Facing glycosphingolipid–Shiga toxin interaction: dire straits for endothelial cells of the human vasculature

Bauwens, Andreas; Betz, Josefine; Meisen, Iris; Kemper, Björn; Karch, Helge; Müthing, Johannes

doi:10.1007/s00018-012-1060-z

Cited by 70 publications

(51 citation statements)

References 354 publications

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“…STEC produce two main AB5 toxin variants-Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2)-consisting of five B chains that are linked noncovalently to a single A chain (8,9). The B pentamer directs the toxins toward cells harboring glycosphingolipids of the globoseries called globotriaosylceramide (Gb3Cer) and globotetraosylceramide (Gb4Cer) (10). Few human cells possess these receptors (11)(12)(13)(14) whose expression characterizes the endothelial lining of the intestine, brain, and kidney, which are indeed the body sites mainly targeted by Stx.…”

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confidence: 99%

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Identification of TLR4 as the Receptor That Recognizes Shiga Toxins in Human Neutrophils

Brigotti

Carnicelli

Arfilli

et al. 2013

The Journal of Immunology

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Hemolytic uremic syndrome (HUS) caused by intestinal Shiga toxin–producing Escherichia coli infections is a worldwide health problem, as dramatically exemplified by the German outbreak occurred in summer 2011 and by a constant burden of cases in children. Shiga toxins (Stx) play a pivotal role in HUS by triggering endothelial damage in kidney and brain through globotriaosylceramide (Gb3Cer) receptor targeting. Moreover, Stx interact with human neutrophils, as experimentally demonstrated in vitro and as observed in patients with HUS. A neutrophil-protective role on endothelial damage (sequestration of circulating toxins) and a causative role in toxin delivery from the gut to the kidney (piggyback transport) have been suggested in different studies. However, the receptor that recognizes Stx in human neutrophils, which do not express Gb3Cer, has not been identified. In this study, by competition and functional experiments with appropriate agonists and antagonists (LPS, anti-TLR4 Abs, respectively), we have identified TLR4 as the receptor that specifically recognizes Stx1 and Stx2 in human neutrophils. Accordingly, these treatments displaced both toxin variants from neutrophils and, upon challenge with Stx1 or Stx2, neutrophils displayed the same pattern of cytokine expression as in response to LPS (assessed by quantitative RT-PCR, ELISA, or multiplexed Luminex-based immunoassays). Moreover, data were supported by adequate controls excluding any potential interference of contaminating LPS in Stx-binding and activation of neutrophils. The identification of the Stx-receptor on neutrophils provides additional elements to foster the understanding of the pathophysiology of HUS and could have an important effect on the development of therapeutic strategies.

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confidence: 99%

“…The Stx-neutrophil interaction is not followed by the internalization of the toxins (35), which conversely occurs in the case of Gb3Cer-or Gb4Cer-bearing cells such as human endothelial cells (10). Indeed, these glycosphingolipids (Gb3Cer or Gb4Cer) are not expressed by human neutrophils (39).…”

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confidence: 99%

Identification of TLR4 as the Receptor That Recognizes Shiga Toxins in Human Neutrophils

Brigotti

Carnicelli

Arfilli

et al. 2013

The Journal of Immunology

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“…Stx/neutrophil interactions are mediated mainly by the enzymatically active A chain of the bacterial toxins (16,23,26), also because human neutrophils lack the glycolipid Gb3Cer (47), which is specifically recognized by the B chains in target cells (5,9). Thus, we hypothesized that a direct interaction between the A chain of Stx and the antibiotic occurred, as in the case of lipid A (39,40), the toxic moiety of LPS, and that this prevented the binding of the toxins to TLR4.…”

Section: Inhibition Of the Enzymatic Activity Of Stx By Polymyxin Bmentioning

confidence: 99%

“…During intestinal human infections by the noninvasive STEC, the bacteria produce and release Stx that cross the intestinal mucosa, reach the bloodstream, and move to the target organs, thereby damaging the intestinal, renal, and cerebral endothelia (5,7,8). Endothelial cells from these body sites are endowed with specific glycolipid receptors, denominated globotriaosylceramide and globotetraosylceramide (Gb3Cer and Gb4Cer, respectively), which avidly interact with the B pentamer of Stx, hence allowing internalization (5,9). The Stx A chain expresses the enzymatic activity by targeting ribosomal 28S RNA (10) and DNA (11,12), hence inducing the related toxic and proinflammatory effects (13)(14)(15).…”

