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Tissue Barriers 2016Beside digesting nutrients and absorbing solutes and electrolytes, the intestinal epithelium with its barrier function is in charge of a tightly controlled antigen... (Review)
Review
Beside digesting nutrients and absorbing solutes and electrolytes, the intestinal epithelium with its barrier function is in charge of a tightly controlled antigen trafficking from the intestinal lumen to the submucosa. This trafficking dictates the delicate balance between tolerance and immune response causing inflammation. Loss of barrier function secondary to upregulation of zonulin, the only known physiological modulator of intercellular tight junctions, leads to uncontrolled influx of dietary and microbial antigens. Additional insights on zonulin mechanism of action and the recent appreciation of the role that altered intestinal permeability can play in the development and progression of chronic inflammatory disorders has increased interest of both basic scientists and clinicians on the potential role of zonulin in the pathogenesis of these diseases. This review focuses on the recent research implicating zonulin as a master regulator of intestinal permeability linked to the development of several chronic inflammatory disorders.
Topics: Animals; Autoimmune Diseases; Cholera Toxin; Endothelial Cells; Haptoglobins; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Protein Precursors; Tight Junctions
PubMed: 28123927
DOI: 10.1080/21688370.2016.1251384 -
Toxins Aug 2021Cholera toxin B-subunit (CTxB) has emerged as one of the most widely utilized tools in membrane biology and biophysics. CTxB is a homopentameric stable protein that... (Review)
Review
Cholera toxin B-subunit (CTxB) has emerged as one of the most widely utilized tools in membrane biology and biophysics. CTxB is a homopentameric stable protein that binds tightly to up to five GM1 glycosphingolipids. This provides a robust and tractable model for exploring membrane structure and its dynamics including vesicular trafficking and nanodomain assembly. Here, we review important advances in these fields enabled by use of CTxB and its lipid receptor GM1.
Topics: Cell Membrane; Cholera Toxin; Clathrin; Endocytosis; Receptors, Cell Surface
PubMed: 34437414
DOI: 10.3390/toxins13080543 -
Infection and Immunity May 2023In order for successful fecal-oral transmission, enteric bacterial pathogens have to successfully compete with the intestinal microbiota and reach high concentrations... (Review)
Review
In order for successful fecal-oral transmission, enteric bacterial pathogens have to successfully compete with the intestinal microbiota and reach high concentrations during infection. Vibrio cholerae requires cholera toxin (CT) to cause diarrheal disease, which is thought to promote the fecal-oral transmission of the pathogen. Besides inducing diarrheal disease, the catalytic activity of CT also alters host intestinal metabolism, which promotes the growth of V. cholerae during infection through the acquisition of host-derived nutrients. Furthermore, recent studies have found that CT-induced disease activates a niche-specific suite of V. cholerae genes during infection, some of which may be important for fecal-oral transmission of the pathogen. Our group is currently exploring the concept that CT-induced disease promotes the fecal-oral transmission of V. cholerae by modulating both host and pathogen metabolism. Furthermore, the role of the intestinal microbiota in pathogen growth and transmission during toxin-induced disease merits further investigation. These studies open the door to investigating whether other bacterial toxins also enhance pathogen growth and transmission during infection, which may shed light on the design of novel therapeutics for intervention or prevention of diarrheal diseases.
Topics: Humans; Cholera Toxin; Cholera; Vibrio cholerae; Bacterial Toxins; Diarrhea
PubMed: 37022166
DOI: 10.1128/iai.00435-22 -
Cellular Signalling Dec 2022Vibrio cholerae colonizes the small intestine and releases cholera toxin into the extracellular space. The toxin binds to the apical surface of the epithelium, is... (Review)
Review
Vibrio cholerae colonizes the small intestine and releases cholera toxin into the extracellular space. The toxin binds to the apical surface of the epithelium, is internalized into the host endomembrane system, and escapes into the cytosol where it activates the stimulatory alpha subunit of the heterotrimeric G protein by ADP-ribosylation. This initiates a cAMP-dependent signaling pathway that stimulates chloride efflux into the gut, with diarrhea resulting from the accompanying osmotic movement of water into the intestinal lumen. G protein signaling is not the only host system manipulated by cholera toxin, however. Other cellular mechanisms and signaling pathways active in the intoxication process include endocytosis through lipid rafts, retrograde transport to the endoplasmic reticulum, the endoplasmic reticulum-associated degradation system for protein delivery to the cytosol, the unfolded protein response, and G protein de-activation through degradation or the function of ADP-ribosyl hydrolases. Although toxin-induced chloride efflux is thought to be an irreversible event, alterations to these processes could facilitate cellular recovery from intoxication. This review will highlight how cholera toxin exploits signaling pathways and other cell biology events to elicit a diarrheal response from the host.
