scholarly journals Shiga Toxin 2a Induces NETosis via NOX-Dependent Pathway

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1807
Author(s):  
Wouter J. C. Feitz ◽  
Samuel Suntharalingham ◽  
Meraj Khan ◽  
Carolina G. Ortiz-Sandoval ◽  
Nades Palaniyar ◽  
...  
Keyword(s):  
Shiga Toxin ◽  
Kidney Injury ◽  
Recovery Phase ◽  
Neutrophil Extracellular Trap ◽  
Healthy Controls ◽  
Healthy Donors ◽  
Uremic Syndrome ◽  
Endothelium Damage ◽  
Dependent Pathway ◽  
Specific Inhibitors

Shiga toxin (Stx)-producing Escherichia coli (STEC) infection is the most common cause of hemolytic uremic syndrome (HUS), one of the main causes of acute kidney injury in children. Stx plays an important role in endothelium damage and pathogenesis of STEC-HUS. However, the effects of Stx on neutrophils and neutrophil extracellular trap (NET) formation are not well understood. In this study, we investigated how Stx2a affects NET formation and NETotic pathways (NADPH or NOX-dependent and -independent) using neutrophils isolated from healthy donors and patients with STEC-HUS, during the acute and recovery phase of the disease. Stx2a dose-dependently induced NETosis in neutrophils isolated from both healthy controls and STEC-HUS patients. NETosis kinetics and mechanistic data with pathway-specific inhibitors including diphenyleneiodonium (DPI)-, ERK-, and P38-inhibitors showed that Stx2a-induced NETosis via the NOX-dependent pathway. Neutrophils from STEC-HUS patients in the acute phase showed less ROS and NETs formation compared to neutrophils of the recovery phase of the disease and in healthy controls. NETs induced by Stx2a may lead to the activation of endothelial cells, which might contribute to the manifestation of thrombotic microangiopathy in STEC-HUS.

Tissue-resident macrophages mediate neutrophil recruitment and kidney injury in shiga toxin-induced hemolytic uremic syndrome.

2021 ◽  
Author(s):  
Julia K. Lill ◽  
Stephanie Thiebes ◽  
Judith-Mira Pohl ◽  
Jenny Bottek ◽  
Nirojah Subramaniam ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Kidney Injury ◽  
Neutrophil Recruitment ◽  
Uremic Syndrome

scholarly journals Platelet Thrombus Formation in eHUS is Prevented by Anti-MBL2

2019 ◽  
Author(s):  
R. I. Kushak ◽  
D.C Boyle ◽  
I.A. Rosales ◽  
J.R. Ingelfinger ◽  
G.L Stahl ◽  
...  
Keyword(s):  
Shiga Toxin ◽  
Thrombus Formation ◽  
Kidney Injury ◽  
Control Group ◽  
Shiga Toxin 2 ◽  
Uremic Syndrome ◽  
Affected Mouse ◽  
Ultrathin Sections ◽  
Platelet Thrombus ◽  
Von Willebrand

AbstractEpidemic Hemolytic Uremic Syndrome (eHUS) caused by Shiga toxin-producing bacteria is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury that cause acute renal failure in up to 65% of affected patients. We hypothesized that the mannose-binding lectin (MBL) pathway of complement activation plays an important role in human eHUS, as we previously demonstrated that injection of Shiga Toxin-2 (Stx-2) led to fibrin deposition in mouse glomeruli that was blocked by co-injection of the anti-MBL-2 antibody 3F8. However, the markers of platelet thrombosis in affected mouse glomeruli were not delineated. To investigate the effect of 3F8 on markers of platelet thrombosis, we used kidney sections from our mouse model (MBL-2+/+ Mbl-A/C−/−;MBL2 KI mouse). Mice in the control group received PBS, while mice in a second group received Stx-2, and those in a third group received 3F8 and Stx-2. Using double immunofluorescence (IF) followed by digital image analysis, kidney sections were stained for fibrin(ogen) and CD41 (marker for platelets), von-Willebrand factor (marker for endothelial cells and platelets), and podocin (marker for podocytes). Electron microscopy (EM) was performed on ultrathin sections from mice and human with HUS. Injection of Stx-2 resulted in an increase of both fibrin and platelets in glomeruli, while administration of 3F8 with Stx-2 reduced both platelet and fibrin to control levels. EM studies confirmed that CD41-positive objects observed by IF were platelets. The increases in platelet number and fibrin levels by injection of Stx-2 are consistent with the generation of platelet-fibrin thrombi that were prevented by 3F8.

