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Toxins
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Shiga Toxin: Occurrence, Pathogenicity, Detection and Therapies
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Shiga Toxin: Occurrence, Pathogenicity, Detection and Therapies

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 21615

Special Issue Editor

Dr. Indira Kudva

E-Mail Website
Guest Editor
Food Safety Enteric Pathogens Research Unit, National Animal Disease Center, United States Department of Agriculture (USDA), Ames, IA 50010, USA
Interests: Shiga-toxin-producing Escherichia coli (STEC); (i) STEC interactions with the bovine gastrointestinal cells, especially those at the recto-anal junction (RAJ); (ii) STEC factors that promote its survival in the bovine rumen and persistence at the RAJ; (iii) adherence mechanisms deployed by STEC in strain- and host-dependent manner; (iv) development of rational subunit vaccines and vaccine alternatives that target STEC in cattle; and (v) development of diagnostic assays to study STEC adherence and to identify STEC-colonized cattle
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Shiga-toxin-producing Escherichia coli (STEC) are the third leading cause of foodborne illness after Campylobacter and Salmonella, and are implicated in 265,000 illnesses in the US and 2.8M infections globally. Significant economic losses incurred by public health, agriculture and the meat industry estimated at $993 million per year prompted the declaration of commonly implicated STEC serotypes (O157, O26, O103, O111, O121, O145, and O45) as food adulterants by the USDA Food Safety and Inspection Service. STEC infections are acquired through the ingestion of bacteria-contaminated food or water, or by hand-to-mouth transmission. Cattle are considered to be the primary STEC reservoirs, as most outbreaks are directly or indirectly associated with cattle. Following infection, some individuals remain asymptomatic, while others develop watery or bloody diarrhea that may progress to fatal secondary sequelae. Successful infection is established following the ingestion of only a few organisms (50–500 viable bacteria), attributable to multiple-acid tolerance and quorum sensing mechanisms. Virulence factors such as the phage-encoded Shiga toxins (Stx), plasmid-encoded hemolysin, and various adherence factors including intimin, encoded by the eae gene on the pathogenicity-island locus of enterocyte effacement (LEE), play a significant role in human disease. Cattle remain asymptomatic due to the absence of receptors for Stx; without uptake of toxin there is no resulting systemic failure as observed in humans. Thus, Stx are the primary virulence factors contributing towards STEC pathogenicity in humans through niche establishment, nutrient acquisition, host immune response modulation/evasion, and targeted cell pathology.

In this Special Issue, we seek to provide a comprehensive collection of publications on Stx in the context of: (i) toxin structure, acquisition, evolution, variants, and mode of action; (ii) host–pathogen interaction—structural and immune; (iii) disease prediction and risk assessment; and (iv) toxin detection and targeted therapies. Review and research papers describing established and novel concepts are welcome.

Dr. Indira Kudva
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

  • E. coli
  • STEC
  • Shiga toxin
  • toxicity
  • variants
  • pathogenicity
  • disease
  • risk
  • detection
  • therapy

Published Papers (5 papers)

