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Pathogenesis of Hemolytic Uremic Syndrome Caused by Shiga Toxin-Producing Escherichia...
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Pathogenesis of Hemolytic Uremic Syndrome Caused by Shiga Toxin-Producing Escherichia coli Infections

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

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 30261

Special Issue Editor

Prof. Dr. Maurizio Brigotti

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Guest Editor
Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale (DIMES), Sede di Patologia Generale, Università di Bologna, Via San Giacomo, 14, 40126 Bologna, Italy
Interests: bacterial toxins; Shiga toxins; hemolytic uremic syndrome; ribosome-inactivating proteins

Special Issue Information

Dear Colleagues,

Human infections by Shiga toxin-producing Escherichia coli (STEC) cause severe and life-threatening diseases. These powerful pathogens are capable of elaborating a wide array of virulence factors which often overwhelm the host defense system. In particular, the exotoxins produced by these pathogenic E. coli strains, namely Shiga toxins, are the key bacterial factors responsible for hemolytic uremic syndrome (HUS), the main cause of acute renal failure in early childhood.

The pathogenesis of HUS is puzzling and not completely understood, despite a great deal of investigation. Toxins target host endothelial cells in the kidney and brain during the ultimate toxemic phase, culminating in HUS. However, a plethora of complex, concurrent and interactive phenomena occur during precocious toxemia when Shiga toxins interact with numerous blood components (neutrophils, monocytes, platelets, erythrocytes, human serum amyloid protein, complement factor H, and Toll-like receptor 4). The formation of platelet–leukocyte aggregates, the release of extracellular vesicles containing HUS-triggering pathogenic factors and the activation of complement system are well known consequences.

This Special Issue is aimed at focusing on all aspects of the interaction of Shiga toxins with host cell and/or molecules involved in the pathogenesis of STEC-induced HUS. The various papers dealing with specific arguments are expected to bring renewed insight on focalized topics, fostering our understanding of the general picture, as well as the single details of a canvas unveil their message only when they are considered in the general context.

Prof. Maurizio Brigotti
Guest Editor

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Keywords

  • Hemolytic uremic syndrome
  • pathogenesis
  • pathogen-host interactions
  • Shiga toxins
  • Shiga toxin-producing Escherichia coli
  • STEC infections

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Published Papers (8 papers)

