Shiga Toxin-2 Induces Neutrophilia and Neutrophil Activation in a Murine Model of Hemolytic Uremic Syndrome

2000 ◽  
Vol 95 (3) ◽  
pp. 227-234 ◽  
Author(s):  
Gabriela C. Fernández ◽  
Carolina Rubel ◽  
Graciela Dran ◽  
Sonia Gómez ◽  
Martı́n A. Isturiz ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Murine Model ◽  
Shiga Toxin ◽  
Neutrophil Activation ◽  
Shiga Toxin 2 ◽  
Uremic Syndrome

Recovery of thalamic microstructural damage after Shiga toxin 2-associated hemolytic–uremic syndrome

2015 ◽  
Vol 356 (1-2) ◽  
pp. 175-183 ◽  
Author(s):  
Julia Krämer ◽  
Michael Deppe ◽  
Kerstin Göbel ◽  
Karsten Tabelow ◽  
Heinz Wiendl ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Microstructural Damage ◽  
Shiga Toxin 2 ◽  
Uremic Syndrome

Anti-Shiga toxin 2 antibodies in enterohemorrhagicEscherichia coliO104:H4 infected patients may predict hemolytic uremic syndrome

2018 ◽  
Vol 33 (7) ◽  
pp. 1353-1356
Author(s):  
Werner Dammermann ◽  
Valentin Mihajlov ◽  
Barbara Middendorf ◽  
Alexander Mellmann ◽  
Helge Karch ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Shiga Toxin 2 ◽  
Uremic Syndrome

scholarly journals Cognitive deficits found in a pro-inflammatory state are independent of ERK 1/2 signaling in the murine brain hippocampus treated with Shiga toxin 2 from enterohemorrhagic Escherichia Coli

2020 ◽  
Author(s):  
Clara Berdasco ◽  
Alipio Pinto ◽  
Mariano Blake ◽  
Fernando Correa ◽  
Nadia A. Longo Carbajosa ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Central Nervous System ◽  
Nervous System ◽  
Hemolytic Uremic Syndrome ◽  
Signaling Pathway ◽  
Shiga Toxin ◽  
Enterohemorrhagic Escherichia Coli ◽  
Shiga Toxin 2 ◽  
Uremic Syndrome ◽  
The Brain

AbstractShiga toxin 2 (Stx2) from enterohemorrhagic Escherichia coli (EHEC) produces hemorrhagic colitis, hemolytic uremic syndrome (HUS) and acute encephalopathy. The mortality rate in HUS increases significantly when the central nervous system (CNS) is involved. Besides, EHEC also releases lipopolysaccharide (LPS). Many reports have described cognitive dysfunctions in HUS patients, the hippocampus being one of the brain areas targeted by EHEC infection. In this context, a translational murine model of encephalopathy was employed to establish the deleterious effects of Stx2 and the contribution of LPS in the hippocampus. Results demonstrate that systemic administration of a sublethal dose of Stx2 reduced memory index and produced depression like behavior, pro-inflammatory cytokine release and NF-kB activation independent of the ERK 1/2 signaling pathway. On the other hand, LPS activated NF-kB dependent on ERK 1/2 signaling pathway. Cotreatment of Stx2 with LPS aggravated the pathologic state, while dexamethasone treatment succeeded in preventing behavioral alterations. Our present work suggests that the use of drugs such as corticosteroids or NF-kB signaling inhibitors may serve as neuroprotectors from EHEC infection.Author SummaryShiga toxin (Stx) from enterohemorrhagic Escherichia coli (EHEC) is one of the most virulent factors responsible for hemolytic uremic syndrome (HUS). Stx2, the endemic variant targets the brain, among other organs, thus inducing encephalopathies. Central nervous system (CNS) compromise was the main predictor of death in patients with HUS. Stx2 may exert a direct action in the CNS, by disrupting the neurovascular unit. In this context, we investigate the molecular signaling triggered by Stx2 in the murine brain hippocampus involved in inflammatory mechanisms that altered hippocampal-related cognitive behaviors. The present data underscore that the use of drugs such as dexamethasone or those blocking the cascade by preventing NF-kB translocation to the nucleus may serve as effective neuroprotectors with potentially beneficial use in the clinic.

scholarly journals Gut–Kidney Axis on Chip for Studying Effects of Antibiotics on Risk of Hemolytic Uremic Syndrome by Shiga Toxin-Producing Escherichia coli

Toxins ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 775
Author(s):  
Yugyeong Lee ◽  
Min-Hyeok Kim ◽  
David Rodrigues Alves ◽  
Sejoong Kim ◽  
Luke P. Lee ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Low Frequency ◽  
Kidney Cells ◽  
Number Of Patients ◽  
Relevant Situation ◽  
Shiga Toxin 2 ◽  
Uremic Syndrome ◽  
On Chip

