Shiga toxin-glycosphingolipid interaction: Status quo of research with focus on primary human brain and kidney endothelial cells

Legros, Nadine; Pohlentz, Gottfried; Steil, Daniel; Müthing, Johannes

doi:10.1016/j.ijmm.2018.09.003

Cited by 37 publications

(53 citation statements)

References 238 publications

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“…These parameters are, respectively, an acute phase protein and a surrogate marker of dehydration and have been repeatedly associated with adverse outcomes in STEC-HUS patients ( 43 – 45 ). In our study, however, these laboratory markers did not significantly affect the development of CNS involvement in the multivariate model, probably due to the key role of alternative pathway activation in the onset of thrombotic microangiopathy onto brain microvascular endothelial cells ( 46 , 47 ).…”

Section: Discussioncontrasting

confidence: 80%

Low C3 Serum Levels Predict Severe Forms of STEC-HUS With Neurologic Involvement

et al. 2020

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Background: The correlation between the severity of hemolytic uremic syndrome related to Shiga toxin-producing Escherichia coli (STEC-HUS) and involvement of the complement system has been examined in a small number of studies, with conflicting results. In the present study, we investigated whether serum C3 levels on admission are associated with neurologic involvement. Methods: To this purpose, 68 consecutive STEC-HUS patients were recruited and main clinical and laboratory variables ad hospital admission were compared between those with or without neurologic involvement. Results: STEC-HUS patients who developed neurologic involvement (NI) showed significant higher leukocyte count, C-reactive protein and hemoglobin, and lower sodium levels as compared with those without. Interestingly, baseline serum levels of C3 were significantly lower in patients with NI as compared with those without (p < 0.001). Moreover, when stratified according to need of Eculizumab rescue therapy due to severe NI, patients treated with this drug showed baseline C3 serum levels significantly lower than those who were not (p < 0.001). Low C3 was independent risk factor for NI in our patients' population when entered as covariate in a multivariate logistic regression analysis including other major variables previously proposed as possible predictors of poor prognosis in STEC-HUS (for instance, leukocyte count, c-reactive protein, sodium levels) (HR 6.401, 95%CI 1.617-25.334, p = 0.008 for C3). To underline the role of complement in the worsening of STEC-HUS patients' clinical conditions and outcomes, all patients were divided into two groups according to the baseline lower vs. normal serum levels of C3 and the main data on care needs were assessed. Interestingly more patients with lower C3 serum levels required renal replacement therapy (p = 0.024), anti-hypertensive therapy (p = 0.011), Intensive Care Unit admission (p = 0.009), and longer hospitalization (p = 0.003), thus displaying Netti et al. C3 and Severe Neurologic STEC-HUS significantly more severe disease features as compared with those with normal C3 serum levels. Conclusions: Our data suggests that children with STEC-HUS with decreased C3 concentrations at admission are more likely to develop neurologic involvement and are at increased risk of having severe clinical complications.

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Section: Discussioncontrasting

confidence: 80%

Low C3 Serum Levels Predict Severe Forms of STEC-HUS With Neurologic Involvement

et al. 2020

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“…These subtypes differ in potency and species specificity, with Stx2a, Stx2c, and Stx2d linked to severe human illness (20)(21)(22)(23)(24). Stx2a is associated with more severe infections than the other Stx2 subtypes or Stx1a (6,21,(25)(26)(27). In contrast, Stx1a is more toxic to cultured Vero cells than Stx2a or Stx2c (28,29).…”

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confidence: 99%

Bimodal Response to Shiga Toxin 2 Subtypes Results from Relatively Weak Binding to the Target Cell

et al. 2019

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There are two major antigenic forms of Shiga toxin (Stx), Stx1 and Stx2, which bind the same receptor and act on the same target but nonetheless differ in potency. Stx1a is more toxic to cultured cells, but Stx2 subtypes are more potent in animal models. To understand this phenomenon in cultured cells, we used a system that combines flow cytometry with a fluorescent reporter to monitor the Stx-induced inhibition of protein synthesis in single cells. We observed that Vero cells intoxicated with Stx1a behave differently than those intoxicated with Stx2 subtypes: cells challenged with Stx1a exhibited a population-wide loss of protein synthesis, while cells exposed to Stx2a or Stx2c exhibited a dose-dependent bimodal response in which one subpopulation of cells was unaffected (i.e., no loss of protein synthesis). Cells challenged with a hybrid toxin containing the catalytic subunit of Stx1a and the cell-binding subunit of Stx2a also exhibited a bimodal response to intoxication, while cells challenged with a hybrid toxin containing the catalytic subunit of Stx2a and the cell-binding subunit of Stx1a exhibited a population-wide loss of protein synthesis. Other experiments further supported a primary role for the subtype of the B subunit in the outcome of host-Stx interactions. Our collective observations indicate that the bimodal response to Stx2 subtypes is due to relatively weak binding between Stx2 and the host cell that reduces the total functional pool of Stx2 in comparison to that of Stx1a. This explains, in part, the molecular basis for the differential cellular toxicity between Stx1a and Stx2 subtypes.