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Research

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21 pages, 3751 KiB  
Article
Stx2 Induces Differential Gene Expression and Disturbs Circadian Rhythm Genes in the Proximal Tubule
by Fumiko Obata, Ryo Ozuru, Takahiro Tsuji, Takashi Matsuba and Jun Fujii
Toxins 2022, 14(2), 69; https://doi.org/10.3390/toxins14020069 - 19 Jan 2022
Cited by 4 | Viewed by 2800
Abstract
Shiga toxin-producing Escherichia coli (STEC) causes proximal tubular defects in the kidney. However, factors altered by Shiga toxin (Stx) within the proximal tubules are yet to be shown. We determined Stx receptor Gb3 in murine and human kidneys and confirmed the receptor expression [...] Read more.
Shiga toxin-producing Escherichia coli (STEC) causes proximal tubular defects in the kidney. However, factors altered by Shiga toxin (Stx) within the proximal tubules are yet to be shown. We determined Stx receptor Gb3 in murine and human kidneys and confirmed the receptor expression in the proximal tubules. Stx2-injected mouse kidney tissues and Stx2-treated human primary renal proximal tubular epithelial cell (RPTEC) were collected and microarray analysis was performed. We compared murine kidney and RPTEC arrays and selected common 58 genes that are differentially expressed vs. control (0 h, no toxin-treated). We found that the most highly expressed gene was GDF15, which may be involved in Stx2-induced weight loss. Genes associated with previously reported Stx2 activities such as src kinase Yes phosphorylation pathway activation, unfolded protein response (UPR) and ribotoxic stress response (RSR) showed differential expressions. Moreover, circadian clock genes were differentially expressed, suggesting Stx2-induced renal circadian rhythm disturbance. Circadian rhythm-regulated proximal tubular Na+-glucose transporter SGLT1 (SLC5A1) was down-regulated, indicating proximal tubular functional deterioration, and mice developed glucosuria confirming proximal tubular dysfunction. Stx2 alters gene expression in murine and human proximal tubules through known activities and newly investigated circadian rhythm disturbance, which may result in proximal tubular dysfunctions. Full article
(This article belongs to the Special Issue Shiga Toxin: Occurrence, Pathogenicity, Detection and Therapies)
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13 pages, 924 KiB  
Article
Prevalence, Antimicrobial Resistance, and Whole Genome Sequencing Analysis of Shiga Toxin-Producing Escherichia coli (STEC) and Enteropathogenic Escherichia coli (EPEC) from Imported Foods in China during 2015–2021
by Jinling Shen, Shuai Zhi, Dehua Guo, Yuan Jiang, Xuebin Xu, Lina Zhao and Jingzhang Lv
Toxins 2022, 14(2), 68; https://doi.org/10.3390/toxins14020068 - 19 Jan 2022
Cited by 12 | Viewed by 4449
Abstract
Shiga toxin-producing Escherichia coli (STEC) and enteropathogenic Escherichia coli (EPEC) are foodborne pathogens that cause hemolytic uremic syndrome and fatal infant diarrhea, respectively, but the characterization of these bacteria from imported food in China are unknown. A total of 1577 food samples from [...] Read more.
Shiga toxin-producing Escherichia coli (STEC) and enteropathogenic Escherichia coli (EPEC) are foodborne pathogens that cause hemolytic uremic syndrome and fatal infant diarrhea, respectively, but the characterization of these bacteria from imported food in China are unknown. A total of 1577 food samples from various countries during 2015–2021 were screened for STEC and EPEC, and the obtained isolates were tested for antimicrobial resistance and whole genome sequencing analysis was performed. The prevalence of STEC and EPEC was 1.01% (16/1577) and 0.51% (8/1577), respectively. Antimicrobial resistances to tetracycline (8%), chloramphenicol (8%), ampicillin (4%), ceftazidime (4%), cefotaxime (4%), and trimethoprim-sulfamethoxazole (4%) were observed. The antimicrobial resistance phenotypes corresponded with genotypes for most strains, and some resistance genes were related to mobile genetic elements. All 16 STEC isolates were eae negative, two solely contained stx1 (stx1a or stx1c), 12 merely carried stx2 (stx2a, stx2d, or stx2e), and two had both stx1 and stx2 (stx1c + stx2b, stx1a + stx2a + stx2c). Although they were eae negative, several STEC isolates carried other adherence factors, such as iha (5/16), sab (1/16), and lpfA (8/16), and belonged to serotypes (O130:H11, O8:H19, and O100:H30) or STs (ST297, ST360), which have caused human infections. All the eight EPEC isolates were atypical EPEC; six serotypes and seven STs were found, and clinically relevant EPEC serotypes O26:H11, O103:H2, and O145:H28 were identified. Two STEC/ETEC (enterotoxigenic E. coli) hybrids and one EPEC/ETEC hybrid were observed, since they harbored sta1 and/or stb. The results revealed that food can act as a reservoir of STEC/EPEC with pathogenic potential, and had the potential ability to transfer antibiotic resistance and virulence genes. Full article
(This article belongs to the Special Issue Shiga Toxin: Occurrence, Pathogenicity, Detection and Therapies)
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15 pages, 1976 KiB  
Article
Gut–Kidney Axis on Chip for Studying Effects of Antibiotics on Risk of Hemolytic Uremic Syndrome by Shiga Toxin-Producing Escherichia coli
by Yugyeong Lee, Min-Hyeok Kim, David Rodrigues Alves, Sejoong Kim, Luke P. Lee, Jong Hwan Sung and Sungsu Park
Toxins 2021, 13(11), 775; https://doi.org/10.3390/toxins13110775 - 2 Nov 2021
Cited by 15 | Viewed by 5226
Abstract
Shiga toxin-producing Escherichia coli (STEC) infects humans by colonizing the large intestine, and causes kidney damage by secreting Shiga toxins (Stxs). The increased secretion of Shiga toxin 2 (Stx2) by some antibiotics, such as ciprofloxacin (CIP), increases the risk of hemolytic–uremic syndrome (HUS), [...] Read more.
Shiga toxin-producing Escherichia coli (STEC) infects humans by colonizing the large intestine, and causes kidney damage by secreting Shiga toxins (Stxs). The increased secretion of Shiga toxin 2 (Stx2) by some antibiotics, such as ciprofloxacin (CIP), increases the risk of hemolytic–uremic syndrome (HUS), which can be life-threatening. However, previous studies evaluating this relationship have been conflicting, owing to the low frequency of EHEC infection, very small number of patients, and lack of an appropriate animal model. In this study, we developed gut–kidney axis (GKA) on chip for co-culturing gut (Caco-2) and kidney (HKC-8) cells, and observed both STEC O157:H7 (O157) infection and Stx intoxication in the gut and kidney cells on the chip, respectively. Without any antibiotic treatment, O157 killed both gut and kidney cells in GKA on the chip. CIP treatment reduced O157 infection in the gut cells, but increased Stx2-induced damage in the kidney cells, whereas the gentamycin treatment reduced both O157 infection in the gut cells and Stx2-induced damage in the kidney cells. This is the first report to recapitulate a clinically relevant situation, i.e., that CIP treatment causes more damage than gentamicin treatment. These results suggest that GKA on chip is very useful for simultaneous observation of O157 infections and Stx2 poisoning in gut and kidney cells, making it suitable for studying the effects of antibiotics on the risk of HUS. Full article
(This article belongs to the Special Issue Shiga Toxin: Occurrence, Pathogenicity, Detection and Therapies)
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15 pages, 1466 KiB  
Article
Variability in the Occupancy of Escherichia coli O157 Integration Sites by Shiga Toxin-Encoding Prophages
by Scott T. Henderson, Pallavi Singh, David Knupp, David W. Lacher, Galeb S. Abu-Ali, James T. Rudrik and Shannon D. Manning
Toxins 2021, 13(7), 433; https://doi.org/10.3390/toxins13070433 - 22 Jun 2021
Cited by 7 | Viewed by 2706
Abstract
Escherichia coli O157:H7 strains often produce Shiga toxins encoded by genes on lambdoid bacteriophages that insert into multiple loci as prophages. O157 strains were classified into distinct clades that vary in virulence. Herein, we used PCR assays to examine Shiga toxin (Stx) prophage [...] Read more.
Escherichia coli O157:H7 strains often produce Shiga toxins encoded by genes on lambdoid bacteriophages that insert into multiple loci as prophages. O157 strains were classified into distinct clades that vary in virulence. Herein, we used PCR assays to examine Shiga toxin (Stx) prophage occupancy in yehV, argW, wrbA, and sbcB among 346 O157 strains representing nine clades. Overall, yehV was occupied in most strains (n = 334, 96.5%), followed by wrbA (n = 213, 61.6%), argW (n = 103, 29.8%), and sbcB (n = 93, 26.9%). Twelve occupancy profiles were identified that varied in frequency and differed across clades. Strains belonging to clade 8 were more likely to have occupied sbcB and argW sites compared to other clades (p < 0.0001), while clade 2 strains were more likely to have occupied wrbA sites (p < 0.0001). Clade 8 strains also had more than the expected number of occupied sites based on the presence of stx variants (p < 0.0001). Deletion of a 20 kb non-Stx prophage occupying yehV in a clade 8 strain resulted in an ~18-fold decrease in stx2 expression. These data highlight the complexity of Stx prophage integration and demonstrate that clade 8 strains, which were previously linked to hemolytic uremic syndrome, have unique Stx prophage occupancy profiles that can impact stx2 expression. Full article
(This article belongs to the Special Issue Shiga Toxin: Occurrence, Pathogenicity, Detection and Therapies)
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Review

