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The ether lipid precursor hexadecylglycerol protects against Shiga toxins

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Abstract

Shiga toxin-producing Escherichia coli bacteria cause hemorrhagic colitis and hemolytic uremic syndrome in humans. Currently, only supportive treatment is available for diagnosed patients. We show here that 24-h pretreatment with an ether lipid precursor, the alkylglycerol sn-1-O-hexadecylglycerol (HG), protects HEp-2 cells against Shiga toxin and Shiga toxin 2. Also the endothelial cell lines HMEC-1 and HBMEC are protected against Shiga toxins after HG pretreatment. In contrast, the corresponding acylglycerol, dl-α-palmitin, has no effect on Shiga toxicity. Although HG treatment provides a strong protection (~30 times higher IC50) against Shiga toxin, only a moderate reduction in toxin binding was observed, suggesting that retrograde transport of the toxin from the plasma membrane to the cytosol is perturbed. Furthermore, endocytosis of Shiga toxin and retrograde sorting from endosomes to the Golgi apparatus remain intact, but transport from the Golgi to the endoplasmic reticulum is inhibited by HG treatment. As previously described, HG reduces the total level of all quantified glycosphingolipids to 50–70 % of control, including the Shiga toxin receptor globotriaosylceramide (Gb3), in HEp-2 cells. In accordance with this, we find that interfering with Gb3 biosynthesis by siRNA-mediated knockdown of Gb3 synthase for 24 h causes a similar cytotoxic protection and only a moderate reduction in toxin binding (to 70 % of control cells). Alkylglycerols, including HG, have been administered to humans for investigation of therapeutic roles in disorders where ether lipid biosynthesis is deficient, as well as in cancer therapy. Further studies may reveal if HG can also have a therapeutic potential in Shiga toxin-producing E. coli infections.

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Acknowledgments

The work performed by the Oslo group has been supported by South-Eastern Norway Regional Health Authority, The Norwegian Cancer Society, and The Research Council of Norway. We thank Anne-Grethe Myrann for technical assistance with cell experiments, and Sirpa Sutela-Tuominen for assistance with lipidomic experiments.

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Authors and Affiliations

  1. Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway

    Jonas Bergan, Tore Skotland, Anne Berit Dyve Lingelem, Roger Simm & Kirsten Sandvig

  2. Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0379, Oslo, Norway

    Jonas Bergan, Tore Skotland, Anne Berit Dyve Lingelem, Roger Simm & Kirsten Sandvig

  3. Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway

    Jonas Bergan & Kirsten Sandvig

  4. Section of Bacteriology-Food and GMO, Norwegian Veterinary Institute, Oslo, Norway

    Bjørn Spilsberg

  5. Department of Food Safety and Infection Biology, Norwegian School of Veterinary Science, Oslo, Norway

    Toril Lindbäck

  6. Zora Biosciences, Espoo, Finland

    Tuulia Sylvänne, Helena Simolin & Kim Ekroos

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  1. Jonas Bergan
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Bergan, J., Skotland, T., Lingelem, A.B.D. et al. The ether lipid precursor hexadecylglycerol protects against Shiga toxins. Cell. Mol. Life Sci. 71, 4285–4300 (2014). https://doi.org/10.1007/s00018-014-1624-1

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