scholarly journals P0334HEMOLYTIC UREMIC SYNDROME: CLINICAL PRESENTATION, LABORATORY FINDINGS, MANAGEMENT AND OUTCOMES

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Issa Al Salmi ◽  
AbdelMasiah Metry ◽  
SUAD Hannawi
Keyword(s):  
Escherichia Coli ◽  
Hemolytic Uremic Syndrome ◽  
Hemolytic Anemia ◽  
Shiga Toxin ◽  
Post Partum ◽  
Kidney Injury ◽  
Partial Recovery ◽  
Laboratory Findings ◽  
Study Results ◽  
Uremic Syndrome

Abstract Background and Aims Hemolytic-uremic syndrome (HUS) is a disease that has been described as a triad of hemolytic anemia, thrombocytopenia and renal impairment. There are two types of HUS, typical and atypical. HUS remains a leading cause of acute renal injury in children and is increasingly recognized as a cause of renal failure in adults. In our study we evaluated the demographic features, clinical characteristics, management and outcome of HUS. Method This is a descriptive study evaluating all cases of Hemolytic Uremic Syndrome (HUS) that have been admitted at Royal Hospital (RH) Oman in the period between 2008 and 2017. Results Thirty-six patients identified. The mean age (SD) of 10.68 (14.07) years. Eighteen (50%) presented with abdominal pain, nausea, vomiting and diarrhea, 9 (25 %) with hypertension, 23 (64 %) with acute kidney injury (AKI), 6 (16.67%) with seizure, 2 (5.56%) with confusion and 1 (2.78%) with cerebrovascular accident (CVA). Twenty-one (58.33 %) diagnosed as typical HUS of which 19 with Shiga toxin producing Escherichia Coli (STEC) HUS and 2 had post Streptococal HUS. Six (16.67%) diagnosed with aHUS, 2 (5.56%) with HELLP, 2 (5.56%) with G6PD, 3 (8.33%) with Autoimmune hemolytic anemia (AIHA ), one (2.78%) with congenital TTP and 1 (2.78%) with post partum HUS. Twenty three (63.89%) needed renal replacement therapy (RRT), while remaining 13 (36.11%) did not require RRT. Eleven (30.56%) received plasma exchange, 5 (13.89%) received Eculizumab while 2 (5.56%) received plasma infusion and 1 (2.78%) patient received Rituximab. The majority 22 (61.11%) had partial recovery after treatment, 5 (13.89 %) had compelte recovery and 3 (8.33% ) ended with end stage kidney disease (ESKD) and 1 (2.78%) died from hypertensive crises. Conclusion The study results showed that HUS population were mostly due to Shiga toxin producing Escherichia Coli (STEC). It showed that HUS population were young, mostly male and only 25% have known medical comorbidities at time of presentation. Also, the majority presented with AKI requiring dialysis, of which PD was main stay of therapy. The duration of RRT and recovery time was almost a month period.

scholarly journals CCR2‐dependent Gr1 high monocytes promote kidney injury in shiga toxin‐induced hemolytic uremic syndrome in mice