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29 pages, 1849 KiB  
Review
AB5 Enterotoxin-Mediated Pathogenesis: Perspectives Gleaned from Shiga Toxins
by Erika N. Biernbaum and Indira T. Kudva
Toxins 2022, 14(1), 62; https://doi.org/10.3390/toxins14010062 - 16 Jan 2022
Cited by 11 | Viewed by 5411
Abstract
Foodborne diseases affect an estimated 600 million people worldwide annually, with the majority of these illnesses caused by Norovirus, Vibrio, Listeria, Campylobacter, Salmonella, and Escherichia coli. To elicit infections in humans, bacterial pathogens express a combination of virulence [...] Read more.
Foodborne diseases affect an estimated 600 million people worldwide annually, with the majority of these illnesses caused by Norovirus, Vibrio, Listeria, Campylobacter, Salmonella, and Escherichia coli. To elicit infections in humans, bacterial pathogens express a combination of virulence factors and toxins. AB5 toxins are an example of such toxins that can cause various clinical manifestations, including dehydration, diarrhea, kidney damage, hemorrhagic colitis, and hemolytic uremic syndrome (HUS). Treatment of most bacterial foodborne illnesses consists of fluid replacement and antibiotics. However, antibiotics are not recommended for infections caused by Shiga toxin-producing E. coli (STEC) because of the increased risk of HUS development, although there are conflicting views and results in this regard. Lack of effective treatment strategies for STEC infections pose a public health threat during outbreaks; therefore, the debate on antibiotic use for STEC infections could be further explored, along with investigations into antibiotic alternatives. The overall goal of this review is to provide a succinct summary on the mechanisms of action and the pathogenesis of AB5 and related toxins, as expressed by bacterial foodborne pathogens, with a primary focus on Shiga toxins (Stx). The role of Stx in human STEC disease, detection methodologies, and available treatment options are also briefly discussed. Full article
(This article belongs to the Special Issue Shiga Toxin: Occurrence, Pathogenicity, Detection and Therapies)
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