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“…The cholera toxin-induced mesenchymal-to-epithelial transition occurred only in cells with functional A4GALT. Cholera toxin is able to induce transition after binding to its receptor, Gb3Cer 42 . Liang et al described greatly reduced levels of Gb3Cer in breast CSCs in comparison to cancer non-stem cells (non-CSCs) 15 .…”

Section: Discussionmentioning

confidence: 99%

Glycosphingolipid expression at breast cancer stem cells after novel thieno[2,3-b]pyridine anticancer compound treatment

Marijan

Markotić

Mastelić

et al. 2020

Sci Rep

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Glycosphingolipid expression differs between human breast cancer stem cells (CSC) and cancer non-stem cells (non-CSC). We performed studies of viability, type of cell death, cancer stem cell percent and glycosphingolipid expression on CSC and non-CSC after treatment of MDA-MB-231 and MDA-MB-453 triple-negative breast cancer cells with a newly developed thienopyridine anticancer compound (3-amino-N-(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide, 1). Compound 1 was cytotoxic for both breast cancer cell lines and the majority of cells died by treatment-induced apoptosis. The percent of cancer stem cells and number of formed mammospheres was significantly lower. Glycosphingolipids IV 6 Neu5Ac-nLc 4 Cer and GalNAc-GM1b (IV 3 Neu5Ac-Gg5Cer) not reported previously, were identified in both CSCs and non-CSCs. IV 6 Neu5Ac-nLc 4 Cer had increased expression in both CSCs and non-CSCs of both cell lines after the treatment with 1, while GM3 (II 3 Neu5Ac-LacCer) had increased expression only on both cell subpopulations in MDA-MB-231 cell line. GalNAc-GM1b, Gb 4 Cer (GalNAcβ1-3Galα1-4Galβ1-4Glcβ1-1Cer) and GM2 (II 3 Neu5Ac-GalNAcβ1-4Galβ1-4Glcβ1-1Cer) were increased only in CSCs of both cell lines while GD3 was decreased in CSC of MDA-MB-231 cell line. Due to its effect in reducing the percentage of cancer stem cells and number of mammospheres, and its influence upon several glycosphingolipid expressions, it can be concluded that compound 1 deserves attention as a potential new drug for triple-negative breast cancer therapy. The thieno[2,3-b]pyridines were initially discovered as potential inhibitors of phospholipase C (PLC) isoforms by virtual high throughput screen (vHTS) 1. Recently, we described glycoconjugate GM3 and CD15s expression in MDA-MB-231 triple negative breast cancer stem cell subpopulation cultured with 3-amino-5-oxo-N-naphthyl-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide, which was developed as a putative PLC inhibitor. A close structural analogue of 3-amino-N-(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide, or compound 1 2 was chosen for this study due to its enhanced potency against the MDA-MB-231 cell line and its mechanism of action has been investigated 3,4. Due to their ability to self-renew and to regenerate the primary tumour phenotypic heterogeneity, cancer stem cells are important therapeutical targets 5. CSCs are defined with their CD44 + /CD24 − or CD133 + phenotype 6. It is believed that CSCs are involved in therapy resistance in various cancers, including triple-negative breast cancers, i.e., breast cancers that do not express the genes for estrogen receptor, progesterone receptor and the human epidermal growth factor receptor-2 7. Glycosphingolipids (GSLs), consisting of a hydrophobic ceramide and hydrophilic carbohydrate residues, are an important component of cell plasma membranes. They regulate numerous cellular processes like adhesion, proliferation, apoptosis, recognition, modulation of signal transduct...

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Shiga toxin-glycosphingolipid interaction: Status quo of research with focus on primary human brain and kidney endothelial cells

Cited by 37 publications

References 238 publications

Low C3 Serum Levels Predict Severe Forms of STEC-HUS With Neurologic Involvement

Low C3 Serum Levels Predict Severe Forms of STEC-HUS With Neurologic Involvement

Bimodal Response to Shiga Toxin 2 Subtypes Results from Relatively Weak Binding to the Target Cell

Glycosphingolipid expression at breast cancer stem cells after novel thieno[2,3-b]pyridine anticancer compound treatment

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