2018 ◽  
Vol 48 (6) ◽  
pp. 990-1000
Author(s):  
Judith‐Mira Pohl ◽  
Julia K. Volke ◽  
Stephanie Thiebes ◽  
Alexandra Brenzel ◽  
Kerstin Fuchs ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Kidney Injury ◽  
Uremic Syndrome

scholarly journals Advances in our understanding of the pathogenesis of hemolytic uremic syndromes

2018 ◽  
Vol 314 (3) ◽  
pp. F454-F461 ◽  
Author(s):  
E. E. Bowen ◽  
R. J. Coward
Keyword(s):  
Health Care ◽  
Acute Kidney Injury ◽  
Global Health ◽  
Shiga Toxin ◽  
Scientific Community ◽  
Kidney Injury ◽  
Microangiopathic Hemolytic Anemia ◽  
Global Health Care ◽  
Uremic Syndrome ◽  
Key Questions

Hemolytic uremic syndrome (HUS) is major global health care issue as it is the leading cause of acute kidney injury in children. It is a triad of acute kidney injury, microangiopathic hemolytic anemia, and thrombocytopenia. In recent years, major advances in our understanding of complement-driven inherited rare forms of HUS have been achieved. However, in children 90% of cases of HUS are associated with a Shiga toxin-producing enteric pathogen. The precise pathological mechanisms in this setting are yet to be elucidated. The purpose of this review is to discuss advances in our understanding of the pathophysiology underlying HUS and identify the key questions yet to be answered by the scientific community.

scholarly journals Heme as Possible Contributing Factor in the Evolvement of Shiga-Toxin Escherichia coli Induced Hemolytic-Uremic Syndrome

2020 ◽  
Vol 11 ◽  
Author(s):  
Kioa L. Wijnsma ◽  
Susan T. Veissi ◽  
Sem de Wijs ◽  
Thea van der Velden ◽  
Elena B. Volokhina ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Plasma Levels ◽  
Nuclear Translocation ◽  
Kidney Injury ◽  
High Plasma ◽  
Endothelial Injury ◽  
Heme Oxygenase 1 ◽  
Uremic Syndrome

Shiga-toxin (Stx)-producing Escherichia coli hemolytic-uremic syndrome (STEC-HUS) is one of the most common causes of acute kidney injury in children. Stx-mediated endothelial injury initiates the cascade leading to thrombotic microangiopathy (TMA), still the exact pathogenesis remains elusive. Interestingly, there is wide variability in clinical presentation and outcome. One explanation for this could be the enhancement of TMA through other factors. We hypothesize that heme, as released during extensive hemolysis, contributes to the etiology of TMA. Plasma levels of heme and its scavenger hemopexin and degrading enzyme heme-oxygenase-1 (HO-1) were measured in 48 STEC-HUS patients. Subsequently, the effect of these disease-specific heme concentrations, in combination with Stx, was assessed on primary human glomerular microvascular endothelial cells (HGMVECs). Significantly elevated plasma heme levels up to 21.2 µM were found in STEC-HUS patients compared to controls and were inversely correlated with low or depleted plasma hemopexin levels (R2 −0.74). Plasma levels of HO-1 are significantly elevated compared to controls. Interestingly, especially patients with high heme levels (n = 12, heme levels above 75 quartile range) had high plasma HO-1 levels with median of 332.5 (86–720) ng/ml (p = 0.008). Furthermore, heme is internalized leading to a significant increase in reactive oxygen species production and stimulated both nuclear translocation of NF-κB and increased levels of its target gene (tissue factor). In conclusion, we are the first to show elevated heme levels in patients with STEC-HUS. These increased heme levels mediate endothelial injury by promoting oxidative stress and a pro-inflammatory and pro-thrombotic state. Hence, heme may be a contributing and driving factor in the pathogenesis of STEC-HUS and could potentially amplify the cascade leading to TMA.

scholarly journals Neutrophil subpopulations and their activation potential in patients with antiphospholipid syndrome and healthy individuals

