The Shiga Toxin Receptor Globotriaosylceramide as Therapeutic Target in Shiga Toxin <i>E. coli</i> Mediated HUS
In 90% of the cases, childhood hemolytic uremic syndrome (HUS) is caused by an infection with the Shiga toxin (Stx) producing <i>E. coli</i> bacteria (STEC-HUS). Stx preferentially binds to its receptor, the glycosphingolipid, globotriaosylceramide (Gb3), present on the surface of human...
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MDPI AG
2021-10-01
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| Series: | Microorganisms |
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| Online Access: | https://www.mdpi.com/2076-2607/9/10/2157 |
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| author | Wouter J. C. Feitz Romy Bouwmeester Thea J. A. M. van der Velden Susan Goorden Christoph Licht Lambert P. J. W. van den Heuvel Nicole C. A. J. van de Kar |
| author_facet | Wouter J. C. Feitz Romy Bouwmeester Thea J. A. M. van der Velden Susan Goorden Christoph Licht Lambert P. J. W. van den Heuvel Nicole C. A. J. van de Kar |
| author_sort | Wouter J. C. Feitz |
| collection | DOAJ |
| description | In 90% of the cases, childhood hemolytic uremic syndrome (HUS) is caused by an infection with the Shiga toxin (Stx) producing <i>E. coli</i> bacteria (STEC-HUS). Stx preferentially binds to its receptor, the glycosphingolipid, globotriaosylceramide (Gb3), present on the surface of human kidney cells and various organs. In this study, the glycosphingolipid pathway in endothelial cells was explored as therapeutic target for STEC-HUS. Primary human glomerular microvascular endothelial cells (HGMVECs) and human blood outgrowth endothelial cells (BOECs) in quiescent and activated state were pre-incubated with Eliglustat (Cerdelga<sup>®</sup>; glucosylceramide synthase inhibitor) or Agalsidase alpha (Replagal<sup>®</sup>; human cell derived alpha-galactosidase) in combination with various concentrations of Stx2a. Preincubation of endothelial cells with Agalsidase resulted in an increase of α-galactosidase activity in the cell, but had no effect on the binding of Stx to the cell surface when compared to control cells. However, the incubation of both types of endothelial cells incubated with or without the pro-inflammatory cytokine TNFα in combination with Eliglustat resulted in significant decrease of Stx binding to the cell surface, a decrease in protein synthesis by Stx2a, and diminished cellular Gb3 levels as compared to control cells. In conclusion, inhibition of the synthesis of Gb3 may be a potential future therapeutic target to protect against (further) endothelial damage caused by Stx. |
| first_indexed | 2024-03-10T06:21:56Z |
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| issn | 2076-2607 |
| language | English |
| last_indexed | 2024-03-10T06:21:56Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Microorganisms |
| spelling | doaj.art-494af96ddb7a437ba2b31e387ac46ae32023-11-22T19:15:15ZengMDPI AGMicroorganisms2076-26072021-10-01910215710.3390/microorganisms9102157The Shiga Toxin Receptor Globotriaosylceramide as Therapeutic Target in Shiga Toxin <i>E. coli</i> Mediated HUSWouter J. C. Feitz0Romy Bouwmeester1Thea J. A. M. van der Velden2Susan Goorden3Christoph Licht4Lambert P. J. W. van den Heuvel5Nicole C. A. J. van de Kar6Department of Pediatrics, Amalia Children’s Hospital, Radboudumc, 6525 GA Nijmegen, The NetherlandsDepartment of Pediatrics, Amalia Children’s Hospital, Radboudumc, 6525 GA Nijmegen, The NetherlandsDepartment of Pediatrics, Amalia Children’s Hospital, Radboudumc, 6525 GA Nijmegen, The NetherlandsLaboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDepartment of Pediatric Nephrology, The Hospital for Sick Children, Toronto, ON M5G 1X8, CanadaDepartment of Pediatrics, Amalia Children’s Hospital, Radboudumc, 6525 GA Nijmegen, The NetherlandsDepartment of Pediatrics, Amalia Children’s Hospital, Radboudumc, 6525 GA Nijmegen, The NetherlandsIn 90% of the cases, childhood hemolytic uremic syndrome (HUS) is caused by an infection with the Shiga toxin (Stx) producing <i>E. coli</i> bacteria (STEC-HUS). Stx preferentially binds to its receptor, the glycosphingolipid, globotriaosylceramide (Gb3), present on the surface of human kidney cells and various organs. In this study, the glycosphingolipid pathway in endothelial cells was explored as therapeutic target for STEC-HUS. Primary human glomerular microvascular endothelial cells (HGMVECs) and human blood outgrowth endothelial cells (BOECs) in quiescent and activated state were pre-incubated with Eliglustat (Cerdelga<sup>®</sup>; glucosylceramide synthase inhibitor) or Agalsidase alpha (Replagal<sup>®</sup>; human cell derived alpha-galactosidase) in combination with various concentrations of Stx2a. Preincubation of endothelial cells with Agalsidase resulted in an increase of α-galactosidase activity in the cell, but had no effect on the binding of Stx to the cell surface when compared to control cells. However, the incubation of both types of endothelial cells incubated with or without the pro-inflammatory cytokine TNFα in combination with Eliglustat resulted in significant decrease of Stx binding to the cell surface, a decrease in protein synthesis by Stx2a, and diminished cellular Gb3 levels as compared to control cells. In conclusion, inhibition of the synthesis of Gb3 may be a potential future therapeutic target to protect against (further) endothelial damage caused by Stx.https://www.mdpi.com/2076-2607/9/10/2157STEC-HUSshiga toxinendothelial cellsglobotriaosylceramideglucosylceramide synthaseeliglustat |
| spellingShingle | Wouter J. C. Feitz Romy Bouwmeester Thea J. A. M. van der Velden Susan Goorden Christoph Licht Lambert P. J. W. van den Heuvel Nicole C. A. J. van de Kar The Shiga Toxin Receptor Globotriaosylceramide as Therapeutic Target in Shiga Toxin <i>E. coli</i> Mediated HUS Microorganisms STEC-HUS shiga toxin endothelial cells globotriaosylceramide glucosylceramide synthase eliglustat |
| title | The Shiga Toxin Receptor Globotriaosylceramide as Therapeutic Target in Shiga Toxin <i>E. coli</i> Mediated HUS |
| title_full | The Shiga Toxin Receptor Globotriaosylceramide as Therapeutic Target in Shiga Toxin <i>E. coli</i> Mediated HUS |
| title_fullStr | The Shiga Toxin Receptor Globotriaosylceramide as Therapeutic Target in Shiga Toxin <i>E. coli</i> Mediated HUS |
| title_full_unstemmed | The Shiga Toxin Receptor Globotriaosylceramide as Therapeutic Target in Shiga Toxin <i>E. coli</i> Mediated HUS |
| title_short | The Shiga Toxin Receptor Globotriaosylceramide as Therapeutic Target in Shiga Toxin <i>E. coli</i> Mediated HUS |
| title_sort | shiga toxin receptor globotriaosylceramide as therapeutic target in shiga toxin i e coli i mediated hus |
| topic | STEC-HUS shiga toxin endothelial cells globotriaosylceramide glucosylceramide synthase eliglustat |
| url | https://www.mdpi.com/2076-2607/9/10/2157 |
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