Lack of specific binding of Shiga-like toxin (verocytotoxin) and non-specific interaction of Shiga-like toxin 2 antibody with human polymorphonuclear leucocytes

Geelen, Joyce; Velden, Thea J A M van der; Loo, D. Maroeska W. M. te; Boerman, Otto C.; Heuvel, L.P.W.J. van den; Monnens, L.A.H.

doi:10.1093/ndt/gfl688

Cited by 30 publications

(36 citation statements)

References 17 publications

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“…The effect of traces of LPS or Stx1 in AST-conditioned medium on PMN activation cannot be completely ruled out. However, it was demonstrated previously that even after PMN priming with LPS, TNF-␣, or IL-8, Stx fails to activate PMN (18,22). Moreover, the enhanced PMNmediated toxicity observed after the combined treatment (LPS and Stx1) compared to that of LPS alone supports the finding that the observed effects may be due to an AST-derived factor(s) (Fig.…”

Section: Vol 78 2010 Stx1-induced Effects On Lps-sensitized Astrocysupporting

confidence: 72%

Shiga Toxin 1-Induced Inflammatory Response in Lipopolysaccharide-Sensitized Astrocytes Is Mediated by Endogenous Tumor Necrosis Factor Alpha

Landoni

Campos-Nebel

Schierloh³

et al. 2010

Infect Immun

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Hemolytic-uremic syndrome (HUS) is generally caused by Shiga toxin (Stx)-producingThe epidemic form of hemolytic-uremic syndrome (HUS) has been associated with enterohemorrhagic infections caused by Shiga toxin (Stx)-producing Escherichia coli (STEC) organisms (33). HUS is the most common cause of acute renal failure in children and is related to the endothelial damage of glomeruli and/or arterioles of the kidney and epithelial cell damage induced by Stx through the interaction with its globotriaosylceramide (Gb 3 ) receptor (35). Although Stx is the main pathogenic factor and is necessary for epidemic HUS development, clinical and experimental evidence suggests that the inflammatory response is able to potentiate Stx toxicity. In fact, both bacterial lipopolysaccharide (LPS) and polymorphonuclear neutrophils (PMN) play a key role in the full development of HUS (15). Moreover, PMN leukocytosis in patients correlates with a poor prognosis (17).Endothelial cell damage is not limited to the kidney but extends to other organs; in severe cases, the brain can be affected. In fact, central nervous system (CNS) complications indicate severe HUS, and brain damage involvement is the most common cause of death (14).However, the pathogenesis of CNS impairment is not yet fully understood. Although it has been demonstrated that human brain endothelial cells (BECs) are relatively resistant to Stx, inflammatory mediators, such as tumor necrosis factor alpha (TNF-␣), markedly increase human BEC sensitivity to Stx cytotoxicity (11).BECs are part of the blood-brain barrier (BBB), which protects the brain from potentially harmful substances and leukocytes present in the bloodstream. Thus, the integrity of BBB function is theorized to be a key component in CNS-associated pathologies, and BEC damage is thought to be one of the possible mechanisms involved in the disruption of the BBB in HUS. In fact, LPS from bacterial infections leads to the release of TNF-␣, interleukin-1␤ (IL-1␤), and reactive oxygen species (ROS), all of which have the ability to open the BBB.Several in vivo studies demonstrated previously that Stx is able to impair BBB function, increasing its permeability (21). Moreover, Stx itself is able to cross the endothelial barrier and enter into the CNS, since Stx activity in cerebrospinal fluid was previously observed (19,23), and Stx was previously immunodetected in many brain cells including astrocytes (ASTs) and neurons (44).

