Susceptibility to Hemolytic-Uremic Syndrome Relates to Erythrocyte Glycosphingolipid Patterns

Newburg, David S.; Chaturvedi, Prasoon; López, Eduardo; Devoto, Susana; Fayad, Alicia; Cleary, Thomas G.

doi:10.1093/infdis/168.2.476

Cited by 43 publications

(25 citation statements)

References 13 publications

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“…The upregulation by TNF-␣ of only one type of species, the NFA-Gb 3 s rather than the HFA-Gb 3 s, and the association of the NFA-Gb 3 species with Shiga toxin binding and toxicity are consistent with our hypothesis (25) that genetic heterogeneity in the expression of Gb 3 species may underlie differential susceptibility to HUS. This hypothesis may now be expanded to the involvement of the CNS in HUS, which may depend on heterogeneity in the expression of specific species of Gb 3 by the cerebral endothelial cells of individuals.…”

supporting

confidence: 85%

Tumor Necrosis Factor Alpha Increases Human Cerebral Endothelial Cell Gb ₃ and Sensitivity to Shiga Toxin

et al. 2001

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Hemolytic uremic syndrome (HUS) is associated with intestinal infection by enterohemorrhagic Escherichia coli strains that produce Shiga toxins. Globotriaosylceramide (Gb3) is the functional receptor for Shiga toxin, and tumor necrosis factor alpha (TNF-α) upregulates Gb3 in both human macrovascular umbilical vein endothelial cells and human microvascular brain endothelial cells. TNF-α treatment enhanced Shiga toxin binding and sensitivity to toxin. This upregulation was specific for Gb3 species containing normal fatty acids (NFA). Central nervous system (CNS) pathology in HUS could involve cytokine-stimulated elevation of endothelial NFA-Gb3 levels. Differential expression of Gb3 species may be a critical determinant of Shiga toxin toxicity and of CNS involvement in HUS

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supporting

confidence: 85%

Tumor Necrosis Factor Alpha Increases Human Cerebral Endothelial Cell Gb ₃ and Sensitivity to Shiga Toxin

et al. 2001

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“…A similar hypothesis has been proposed for P blood types in human patients (32). However, a recent study refuted this possibility by showing that the P1 blood group was equally represented in healthy controls and E. coli O157:H7-infected children regardless of whether patients had uncomplicated illness or HUS (13), confirming the findings of previous studies that failed to associate P1 expression with diminished risk for the development of HUS after infection with E. coli O157:H7 (2,21,24,27).…”

Section: Discussionsupporting

confidence: 72%

“…Stx bind to human RBCs, monocytes, and neutrophils in vitro without causing morphological changes in these cells (4,26,34 (32). However, epidemiological data suggest that the P1 phenotype does not protect STEC-infected patients from HUS (2,13,21,24,27).…”

mentioning

confidence: 99%

Binding of Shiga Toxin 2e to Porcine Erythrocytes In Vivo and In Vitro

et al. 2003

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“…It has been suggested that polymorphonuclear leukocytes, 17 monocytes, 44 or erthrocytes 60,61 may transport Stx in the circulation from the intestine to the kidney. The results of this investigation suggest that on contact with the intestinal circulation, Stx may bind to platelets and to other blood cells.…”

Section: Discussionmentioning

confidence: 99%

Platelet activation by Shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic uremic syndrome