Rheumatology ◽  
2020 ◽  
Author(s):  
Lisa-Marie Mauracher ◽  
Moritz Krall ◽  
Johanna Roiß ◽  
Lena Hell ◽  
Silvia Koder ◽  
...  
Keyword(s):  
Gradient Centrifugation ◽  
Absolute Number ◽  
Neutrophil Extracellular Trap ◽  
Healthy Controls ◽  
Activation Markers ◽  
Healthy Donors ◽  
Increased Risk ◽  
High Median ◽  
Insight Into ◽  
Net Release

Abstract Objectives Patients with APS are at increased risk of thromboembolism. Neutrophils have been shown to play a role in inducing thrombosis. We aimed to investigate differences in neutrophil subpopulations, their potential of activation and neutrophil extracellular trap (NET) formation comparing high and low-density neutrophils (HDNs/LDNs) as well as subpopulations in patients with APS and controls to gain deeper insight into their potential role in thrombotic manifestations in patients with APS. Methods HDNs and LDNs of 20 patients with APS and 20 healthy donors were isolated by density gradient centrifugation and stimulated. Neutrophil subpopulations, their activation and NET release were assessed by flow cytometry. Results LDNs of both groups showed higher baseline activation, lower response to stimulation (regulation of activation markers CD11b/CD66b), but higher NET formation compared with HDNs. In patients with APS, the absolute number of LDNs was higher compared with controls. HDNs of APS patients showed higher spontaneous activation [%CD11b high: median (interquartile range): 2.78% (0.58–10.24) vs 0.56% (0.19–1.37)] and response to stimulation with ionomycin compared with HDNs of healthy donors [%CD11b high: 98.20 (61.08–99.13) vs 35.50% (13.50–93.85)], whereas no difference was found in LDNs. NET formation was increased in patients’ HDNs upon stimulation. Conclusion HDNs and LDNs act differently, unstimulated and upon various stimulations in both healthy controls and APS patients. Differences in HDNs and LDNs between patients with APS and healthy controls indicate that neutrophils may enhance the risk of thrombosis in these patients and could thus be a target for prevention of thrombosis in APS.

Epidemiology and pathophysiology of hemolytic uremic syndrome associated with shiga toxin (literature review)

2021 ◽  
Vol 25 (3) ◽  
pp. 36-42
Author(s):  
S. V. Baiko
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Tap Water ◽  
Kidney Injury ◽  
Human Immune System ◽  
E Coli ◽  
Unpasteurized Milk ◽  
Pathogenic Genes ◽  
Inflammatory Chemokines ◽  
Uremic Syndrome

Hemolytic uremic syndrome (HUS) associated with shiga toxin E. coli(STEC) is one of the most common causes of acute kidney injury in young children. The share of STEC-HUS among all HUS variants is up to 90%. Not all STECs are pathogenic to humans, and those that cause disease (hemorrhagic colitis, HUS) are referred to as enterohemorrhagic E. coli(EHEC). The main pathogens causing STEC-HUS include the serotype E. coliO157: H7, less often serotypes O26, O80, O103, O121, O145. EHEC exist as normal microbiota in cattle, but can also be found in goats, sheep, pigs, chickens, dogs, and rats. Infection can occur when using undercooked ground beef, unpasteurized milk, water, including tap water and from open ponds and pools, from an infected person and when visiting farms and zoos. The epidemiological history should be carefully assessed in each patient with HUS, taking into account the annual outbreaks of this disease in different regions of the world. In recent years actively discussed the issue of the transfer of shiga toxin (Stx) from the intestine to the blood and from the blood to target organs in the form of microvesicles, the wall of which is the outer shell of E.coliand blood cells. This allows Stx to escape the response of the human immune system. The article describes in detail the mechanisms of infection and expression of pathogenic genes of EHEC, the effect of Stx on endothelial cells, on expression of adhesion molecules and inflammatory chemokines, activation of the alternative complement pathway, which determine the development of HUS.

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