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Frontiers in Cellular and Infection... 2012Enterohemorrhagic Escherichia coli (EHEC) are responsible for major outbreaks of bloody diarrhea and hemolytic uremic syndrome (HUS) throughout the world. The mortality... (Review)
Review
Enterohemorrhagic Escherichia coli (EHEC) are responsible for major outbreaks of bloody diarrhea and hemolytic uremic syndrome (HUS) throughout the world. The mortality associated with EHEC infections stems from the production and release of a potent Shiga toxin (Stx) by these bacteria. Stx induces cell death in endothelial cells, primarily in the urinary tract, causing HUS. Stx was first described in Shigella dysenteriae serotype I by Kiyoshi Shiga and was discovered later in EHEC. Multiple environmental cues regulate the expression of Stx, including temperature, growth phase, antibiotics, reactive oxygen species (ROS), and quorum sensing. Currently, there is no effective treatment or prophylaxis for HUS. Because antibiotics trigger Stx production and their use to treat EHEC infections is controversial, alternative therapeutic strategies have become the focus of intense research. One such strategy explores quorum sensing inhibitors as therapeutics. These inhibitors target quorum sensing regulation of Stx expression without interfering with bacterial growth, leading to the hypothesis that these inhibitors impose less selective pressure for bacteria to develop drug resistance. In this review, we discuss factors that regulate Stx production in EHEC, as well as novel strategies to prevent and/or minimize the development of HUS in infected subjects.
Topics: Enterohemorrhagic Escherichia coli; Gene Expression Regulation, Bacterial; Hemolytic-Uremic Syndrome; Humans; Quorum Sensing; Shiga Toxin; Virulence Factors
PubMed: 22919672
DOI: 10.3389/fcimb.2012.00081 -
Oxidative Medicine and Cellular... 2016Virulence of enterohemorrhagic Escherichia coli (EHEC) strains depends on production of Shiga toxins. These toxins are encoded in genomes of lambdoid bacteriophages... (Review)
Review
Virulence of enterohemorrhagic Escherichia coli (EHEC) strains depends on production of Shiga toxins. These toxins are encoded in genomes of lambdoid bacteriophages (Shiga toxin-converting phages), present in EHEC cells as prophages. The genes coding for Shiga toxins are silent in lysogenic bacteria, and prophage induction is necessary for their efficient expression and toxin production. Under laboratory conditions, treatment with UV light or antibiotics interfering with DNA replication are commonly used to induce lambdoid prophages. Since such conditions are unlikely to occur in human intestine, various research groups searched for other factors or agents that might induce Shiga toxin-converting prophages. Among other conditions, it was reported that treatment with H2O2 caused induction of these prophages, though with efficiency significantly lower relative to UV-irradiation or mitomycin C treatment. A molecular mechanism of this phenomenon has been proposed. It appears that the oxidative stress represents natural conditions provoking induction of Shiga toxin-converting prophages as a consequence of H2O2 excretion by either neutrophils in infected humans or protist predators outside human body. Finally, the recently proposed biological role of Shiga toxin production is described in this paper, and the "bacterial altruism" and "Trojan Horse" hypotheses, which are connected to the oxidative stress, are discussed.
Topics: Animals; Enterohemorrhagic Escherichia coli; Humans; Hydrogen Peroxide; Oxidative Stress; Prophages; Shiga Toxin
PubMed: 26798420
DOI: 10.1155/2016/3578368 -
Frontiers in Cellular and Infection... 2020
Topics: Escherichia coli Infections; Hemolytic-Uremic Syndrome; Humans; Shiga Toxin; Shiga-Toxigenic Escherichia coli; Shigella
PubMed: 33324585
DOI: 10.3389/fcimb.2020.620703 -
Toxins Mar 2023Shiga toxins (Stxs) produced by ingested can induce hemolytic uremic syndrome after crossing the intact intestinal barrier, entering the bloodstream, and targeting...