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Research

Jump to: Review

12 pages, 3571 KiB  
Article
Method for the Detection of the Cleaved Form of Shiga Toxin 2a Added to Normal Human Serum
by Lucrezia Rocchetti, Beatrice Munari, Elisa Varrone, Elisa Porcellini, Dorothea Orth-Höller, Reinhard Würzner, Domenica Carnicelli and Maurizio Brigotti
Toxins 2021, 13(2), 94; https://doi.org/10.3390/toxins13020094 - 26 Jan 2021
Cited by 3 | Viewed by 1777
Abstract
The pathogenesis of Escherichia coli-induced hemolytic uremic syndrome (eHUS) caused by infections with pathogenic Shiga toxin (Stx) producing E. coli (STEC) is centered on bacterial (e.g., Stx) and host factors (circulating cells, complement system, serum proteins) whose interaction is crucial for the [...] Read more.
The pathogenesis of Escherichia coli-induced hemolytic uremic syndrome (eHUS) caused by infections with pathogenic Shiga toxin (Stx) producing E. coli (STEC) is centered on bacterial (e.g., Stx) and host factors (circulating cells, complement system, serum proteins) whose interaction is crucial for the immediate outcome and for the development of this life-threatening sequela. Stx2a, associated to circulating cells (early toxemia) or extracellular vesicles (late toxemia) in blood, is considered the main pathogenic factor in the development of eHUS. Recently, it was found that the functional properties of Stx2a (binding to circulating cells and complement components) change according to modifications of the structure of the toxin, i.e., after a single cleavage of the A subunit resulting in two fragments, A1 and A2, linked by a disulfide bridge. Herein, we describe a method to be used for the detection of the cleaved form of Stx2a in the serum of STEC-infected or eHUS patients. The method is based on the detection of the boosted inhibitory activity of the cleaved toxin, upon treatment with reducing agents, on a rabbit cell-free translation system reconstituted with human ribosomes. The method overcomes the technical problem caused by the presence of inhibitors of translation in human serum that have been stalled by the addition of RNAase blockers and by treatment with immobilized protein G. This method, allowing the detection of Stx2a at concentrations similar to those found by ELISA in the blood of STEC-infected patients, could be a useful tool to study the contribution of the cleaved form of Stx2a in the pathogenesis of eHUS. Full article
(This article belongs to the Special Issue Pathogenesis of Hemolytic Uremic Syndrome Caused by Shiga Toxin-Producing Escherichia coli Infections)
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14 pages, 2611 KiB  
Article
Shiga Toxin 2a Binds to Complement Components C3b and C5 and Upregulates Their Gene Expression in Human Cell Lines
by Sára Kellnerová, Sneha Chatterjee, Rafael Bayarri-Olmos, Louise Justesen, Heribert Talasz, Wilfried Posch, Samyr Kenno, Peter Garred, Dorothea Orth-Höller, Marco Grasse and Reinhard Würzner
Toxins 2021, 13(1), 8; https://doi.org/10.3390/toxins13010008 - 24 Dec 2020
Cited by 2 | Viewed by 3084
Abstract
Enterohemorrhagic Escherichia coli (EHEC) infections can cause EHEC-associated hemolytic uremic syndrome (eHUS) via its main virulent factor, Shiga toxins (Stxs). Complement has been reported to be involved in the progression of eHUS. The aim of this study was to investigate the interactions of [...] Read more.
Enterohemorrhagic Escherichia coli (EHEC) infections can cause EHEC-associated hemolytic uremic syndrome (eHUS) via its main virulent factor, Shiga toxins (Stxs). Complement has been reported to be involved in the progression of eHUS. The aim of this study was to investigate the interactions of the most effective subtype of the toxin, Stx2a, with pivotal complement proteins C3b and C5. The study further examined the effect of Stx2a stimulation on the transcription and synthesis of these complement proteins in human target cell lines. Binding of Stx2a to C3b and C5 was evaluated by ELISA. Kidney and gut cell lines (HK-2 and HCT-8) were stimulated with varied concentrations of Stx2a. Subsequent evaluation of complement gene transcription was studied by real-time PCR (qPCR), and ELISAs and Western blots were performed to examine protein synthesis of C3 and C5 in supernatants and lysates of stimulated HK-2 cells. Stx2a showed a specific binding to C3b and C5. Gene transcription of C3 and C5 was upregulated with increasing concentrations of Stx2a in both cell lines, but protein synthesis was not. This study demonstrates the binding of Stx2a to complement proteins C3b and C5, which could potentially be involved in regulating complement during eHUS infection, supporting further investigations into elucidating the role of complement in eHUS pathogenesis. Full article
(This article belongs to the Special Issue Pathogenesis of Hemolytic Uremic Syndrome Caused by Shiga Toxin-Producing Escherichia coli Infections)