Topics: Cholera Toxin; Endoplasmic Reticulum-Associated Degradation; Chlorides; Signal Transduction; GTP-Binding Proteins
PubMed: 36216164
DOI: 10.1016/j.cellsig.2022.110489 -
Journal of Bacteriology Aug 2021Vibrio cholerae infects human hosts following ingestion of contaminated food or water, resulting in the severe diarrheal disease cholera. The watery diarrhea that is...
Vibrio cholerae infects human hosts following ingestion of contaminated food or water, resulting in the severe diarrheal disease cholera. The watery diarrhea that is characteristic of the disease is directly caused by the production of cholera toxin (CT). A complex regulatory cascade controls the production of CT and other virulence factors. However, ultimately, a single protein, ToxT, directly binds to virulence gene promoters and activates their transcription. Previously, we identified two ToxT binding sites, or toxboxes, within the cholera toxin promoter (P). The toxboxes overlap the two promoter-proximal GATTTTT heptad repeats found within P in classical biotype V. cholerae strain O395. These heptad repeats were previously found to be located within a large DNA region bound by H-NS, a global transcriptional repressor present in Gram-negative bacteria. The current model for the control of P transcription proposes complete H-NS displacement from the DNA by ToxT, followed by direct activation by ToxT-RNA polymerase (RNAP) contacts. The goal of this study was to determine more precisely where H-NS binds to P and test the hypothesis that ToxT completely displaces H-NS from the P promoter before activating transcription. The results suggest that H-NS binds only to the region of P encompassing the heptad repeats and that ToxT displaces H-NS only from its most promoter-proximal binding sites, calling for a revision of the current model involving H-NS and ToxT at P. H-NS is a global negative regulator of transcription in Gram-negative bacteria, particularly in horizontally acquired genetic islands. Previous work in Vibrio cholerae suggested that H-NS represses the transcription of cholera toxin genes by binding to a large region upstream of its promoter and that the virulence activator ToxT derepresses transcription by removing H-NS from the promoter. Here, new data support a revised model in which ToxT displaces only H-NS bound to the most promoter-proximal DNA sites that overlap the ToxT binding sites, leaving the upstream sites occupied by H-NS. This introduces a higher-resolution mechanism for the antirepression of H-NS in the control of cholera toxin production.
Topics: Bacterial Proteins; Cholera Toxin; DNA-Binding Proteins; Gene Expression Regulation, Bacterial; Promoter Regions, Genetic; Protein Binding; Transcription Factors; Transcriptional Activation; Vibrio cholerae; Virulence; Virulence Factors
PubMed: 34228499
DOI: 10.1128/JB.00187-21 -
Microbiological Reviews Dec 1992Cholera and the related Escherichia coli-associated diarrheal disease are important problems confronting Third World nations and any area where water supplies can become... (Comparative Study)
Comparative Study Review
Cholera and the related Escherichia coli-associated diarrheal disease are important problems confronting Third World nations and any area where water supplies can become contaminated. The disease is extremely debilitating and may be fatal in the absence of treatment. Symptoms are caused by the action of cholera toxin, secreted by the bacterium Vibrio cholerae, or by a closely related heat-labile enterotoxin, produced by Escherichia coli, that causes a milder, more common traveler's diarrhea. Both toxins bind receptors in intestinal epithelial cells and insert an enzymatic subunit that modifies a G protein associated with the adenylate cyclase complex. The consequent stimulated production of cyclic AMP, or other factors such as increased synthesis of prostaglandins by intoxicated cells, initiates a metabolic cascade that results in the excessive secretion of fluid and electrolytes characteristic of the disease. The toxins have a very high degree of structural and functional homology and may be evolutionarily related. Several effective new vaccine formulations have been developed and tested, and a growing family of endogenous cofactors is being discovered in eukaryotic cells. The recent elucidation of the three-dimensional structure of the heat-labile enterotoxin has provided an opportunity to examine and compare the correlations between structure and function of the two toxins. This information may improve our understanding of the disease process itself, as well as illuminate the role of the toxin in studies of signal transduction and G-protein function.