Shiga toxins (Stxs) produced by ingested can induce hemolytic uremic syndrome after crossing the intact intestinal barrier, entering the bloodstream, and targeting endothelial cells in the kidney. The method(s) by which the toxins reach the bloodstream are not fully defined. Here, we used two polarized cell models to evaluate Stx translocation: (i) a single-layer primary colonic epithelial cell model and (ii) a three-cell-layer model with colonic epithelial cells, myofibroblasts, and colonic endothelial cells. We traced the movement of Stx types 1a and 2a across the barrier models by measuring the toxicity of apical and basolateral media on Vero cells. We found that Stx1a and Stx2a crossed both models in either direction. However, approximately 10-fold more Stx translocated in the three-layer model as compared to the single-layer model. Overall, the percentage of toxin that translocated was about 0.01% in the epithelial-cell-only model but up to 0.09% in the three-cell-layer model. In both models, approximately 3- to 4-fold more Stx2a translocated than Stx1a. Infection of the three-cell-layer model with Stx-producing (STEC) strains showed that serotype O157:H7 STEC reduced barrier function in the model and that the damage was not dependent on the presence of the gene. Infection of the three-layer model with O26:H11 STEC strain TW08571 (Stx1a+ and Stx2a+), however, allowed translocation of modest amounts of Stx without reducing barrier function. Deletion of stx2a from TW08571 or the use of anti-Stx1 antibody prevented translocation of toxin. Our results suggest that single-cell models may underestimate the amount of Stx translocation and that the more biomimetic three-layer model is suited for Stx translocation inhibitor studies.
Topics: Animals; Chlorocebus aethiops; Shiga Toxin; Vero Cells; Endothelial Cells; Shiga-Toxigenic Escherichia coli; Shiga Toxins; Escherichia coli Infections
PubMed: 36977098
DOI: 10.3390/toxins15030207 -
Microbial Biotechnology Jan 2011Shiga and the Shiga-like toxins are related protein toxins produced by Shigella dysenteriae and certain strains of Escherichia coli. These toxins are composed of two... (Review)
Review
Shiga and the Shiga-like toxins are related protein toxins produced by Shigella dysenteriae and certain strains of Escherichia coli. These toxins are composed of two non-covalently attached, modular parts: the A moiety (StxA) containing the enzymatically active A1 fragment, and the non-toxic, pentameric binding moiety (StxB). Stx binds specifically to the glycosphingolipid globotriaosylceramide (Gb3) at the surface of target cells and is then internalized by endocytosis. Subsequently, in toxin-sensitive cells, the Stx/Gb3 complex is transported in a retrograde manner via the Golgi apparatus to the endoplasmic reticulum, where the enzymatically active part of Stx is translocated to the cytosol, enabling it to irreversibly inhibit protein synthesis via modification of ribosomal 28S RNA. Whereas Gb3 shows a relatively restricted expression in normal human tissues, it has been reported to be highly expressed in many types of cancers. This review gives a brief introduction to Stx and its intracellular transport. Furthermore, after a description of Gb3 and the methods that are currently used to detect its cellular expression, we provide an updated overview of the published reports on Gb3 overexpression in human cancers. Finally, we discuss the possibility of utilizing Stx or StxB coupled to therapeutic compounds or contrast agents in targeted cancer therapy and imaging.
Topics: Animals; Biological Transport; Drug Delivery Systems; Globosides; Humans; Molecular Imaging; Neoplasms; Shiga Toxin; Trihexosylceramides
PubMed: 21255370
DOI: 10.1111/j.1751-7915.2010.00180.x -
Toxins Oct 2021It has long been accepted that Shiga toxin (Stx) only exists in serotype 1. However, in recent decades, the presence of Shiga toxin genes () in other spp. have been...
It has long been accepted that Shiga toxin (Stx) only exists in serotype 1. However, in recent decades, the presence of Shiga toxin genes () in other spp. have been reported. We screened 366 strains from Alberta, Canada (2003 to 2016) for and 26 positive strains were identified. These isolates are highly related with the majority originating from the Dominican Republic and three isolates with Haiti origin. Both phylogenetic and spanning tree analysis of the 26 Alberta and 29 positive originating from the U.S., France, Canada (Quebec) and Haiti suggests that there are geographic specific distribution patterns (Haiti and Dominican Republic clades). This study provides the first comprehensive whole genome based phylogenetic analysis of positive strains as well as their global transmission, which signify the public health risks of global spreading of these strains.