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13 pages, 3031 KiB  
Article
Primary Human Derived Blood Outgrowth Endothelial Cells: An Appropriate In Vitro Model to Study Shiga Toxin Mediated Damage of Endothelial Cells
by Wouter J. C. Feitz, Nicole C. A. J. van de Kar, Ian Cheong, Thea J. A. M. van der Velden, Carolina G. Ortiz-Sandoval, Dorothea Orth-Höller, Lambert P. J. W. van den Heuvel and Christoph Licht
Toxins 2020, 12(8), 483; https://doi.org/10.3390/toxins12080483 - 29 Jul 2020
Cited by 4 | Viewed by 3395
Abstract
Hemolytic uremic syndrome (HUS) is a rare disease primarily characterized by hemolytic anemia, thrombocytopenia, and acute renal failure. Endothelial damage is the hallmark of the pathogenesis of HUS with an infection with the Shiga toxin (Stx) producing Escherichia coli (STEC-HUS) as the main [...] Read more.
Hemolytic uremic syndrome (HUS) is a rare disease primarily characterized by hemolytic anemia, thrombocytopenia, and acute renal failure. Endothelial damage is the hallmark of the pathogenesis of HUS with an infection with the Shiga toxin (Stx) producing Escherichia coli (STEC-HUS) as the main underlying cause in childhood. In this study, blood outgrowth endothelial cells (BOECs) were isolated from healthy donors serving as controls and patients recovered from STEC-HUS. We hypothesized that Stx is more cytotoxic for STEC-HUS BOECs compared to healthy donor control BOECs explained via a higher amount of Stx bound to the cell surface. Binding of Shiga toxin-2a (Stx2a) was investigated and the effect on cytotoxicity, protein synthesis, wound healing, and cell proliferation was studied in static conditions. Results show that BOECs are highly susceptible for Stx2a. Stx2a is able to bind to the cell surface of BOECs with cytotoxicity in a dose-dependent manner as a result. Pre-treatment with tumor necrosis factor alpha (TNF-α) results in enhanced Stx binding with 20–30% increased lactate dehydrogenase (LDH) release. Endothelial wound healing is delayed in a Stx2a-rich environment; however, this is not caused by an effect on the proliferation rate of BOECs. No significant differences were found between control BOECs and BOECs from recovered STEC-HUS patients in terms of Stx2a binding and inhibition of protein synthesis. Full article
(This article belongs to the Special Issue Pathogenesis of Hemolytic Uremic Syndrome Caused by Shiga Toxin-Producing Escherichia coli Infections)
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12 pages, 1823 KiB  
Article
Shiga Toxin Selectively Upregulates Expression of Syndecan-4 and Adhesion Molecule ICAM-1 in Human Glomerular Microvascular Endothelium
by Elena B. Volokhina, Wouter J. C. Feitz, Lonneke M. Elders, Thea J. A. M. van der Velden, Nicole C. A. J. van de Kar and Lambertus P. W. J. van den Heuvel
Toxins 2020, 12(7), 435; https://doi.org/10.3390/toxins12070435 - 3 Jul 2020
Cited by 3 | Viewed by 3095
Abstract
Hemolytic uremic syndrome (HUS) is a severe renal disease that is often preceded by infection with Shiga toxin (Stx)-producing Escherichia coli (STEC). The exact mechanism of Stx-mediated inflammation on human glomerular microvascular endothelial cells (HGMVECs) during HUS is still not well understood. In [...] Read more.
Hemolytic uremic syndrome (HUS) is a severe renal disease that is often preceded by infection with Shiga toxin (Stx)-producing Escherichia coli (STEC). The exact mechanism of Stx-mediated inflammation on human glomerular microvascular endothelial cells (HGMVECs) during HUS is still not well understood. In this study, we investigated the effect of Stx1 on the gene expression of proteins involved in leucocyte-mediated and complement-mediated inflammation. Our results showed that Stx1 enhances the mRNA and protein expression of heparan sulfate proteoglycan (HSPG) syndecan-4 in HGMVECs pre-stimulated with tumor necrosis factor α (TNFα). CD44 was upregulated on mRNA but not on protein level; no effect on the mRNA expression of other tested HSPGs glypican-1 and betaglycan was observed. Furthermore, Stx1 upregulated the mRNA, cell surface expression, and supernatant levels of the intercellular adhesion molecule-1 (ICAM-1) in HGMVECs. Interestingly, no effect on the protein levels of alternative pathway (AP) components was observed, although C3 mRNA was upregulated. All observed effects were much stronger in HGMVECs than in human umbilical endothelial cells (HUVECs), a common model cell type used in endothelial studies. Our results provide new insights into the role of Stx1 in the pathogenesis of HUS. Possibilities to target the overexpression of syndecan-4 and ICAM-1 for STEC-HUS therapy should be investigated in future studies. Full article
(This article belongs to the Special Issue Pathogenesis of Hemolytic Uremic Syndrome Caused by Shiga Toxin-Producing Escherichia coli Infections)