Topics: Amino Acid Sequence; Bacterial Toxins; Carbohydrate Sequence; Cholera Toxin; Enterotoxins; Escherichia coli; Escherichia coli Proteins; Models, Molecular; Molecular Sequence Data; Receptors, Immunologic; Sequence Homology, Amino Acid
PubMed: 1480112
DOI: 10.1128/mr.56.4.622-647.1992 -
Frontiers in Cellular and Infection... 2020Cholera is an acute secretory diarrhoeal disease caused by the bacterium . The key determinants of cholera pathogenicity, cholera toxin (CT), and toxin co-regulated... (Review)
Review
Cholera is an acute secretory diarrhoeal disease caused by the bacterium . The key determinants of cholera pathogenicity, cholera toxin (CT), and toxin co-regulated pilus (TCP) are part of the genome of two horizontally acquired Mobile Genetic Elements (MGEs), CTXΦ, and Vibrio pathogenicity island 1 (VPI-1), respectively. Besides, genome harbors several others MGEs that provide antimicrobial resistance, metabolic functions, and other fitness traits. VPI-1, one of the most well characterized genomic island (GI), deserved a special attention, because (i) it encodes many of the virulence factors that facilitate development of cholera (ii) it is essential for the acquisition of CTXΦ and production of CT, and (iii) it is crucial for colonization of in the host intestine. Nevertheless, VPI-1 is ubiquitously present in all the epidemic strains. Therefore, to understand the role of MGEs in the evolution of cholera pathogen from a natural aquatic habitat, it is important to understand the VPI-1 encoded functions, their acquisition and possible mode of dissemination. In this review, we have therefore discussed our present understanding of the different functions of VPI-1 those are associated with virulence, important for toxin production and essential for the disease development.
Topics: Cholera; Cholera Toxin; Fimbriae, Bacterial; Genomic Islands; Humans; Vibrio cholerae
PubMed: 33123494
DOI: 10.3389/fcimb.2020.561296 -
Scientific Reports Mar 2023Cholera toxin B subunit (CTB) is a potent immunomodulator exploitable in mucosal vaccine and immunotherapeutic development. To aid in the characterization of pleiotropic...
Cholera toxin B subunit (CTB) is a potent immunomodulator exploitable in mucosal vaccine and immunotherapeutic development. To aid in the characterization of pleiotropic biological functions of CTB and its variants, we generated a panel of anti-CTB monoclonal antibodies (mAbs). By ELISA and surface plasmon resonance, two mAbs, 7A12B3 and 9F9C7, were analyzed for their binding affinities to cholera holotoxin (CTX), CTB, and EPICERTIN: a recombinant CTB variant possessing mucosal healing activity. Both 7A12B3 and 9F9C7 bound efficiently to CTX, CTB, and EPICERTIN with equilibrium dissociation constants at low to sub-nanomolar concentrations but bound weakly, if at all, to Escherichia coli heat-labile enterotoxin B subunit. In a cyclic adenosine monophosphate assay using Caco2 human colon epithelial cells, the 7A12B3 mAb was found to be a potent inhibitor of CTX, whereas 9F9C7 had relatively weak inhibitory activity. Meanwhile, the 9F9C7 mAb effectively detected CTB and EPICERTIN bound to the surface of Caco2 cells and mouse spleen leukocytes by flow cytometry. Using 9F9C7 in immunohistochemistry, we confirmed the preferential localization of EPICERTIN in colon crypts following oral administration of the protein in mice. Collectively, these mAbs provide valuable tools to investigate the biological functions and preclinical development of CTB variants.
Topics: Humans; Animals; Mice; Cholera Toxin; Antibodies, Monoclonal; Caco-2 Cells; Adjuvants, Immunologic; Cholera
PubMed: 36922604
DOI: 10.1038/s41598-023-30834-2 -
The American Journal of Tropical... Aug 2016
Topics: ABO Blood-Group System; Cholera; Cholera Toxin; Humans
PubMed: 27402512
DOI: 10.4269/ajtmh.16-0440 -
Toxins Mar 2015Cholera, a waterborne acute diarrheal disease caused by Vibrio cholerae, remains prevalent in underdeveloped countries and is a serious health threat to those living in... (Review)
Review
Cholera, a waterborne acute diarrheal disease caused by Vibrio cholerae, remains prevalent in underdeveloped countries and is a serious health threat to those living in unsanitary conditions. The major virulence factor is cholera toxin (CT), which consists of two subunits: the A subunit (CTA) and the B subunit (CTB). CTB is a 55 kD homopentameric, non-toxic protein binding to the GM1 ganglioside on mammalian cells with high affinity. Currently, recombinantly produced CTB is used as a component of an internationally licensed oral cholera vaccine, as the protein induces potent humoral immunity that can neutralize CT in the gut. Additionally, recent studies have revealed that CTB administration leads to the induction of anti-inflammatory mechanisms in vivo. This review will cover the potential of CTB as an immunomodulatory and anti-inflammatory agent. We will also summarize various recombinant expression systems available for recombinant CTB bioproduction.
Topics: Anti-Inflammatory Agents; Cholera Toxin; Cholera Vaccines; G(M1) Ganglioside; Protein Binding; Protein Conformation; Recombinant Proteins; Vibrio cholerae
PubMed: 25802972
DOI: 10.3390/toxins7030974