Topics: Alberta; Communicable Diseases, Imported; Dominican Republic; Dysentery, Bacillary; Haiti; Phylogeny; Shiga Toxin; Shigella dysenteriae; Travel; Whole Genome Sequencing
PubMed: 34822539
DOI: 10.3390/toxins13110755 -
Gut Microbes 2022Shiga toxin (Stx)-producing enterohemorrhagic (EHEC) cause gastrointestinal infection and, in severe cases, hemolytic uremic syndrome which may lead to death. There is,...
Shiga toxin (Stx)-producing enterohemorrhagic (EHEC) cause gastrointestinal infection and, in severe cases, hemolytic uremic syndrome which may lead to death. There is, to-date, no therapy for this infection. Stx induces ATP release from host cells and ATP signaling mediates its cytotoxic effects. Apyrase cleaves and neutralizes ATP and its effect on Stx and EHEC infection was therefore investigated. Apyrase decreased bacterial RecA and dose-dependently decreased toxin release from O157:H7 , demonstrated by reduced phage DNA and protein levels. The effect was investigated in a mouse model of O157:H7 infection. BALB/c mice infected with Stx2-producing O157:H7 were treated with apyrase intraperitoneally, on days 0 and 2 post-infection, and monitored for 11 days. Apyrase-treated mice developed disease two days later than untreated mice. Untreated infected mice lost significantly more weight than those treated with apyrase. Apyrase-treated mice exhibited less colonic goblet cell depletion and apoptotic cells, as well as lower fecal ATP and Stx2, compared to untreated mice. Apyrase also decreased platelet aggregation induced by co-incubation of human platelet-rich-plasma with Stx2 and O157 lipopolysaccharide in the presence of collagen. Thus, apyrase had multiple protective effects, reducing RecA levels, and toxin release from EHEC, reducing fecal Stx2 and protecting mouse intestinal cells, as well as decreasing platelet activation, and could thereby delay the development of disease.
Topics: Adenosine Triphosphate; Animals; Apyrase; Bacteriophages; Escherichia coli Infections; Escherichia coli O157; Gastrointestinal Microbiome; Humans; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Shiga Toxin; Shiga Toxin 2
PubMed: 36138514
DOI: 10.1080/19490976.2022.2122667 -
Microbiology Spectrum Aug 2022Shiga toxin (Stx)-producing Escherichia coli (STEC) is a zoonotic pathogen with the ability to cause severe diseases like hemorrhagic colitis (HC) and hemolytic uremic...
Shiga toxin (Stx)-producing Escherichia coli (STEC) is a zoonotic pathogen with the ability to cause severe diseases like hemorrhagic colitis (HC) and hemolytic uremic syndrome (HUS). Shiga toxin (Stx) is the key virulence factor in STEC and can be classified into two types, Stx1 and Stx2, and different subtypes. Stx2k is a newly reported Stx2 subtype in E. coli strains from diarrheal patients, animals, and raw meats exclusively in China so far. To understand the reservoir of Stx2k-producing E. coli (Stx2k-STEC), we investigated Stx2k-STEC strains in goat herds and examined their genetic characteristics using whole-genome sequencing. A total of 448 STEC strains were recovered from 2,896 goat fecal samples, and 37.95% (170/448) were Stx2k-STEC. Stx2k-STEC strains of serotype O93:H28 and sequence type 4038 (ST4038) were the most predominant and were detected over several years. Notably, 55% of Stx2k-STEC strains carried the heat-labile toxin (LT)-encoding gene () defining enterotoxigenic E. coli (ETEC), thereby exhibiting the hybrid STEC/ETEC pathotype. Stx2k-converting prophage genomes clustered into four groups and exhibited high similarity within each group. Strains from patients, raw meat, sheep, and goats were intermixed distributed in the phylogenetic tree, indicating the risk for cross-species spread of Stx2k-STEC and pathogenic potential for humans. Further studies are required to investigate the Stx2k-STEC strains in other reservoirs and to understand the mechanism of persistence in these hosts. Strains of the recently reported Stx2k-STEC have been circulating in a variety of sources over time in China. Here, we show a high prevalence of Stx2k-STEC in goat herds. More than half of the strains were of the hybrid STEC/ETEC pathotype. Stx2k-STEC strains of predominant serotypes have been widespread in the goat herds over several years. Stx2k-converting prophages have exhibited a high level of similarity across geographical regions and time and might be maintained and transmitted horizontally. Given that goat-derived Stx2k-STEC strains share similar genetic backbones with patient-derived strains, the high prevalence of Stx2k-STEC in goats suggests that there is a risk of cross-species spread and that these strains may pose pathogenetic potential to humans. Our study thus highlights the need to monitor human Stx2k-STEC infections in this region and, by extension, in other geographic locations.