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18 pages, 2044 KiB  
Article
Role of Shiga Toxins in Cytotoxicity and Immunomodulatory Effects of Escherichia coli O157:H7 during Host-Bacterial Interactions in vitro
by Andrea Cecilia Bruballa, Carolina Maiumi Shiromizu, Alan Mauro Bernal, Gonzalo Ezequiel Pineda, Florencia Sabbione, Analia Silvina Trevani, Leticia Verónica Bentancor, María Victoria Ramos, Romina Jimena Fernández-Brando, Manuel Javier Muñoz and Marina Sandra Palermo
Toxins 2020, 12(1), 48; https://doi.org/10.3390/toxins12010048 - 14 Jan 2020
Cited by 10 | Viewed by 4186
Abstract
Enterohemorrhagic Escherichia coli (EHEC) strains are food-borne pathogens that can cause different clinical conditions. Shiga toxin 2a and/or 2c (Stx2)-producing E. coli O157:H7 is the serotype most frequently associated with severe human disease. In this work we analyzed the hypothesis that host cells [...] Read more.
Enterohemorrhagic Escherichia coli (EHEC) strains are food-borne pathogens that can cause different clinical conditions. Shiga toxin 2a and/or 2c (Stx2)-producing E. coli O157:H7 is the serotype most frequently associated with severe human disease. In this work we analyzed the hypothesis that host cells participate in Stx2 production, cell damage, and inflammation during EHEC infection. With this aim, macrophage-differentiated THP-1 cells and the intestinal epithelial cell line HCT-8 were incubated with E. coli O157:H7. A time course analysis of cellular and bacterial survival, Stx2 production, stx2 transcription, and cytokine secretion were analyzed in both human cell lines. We demonstrated that macrophages are able to internalize and kill EHEC. Simultaneously, Stx2 produced by internalized bacteria played a major role in macrophage death. In contrast, HCT-8 cells were completely resistant to EHEC infection. Besides, macrophages and HCT-8 infected cells produce IL-1β and IL-8 inflammatory cytokines, respectively. At the same time, bacterial stx2-specific transcripts were detected only in macrophages after EHEC infection. The interplay between bacteria and host cells led to Stx production, triggering of inflammatory response and cell damage, all of which could contribute to a severe outcome after EHEC infections. Full article
(This article belongs to the Special Issue Pathogenesis of Hemolytic Uremic Syndrome Caused by Shiga Toxin-Producing Escherichia coli Infections)
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17 pages, 2773 KiB  
Article
Crosstalk between Human Microvascular Endothelial Cells and Tubular Epithelial Cells Modulates Pro-Inflammatory Responses Induced by Shiga Toxin Type 2 and Subtilase Cytotoxin
by Romina S. Álvarez, Carolina Jancic, Nicolás Garimano, Flavia Sacerdoti, Adrienne W. Paton, James C. Paton, Cristina Ibarra and María M. Amaral
Toxins 2019, 11(11), 648; https://doi.org/10.3390/toxins11110648 - 7 Nov 2019
Cited by 6 | Viewed by 3275
Abstract
Hemolytic uremic syndrome (HUS) is a consequence of Shiga toxin (Stx)-producing Escherichia coli (STEC) infection and is the most frequent cause of acute renal failure (ARF) in children. Subtilase cytotoxin (SubAB) has also been associated with HUS pathogenesis. We previously reported that Stx2 [...] Read more.
Hemolytic uremic syndrome (HUS) is a consequence of Shiga toxin (Stx)-producing Escherichia coli (STEC) infection and is the most frequent cause of acute renal failure (ARF) in children. Subtilase cytotoxin (SubAB) has also been associated with HUS pathogenesis. We previously reported that Stx2 and SubAB cause different effects on co-cultures of human renal microvascular endothelial cells (HGEC) and human proximal tubular epithelial cells (HK-2) relative to HGEC and HK-2 monocultures. In this work we have analyzed the secretion of pro-inflammatory cytokines by co-cultures compared to monocultures exposed or not to Stx2, SubAB, and Stx2+SubAB. Under basal conditions, IL-6, IL-8 and TNF-α secretion was different between monocultures and co-cultures. After toxin treatments, high concentrations of Stx2 and SubAB decreased cytokine secretion by HGEC monocultures, but in contrast, low toxin concentrations increased their release. Toxins did not modulate the cytokine secretion by HK-2 monocultures, but increased their release in the HK-2 co-culture compartment. In addition, HK-2 monocultures were stimulated to release IL-8 after incubation with HGEC conditioned media. Finally, Stx2 and SubAB were detected in HGEC and HK-2 cells from the co-cultures. This work describes, for the first time, the inflammatory responses induced by Stx2 and SubAB, in a crosstalk model of renal endothelial and epithelial cells. Full article
(This article belongs to the Special Issue Pathogenesis of Hemolytic Uremic Syndrome Caused by Shiga Toxin-Producing Escherichia coli Infections)
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Review

