToxT by the ToxR regulon. Full article
(This article belongs to the Special Issue Cholera Toxin)
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16 pages, 7278 KiB  
Article
The Functions of Cholera Toxin Subunit B as a Modulator of Silica Nanoparticle Endocytosis
by Eva Susnik, Sandor Balog, Patricia Taladriz-Blanco, Alke Petri-Fink and Barbara Rothen-Rutishauser
Toxins 2023, 15(8), 482; https://doi.org/10.3390/toxins15080482 - 29 Jul 2023
Viewed by 1319
Abstract
The gastrointestinal tract is the main target of orally ingested nanoparticles (NPs) and at the same time is exposed to noxious substances, such as bacterial components. We investigated the interaction of 59 nm silica (SiO2) NPs with differentiated Caco-2 intestinal epithelial [...] Read more.
The gastrointestinal tract is the main target of orally ingested nanoparticles (NPs) and at the same time is exposed to noxious substances, such as bacterial components. We investigated the interaction of 59 nm silica (SiO2) NPs with differentiated Caco-2 intestinal epithelial cells in the presence of cholera toxin subunit B (CTxB) and compared the effects to J774A.1 macrophages. CTxB can affect cellular functions and modulate endocytosis via binding to the monosialoganglioside (GM1) receptor, expressed on both cell lines. After stimulating macrophages with CTxB, we observed notable changes in the membrane structure but not in Caco-2 cells, and no secretion of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) was detected. Cells were then exposed to 59 nm SiO2 NPs and CtxB sequentially and simultaneously, resulting in a high NP uptake in J774A.1 cells, but no uptake in Caco-2 cells was detected. Flow cytometry analysis revealed that the exposure of J774A.1 cells to CTxB resulted in a significant reduction in the uptake of SiO2 NPs. In contrast, the uptake of NPs by highly selective Caco-2 cells remained unaffected following CTxB exposure. Based on colocalization studies, CTxB and NPs might enter cells via shared endocytic pathways, followed by their sorting into different intracellular compartments. Our findings provide new insights into CTxB’s function of modulating SiO2 NP uptake in phagocytic but not in differentiated intestine cells. Full article
(This article belongs to the Special Issue Cholera Toxin)
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