Topics: Animals; Escherichia coli Infections; Escherichia coli Proteins; Goats; Humans; Phylogeny; Prevalence; Sheep; Shiga Toxin; Shiga-Toxigenic Escherichia coli
PubMed: 35938860
DOI: 10.1128/spectrum.01571-22 -
Frontiers in Cellular and Infection... 2014In this review we highlight recent work that has increased our understanding of the distribution of Shiga toxin-converting phages that can be detected as free phage... (Review)
Review
In this review we highlight recent work that has increased our understanding of the distribution of Shiga toxin-converting phages that can be detected as free phage particles, independently of Shiga toxin-producing bacteria (STEC). Stx phages are a quite diverse group of temperate phages that can be found in their prophage state inserted within the STEC chromosome, but can also be found as phages released from the cell after activation of their lytic cycle. They have been detected in extraintestinal environments such as water polluted with feces from humans or animals, food samples or even in stool samples of healthy individuals. The high persistence of phages to several inactivation conditions makes them suitable candidates for the successful mobilization of stx genes, possibly resulting in the genes reaching a new bacterial genomic background by means of transduction, where ultimately they may be expressed, leading to Stx production. Besides the obvious fact that Stx phages circulating between bacteria can be, and probably are, involved in the emergence of new STEC strains, we review here other possible ways in which free Stx phages could interfere with the detection of STEC in a given sample by current laboratory methods and how to avoid such interference.
Topics: Animals; Bacteriophages; Biological Evolution; Escherichia coli Infections; Feces; Food Microbiology; Humans; Shiga Toxin; Shiga-Toxigenic Escherichia coli; Water Microbiology; Water Pollution
PubMed: 24795866
DOI: 10.3389/fcimb.2014.00046 -
Toxins Mar 2022Immunotherapy against cancer and infectious disease holds the promise of high efficacy with minor side effects. Mucosal vaccines to protect against tumors or infections... (Review)
Review
Immunotherapy against cancer and infectious disease holds the promise of high efficacy with minor side effects. Mucosal vaccines to protect against tumors or infections disease agents that affect the upper airways or the lung are still lacking, however. One mucosal vaccine candidate is the B-subunit of Shiga toxin, STxB. In this review, we compare STxB to other immunotherapy vectors. STxB is a non-toxic protein that binds to a glycosylated lipid, termed globotriaosylceramide (Gb3), which is preferentially expressed by dendritic cells. We review the use of STxB for the cross-presentation of tumor or viral antigens in a MHC class I-restricted manner to induce humoral immunity against these antigens in addition to polyfunctional and persistent CD4 and CD8 T lymphocytes capable of protecting against viral infection or tumor growth. Other literature will be summarized that documents a powerful induction of mucosal IgA and resident memory CD8 T cells against mucosal tumors specifically when STxB-antigen conjugates are administered via the nasal route. It will also be pointed out how STxB-based vaccines have been shown in preclinical cancer models to synergize with other therapeutic modalities (immune checkpoint inhibitors, anti-angiogenic therapy, radiotherapy). Finally, we will discuss how molecular aspects such as low immunogenicity, cross-species conservation of Gb3 expression, and lack of toxicity contribute to the competitive positioning of STxB among the different DC targeting approaches. STxB thereby appears as an original and innovative tool for the development of mucosal vaccines in infectious diseases and cancer.
Topics: Antigens; CD8-Positive T-Lymphocytes; Humans; Neoplasms; Shiga Toxin; Vaccination
PubMed: 35324699
DOI: 10.3390/toxins14030202