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26 pages, 557 KiB  
Review
Shiga Toxin-Associated Hemolytic Uremic Syndrome: Specificities of Adult Patients and Implications for Critical Care Management
by Benoit Travert, Cédric Rafat, Patricia Mariani, Aurélie Cointe, Antoine Dossier, Paul Coppo and Adrien Joseph
Toxins 2021, 13(5), 306; https://doi.org/10.3390/toxins13050306 - 26 Apr 2021
Cited by 20 | Viewed by 4294
Abstract
Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) is a form of thrombotic microangiopathy secondary to an infection by an enterohemorrhagic E. coli. Historically considered a pediatric disease, its presentation has been described as typical, with bloody diarrhea at the forefront. [...] Read more.
Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) is a form of thrombotic microangiopathy secondary to an infection by an enterohemorrhagic E. coli. Historically considered a pediatric disease, its presentation has been described as typical, with bloody diarrhea at the forefront. However, in adults, the clinical presentation is more diverse and makes the early diagnosis hazardous. In this review, we review the epidemiology, most important outbreaks, physiopathology, clinical presentation and prognosis of STEC-HUS, focusing on the differential features between pediatric and adult disease. We show that the clinical presentation of STEC-HUS in adults is far from typical and marked by the prevalence of neurological symptoms and a poorer prognosis. Of note, we highlight knowledge gaps and the need for studies dedicated to adult patients. The differences between pediatric and adult patients have implications for the treatment of this disease, which remains a public health threat and lack a specific treatment. Full article
(This article belongs to the Special Issue Pathogenesis of Hemolytic Uremic Syndrome Caused by Shiga Toxin-Producing Escherichia coli Infections)
53 pages, 4319 KiB  
Review
Valid Presumption of Shiga Toxin-Mediated Damage of Developing Erythrocytes in EHEC-Associated Hemolytic Uremic Syndrome
by Johanna Detzner, Gottfried Pohlentz and Johannes Müthing
Toxins 2020, 12(6), 373; https://doi.org/10.3390/toxins12060373 - 4 Jun 2020
Cited by 9 | Viewed by 5799
Abstract
The global emergence of clinical diseases caused by enterohemorrhagic Escherichia coli (EHEC) is an issue of great concern. EHEC release Shiga toxins (Stxs) as their key virulence factors, and investigations on the cell-damaging mechanisms toward target cells are inevitable for the development of [...] Read more.
The global emergence of clinical diseases caused by enterohemorrhagic Escherichia coli (EHEC) is an issue of great concern. EHEC release Shiga toxins (Stxs) as their key virulence factors, and investigations on the cell-damaging mechanisms toward target cells are inevitable for the development of novel mitigation strategies. Stx-mediated hemolytic uremic syndrome (HUS), characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal injury, is the most severe outcome of an EHEC infection. Hemolytic anemia during HUS is defined as the loss of erythrocytes by mechanical disruption when passing through narrowed microvessels. The formation of thrombi in the microvasculature is considered an indirect effect of Stx-mediated injury mainly of the renal microvascular endothelial cells, resulting in obstructions of vessels. In this review, we summarize and discuss recent data providing evidence that HUS-associated hemolytic anemia may arise not only from intravascular rupture of erythrocytes, but also from the extravascular impairment of erythropoiesis, the development of red blood cells in the bone marrow, via direct Stx-mediated damage of maturing erythrocytes, leading to “non-hemolytic” anemia. Full article
(This article belongs to the Special Issue Pathogenesis of Hemolytic Uremic Syndrome Caused by Shiga Toxin-Producing Escherichia coli Infections)
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