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confidence: 99%

The Antibiotic Polymyxin B Impairs the Interactions between Shiga Toxins and Human Neutrophils

Carnicelli

Arfilli

Ricci

et al. 2016

The Journal of Immunology

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Hemolytic uremic syndrome (HUS) is the life-threatenig sequela of intestinal infections by Shiga toxin (Stx)–producing Escherichia coli (STEC) in children. Human neutrophils specifically bind Stx through TLR4, the receptor of LPS. The binding could be considered protective (Stx sequestration) or harmful (toxin delivery to target organs). The amount of Stx on neutrophils is in equilibrium with the amount of Stx present in the gut, and it is also related to renal and neurologic symptoms. The TLR4-mediated interaction of LPS with innate immune cells is hampered by the well-known antibiotic polymyxin B. In this study, we show that the same antibiotic impairs the binding of Stx to neutrophils, also blocking their functional effects (release of CXCL8, formation of neutrophil/platelet aggregates) involved in HUS pathogenesis. Controls for contaminating LPS in Stx-induced neutrophil responses inhibited by polymyxin B were performed. Stx interact with human neutrophils through their A chain, since these leukocytes do not express globotriaosylceramide, the specific receptor for Stx B chains. Consistently, polymyxin B blocked the enzymatic activity of Stx1, Stx2, Stx1 A chain, and the analogous plant protein gelonin, whereas the antibiotic did not show any protective effect on Stx-induced cytotoxicity in globotriaosylceramide-expressing Raji cells. Antibiotic administration is not recommended in human STEC infections during the prodromal intestinal phase, and the toxicity of polymyxin B could further discourage its therapeutic use. However, nontoxic, nonbactericidal polymyxin derivatives have been developed and might be used in animal models of STEC infection to study their efficacy in preventing the onset of HUS during the systemic blood phase of Stx.

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“…Shiga toxin (Stx) from Shigella dysenteriae type 1, is the prototype toxin for the family of Shiga toxins [32]. When Shiga toxin-producing E. coli (STEC) strains were associated with haemolytic uraemic syndrome (HUS), the scientific community realised that the causative agents were either identical to Shigella-derived or highly related toxins.…”

Section: Anti-adhesion Molecules Targeting Toxin Binding Shiga Toxinmentioning

confidence: 99%

Exploitation of Glycobiology in Anti-Adhesion Approaches against Biothreat Agents

Utratna¹,

Deegan²,

Joshi³

2016

J Bioterror Biodef

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Pathogen adherence to a host cell is one of the first essential steps for establishing invasion, colonization and release of virulence factors such as toxins. Understanding the mechanisms used by pathogens and toxins to adhere and invade human cells could lead to the development of new strategies for preventing and controlling the spread of infectious diseases. This review focuses on carbohydrate-lectin interactions utilized by selected biothreat agents to bind and invade host cells. The principle of using anti-adhesion molecules, based on glycobiology research, has already been shown to be effective in the treatment of influenza. Therefore, translating the same principle to other biothreat agents that mediate invasion of a host cell through carbohydrate-lectin mechanisms is a very promising strategy. We investigate recent literature to highlight the latest developments in the field of glycobiology focused on inhibiting the initial steps of pathogen invasion, with examples for bacteria, toxin and virus interactions. The successful glycomimetics and glycoconjugates represent strategies for interruption of adhesion by single molecules and in multivalent systems against uropathogenic E. coli, several toxins (Shiga-like, cholera, botulinum) and wellknown or emerging viruses (influenza, HIV, Ebola, and Zika). This review provides promising directions and prophylactic as well as therapeutic potential of anti-adhesive strategies against selected biothreat targets.

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Facing glycosphingolipid–Shiga toxin interaction: dire straits for endothelial cells of the human vasculature

Cited by 70 publications

References 354 publications

Identification of TLR4 as the Receptor That Recognizes Shiga Toxins in Human Neutrophils

Identification of TLR4 as the Receptor That Recognizes Shiga Toxins in Human Neutrophils

The Antibiotic Polymyxin B Impairs the Interactions between Shiga Toxins and Human Neutrophils

Exploitation of Glycobiology in Anti-Adhesion Approaches against Biothreat Agents

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