Karpman

Papadopoulou

Nilsson

et al. 2001

Blood

129

117

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Thrombocytopenia caused by platelet consumption in thrombi is a major manifestation of hemolytic uremic syndrome (HUS) associated with Shiga toxin (Stx) producing Escherichia coli. Platelets have glycosphingolipid receptors capable of binding Stx, but a direct interaction between the toxin and platelets, leading to platelet activation, has not been reported. In this study, it is shown that Stx1 and its B (binding) subunit (Stx1B), at 10 pg/mL to 10 ng/mL, bound to platelets. IntroductionShiga toxin (Stx)-producing Escherichia coli (STEC) have been associated with cases of hemolytic uremic syndrome (HUS). Microangiopathic hemolytic anemia, acute renal failure, and thrombocytopenia characterize this syndrome. Stx has been specifically implicated as a causal factor 1 of HUS because cases of the disease have been associated with Stx-producing strains, 2 the toxin has been identified in the kidney of a patient with HUS, 3 and the toxin has been found to be cytotoxic for renal endothelial and epithelial cells. [4][5][6][7][8] In addition, animal models have reproduced aspects of HUS using wild-type bacteria that produce the toxin 9,10 or purified toxin. 11 The toxin is composed of 5 B, or binding, subunits and 1 enzymatically active A subunit. 12 The molecular weight of the A subunit is 33 000 kd, and that of the pentameric B subunit is approximately 35 000 kd. 13 The B subunit (StxB) binds to a glycosphingolipid receptor on cell membranes, globotriaosyl ceramide (Gb3), containing the terminal disaccharide galactose ␣(1-4) galactose ␤. 14 A recent study showed that Stx could bind to platelets through Gb3 and a novel platelet glycosphingolipid termed band 0.03. 15 Other studies have not been able to reproduce these results. 16,17 Binding to the cell mediates endocytosis of the holotoxin. Intracellularly the A subunit is proteolytically nicked, binds to 60S ribosomes, and thereby inhibits protein synthesis leading to cell death. 18 Thrombocytopenia is an important feature of HUS. Platelets are consumed in small thrombi, and these thrombi may compromise the blood supply to various organs, particularly the kidney. The mechanism by which these thrombi are formed is unclear, and platelet activation has been suggested. Studies performed on platelets from patients with HUS showed impaired aggregating responses 19,20 and reduced ␤-thromboglobulin (␤-TG) content. 19 Platelet-derived products such as ␤-TG, platelet factor 4, 21 and soluble P-selectin 22 were found to be elevated during acute HUS. Furthermore, changes in platelet ultramorphology were noted. 23 Increased platelet-derived microvesicles were found in these patients, 24 indicating platelet activation. Plasma from patients with HUS increased aggregation of normal platelets, but the factor causing this was not determined. 25 Several previous studies have investigated a direct interaction between Stx and platelets. Culture filtrates from Stx-producing E coli were found to induce platelet-aggregating activity, 26 but purified Stx did not increase platelet aggregation 16...

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Susceptibility to Hemolytic-Uremic Syndrome Relates to Erythrocyte Glycosphingolipid Patterns

Cited by 43 publications

References 13 publications

Tumor Necrosis Factor Alpha Increases Human Cerebral Endothelial Cell Gb ₃ and Sensitivity to Shiga Toxin

Tumor Necrosis Factor Alpha Increases Human Cerebral Endothelial Cell Gb ₃ and Sensitivity to Shiga Toxin

Binding of Shiga Toxin 2e to Porcine Erythrocytes In Vivo and In Vitro

Platelet activation by Shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic uremic syndrome

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Susceptibility to Hemolytic-Uremic Syndrome Relates to Erythrocyte Glycosphingolipid Patterns

Cited by 43 publications

References 13 publications

Tumor Necrosis Factor Alpha Increases Human Cerebral Endothelial Cell Gb 3 and Sensitivity to Shiga Toxin

Tumor Necrosis Factor Alpha Increases Human Cerebral Endothelial Cell Gb 3 and Sensitivity to Shiga Toxin

Binding of Shiga Toxin 2e to Porcine Erythrocytes In Vivo and In Vitro

Platelet activation by Shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic uremic syndrome

Contact Info

Product

Resources

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Tumor Necrosis Factor Alpha Increases Human Cerebral Endothelial Cell Gb ₃ and Sensitivity to Shiga Toxin

Tumor Necrosis Factor Alpha Increases Human Cerebral Endothelial Cell Gb ₃ and Sensitivity to Shiga Toxin