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.

scholarly journals Mouse Model of Hemolytic-Uremic Syndrome Caused by Endotoxin-Free Shiga Toxin 2 (Stx2) and Protection from Lethal Outcome by Anti-Stx2 Antibody

2008 ◽  
Vol 76 (10) ◽  
pp. 4469-4478 ◽  
Author(s):  
Kristin A. D. Sauter ◽  
Angela R. Melton-Celsa ◽  
Kay Larkin ◽  
Megan L. Troxell ◽  
Alison D. O'Brien ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Passive Immunization ◽  
Endothelial Damage ◽  
Lethal Outcome ◽  
Lethal Effects ◽  
Proinflammatory Mediators ◽  
Shiga Toxin 2 ◽  
Uremic Syndrome

ABSTRACT Hemolytic-uremic syndrome (HUS) results from infection by Shiga toxin (Stx)-producing Escherichia coli and is the most common cause of acute renal failure in children. We have developed a mouse model of HUS by administering endotoxin-free Stx2 in multiple doses over 7 to 8 days. At sacrifice, moribund animals demonstrated signs of HUS: increased blood urea nitrogen and serum creatinine levels, proteinuria, deposition of fibrin(ogen), glomerular endothelial damage, hemolysis, leukocytopenia, and neutrophilia. Increased expression of proinflammatory chemokines and cytokines in the sera of Stx2-treated mice indicated a systemic inflammatory response. Currently, specific therapeutics for HUS are lacking, and therapy for patients is primarily supportive. Mice that received 11E10, a monoclonal anti-Stx2 antibody, 4 days after starting injections of Stx2 recovered fully, displaying normal renal function and normal levels of neutrophils and lymphocytes. In addition, these mice showed decreased fibrin(ogen) deposition and expression of proinflammatory mediators compared to those of Stx2-treated mice in the absence of antibody. These results indicate that, when performed during progression of HUS, passive immunization of mice with anti-Stx2 antibody prevented the lethal effects of Stx2.

scholarly journals LPS-primed CD11b+ leukocytes serve as an effective carrier of Shiga toxin 2 to cause hemolytic uremic syndrome in mice

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Shuo Niu ◽  
John Paluszynski ◽  
Zhen Bian ◽  
Lei Shi ◽  
Koby Kidder ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Shiga Toxin 2 ◽  
Uremic Syndrome ◽  
Effective Carrier

Particulate Shiga Toxin 2 in Blood is Associated to the Development of Hemolytic Uremic Syndrome in Children

2019 ◽  
Vol 120 (01) ◽  
pp. 107-120 ◽  
Author(s):  
Maurizio Brigotti ◽  
Xiaohua He ◽  
Domenica Carnicelli ◽  
Valentina Arfilli ◽  
Elisa Porcellini ◽  
...  
Keyword(s):  
Blood Cell ◽  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Time Course ◽  
Hemorrhagic Colitis ◽  
Shiga Toxins ◽  
Circulating Cells ◽  
Shiga Toxin 2 ◽  
Uremic Syndrome ◽  
The Relationship

AbstractHemolytic uremic syndrome (HUS), the leading cause of acute renal failure in children (< 3 years), is mainly related to Shiga toxins (Stx)-producing Escherichia coli (STEC) infections. STEC are confined to the gut resulting in hemorrhagic colitis, whereas Stx are delivered in blood to target kidney and brain, with unclear mechanisms, triggering HUS in 5 to 15% of infected children. Stx were found on circulating cells, free in sera (soluble Stx) or in blood cell-derived microvesicles (particulate Stx), whereby the relationship between these forms of circulating toxins is unclear. Here, we have examined 2,846 children with bloody diarrhea and found evidence of STEC infection in 5%. Twenty patients were enrolled to study the natural course of STEC infections before the onset of HUS. In patients, Stx were found to be associated to circulating cells and/or free and functionally active in sera. In most children, Stx were bound to neutrophils when high amounts of toxins were found in feces. Time-course analysis showed that Stx increased transiently in patients' sera while the decrease of toxin amount on leukocytes was observed. Notably, patients who recovered (85%) displayed different settings than those who developed HUS (15%). The distinctive feature of the latter group was the presence in blood of particulate Stx2 (Stx2 sedimented at g-forces corresponding to 1 μm microvesicles) the day before diagnosis of HUS, during the release phase of toxins from circulating cells. This observation strongly suggests the involvement of blood cell-derived particulate Stx2 in the transition from hemorrhagic colitis to HUS.

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