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Section: Vol 78 2010 Stx1-induced Effects On Lps-sensitized Astrocysupporting

confidence: 72%

Shiga Toxin 1-Induced Inflammatory Response in Lipopolysaccharide-Sensitized Astrocytes Is Mediated by Endogenous Tumor Necrosis Factor Alpha

Landoni

Campos-Nebel

Schierloh³

et al. 2010

Infect Immun

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“…Furthermore, some authors have proposed that PMN might facilitate the systemic absorption of Stx2, which in turn would increase the risk of developing HUS [35]. In contrast, other studies have failed to detect direct binding of Stx2 to resting human PMN [36,37,38] or Stx2 bound to PMN in HUS patients [31,33,34]. However, our findings indicating that Stx2 increases the expression of activation markers, stimulates ROS production, and triggers NETosis support the notion that this toxin is able to directly activate PMN in culture.…”

Section: Discussionmentioning

confidence: 99%

Induction of Neutrophil Extracellular Traps in Shiga Toxin-Associated Hemolytic Uremic Syndrome

et al. 2016

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Hemolytic uremic syndrome (HUS), a vascular disease characterized by hemolytic anemia, thrombocytopenia, and acute renal failure, is caused by enterohemorrhagic Shiga toxin (Stx)-producing bacteria, which mainly affect children. Besides Stx, the inflammatory response mediated by neutrophils (PMN) is essential to HUS evolution. PMN can release neutrophil extracellular traps (NET) composed of DNA, histones, and other proteins. Since NET are involved in infectious and inflammatory diseases, the aim of this work was to investigate the contribution of NET to HUS. Plasma from HUS patients contained increased levels of circulating free-DNA and nucleosomes in comparison to plasma from healthy children. Neutrophils from HUS patients exhibited a greater capacity to undergo spontaneous NETosis. NET activated human glomerular endothelial cells, stimulating secretion of the proinflammatory cytokines IL-6 and IL-8. Stx induced PMN activation as judged by its ability to trigger reactive oxygen species production, increase CD11b and CD66b expression, and induce NETosis in PMN from healthy donors. During HUS, NET can contribute to the inflammatory response and thrombosis in the microvasculature and thus to renal failure. Intervention strategies to inhibit inflammatory mechanisms mediated by PMN, such as NETosis, could have a potential therapeutic impact towards amelioration of the severity of HUS.

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“…However, a few years later, some of these authors reversed their position because they found that the binding of Stx to PMN was not specific, and they interpreted their own previous results as artifacts (7). In the meantime, other authors claimed that the PMN/Stx interaction was of little biological significance and failed to reproduce the early observations (8,9).…”

Section: Hemolytic Uremic Syndrome (Hus)mentioning

confidence: 99%

“…It should be noted that the three different groups that gave positive (10 -13) or partially positive (15) results on this topic have purified Stx by single-step affinity chromatography. In contrast, the three groups that were unable to reproduce Stx binding to PMN obtained the toxins by multistep purification methods (7,8) or from commercial sources (7,9). The methods employed, although sound and well known, contain numerous steps and chromatographic runs, which might have caused the partial conformational change inhibiting the binding of Stx1 to PMN.…”

Section: Treatmentsmentioning

confidence: 99%

Change in Conformation with Reduction of α-Helix Content Causes Loss of Neutrophil Binding Activity in Fully Cytotoxic Shiga Toxin 1

Brigotti

Carnicelli

Arfilli

et al. 2011

Journal of Biological Chemistry

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Background:The role of Shiga toxins/neutrophils interactions in the pathogenesis of hemolytic uremic syndrome has been greatly debated. Results: We show that limited toxin unfolding induces loss of neutrophil binding activity while maintaining toxicity. Conclusion:The data indicate that Trp-203-related A chain moieties are recognized by neutrophils. Significance: We gain new insights into the structure/function relationship of these well known toxins, explaining some conflicting results.

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Lack of specific binding of Shiga-like toxin (verocytotoxin) and non-specific interaction of Shiga-like toxin 2 antibody with human polymorphonuclear leucocytes

Cited by 30 publications

References 17 publications

Shiga Toxin 1-Induced Inflammatory Response in Lipopolysaccharide-Sensitized Astrocytes Is Mediated by Endogenous Tumor Necrosis Factor Alpha

Shiga Toxin 1-Induced Inflammatory Response in Lipopolysaccharide-Sensitized Astrocytes Is Mediated by Endogenous Tumor Necrosis Factor Alpha

Induction of Neutrophil Extracellular Traps in Shiga Toxin-Associated Hemolytic Uremic Syndrome

Change in Conformation with Reduction of α-Helix Content Causes Loss of Neutrophil Binding Activity in Fully Cytotoxic Shiga Toxin 1

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