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Cholesterol glucosylation promotes immune evasion by Helicobacter pylori

Nature Medicine volume 12, pages 1030–1038 (2006)Cite this article

Abstract

Helicobacter pylori infection causes gastric pathology such as ulcer and carcinoma. Because H. pylori is auxotrophic for cholesterol, we have explored the assimilation of cholesterol by H. pylori in infection. Here we show that H. pylori follows a cholesterol gradient and extracts the lipid from plasma membranes of epithelial cells for subsequent glucosylation. Excessive cholesterol promotes phagocytosis of H. pylori by antigen-presenting cells, such as macrophages and dendritic cells, and enhances antigen-specific T cell responses. A cholesterol-rich diet during bacterial challenge leads to T cell–dependent reduction of the H. pylori burden in the stomach. Intrinsic α-glucosylation of cholesterol abrogates phagocytosis of H. pylori and subsequent T cell activation. We identify the gene hp0421 as encoding the enzyme cholesterol-α-glucosyltransferase responsible for cholesterol glucosylation. Generation of knockout mutants lacking hp0421 corroborates the importance of cholesteryl glucosides for escaping phagocytosis, T cell activation and bacterial clearance in vivo. Thus, we propose a mechanism regulating the host–pathogen interaction whereby glucosylation of a lipid tips the scales towards immune evasion or response.

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Figure 1: H. pylori follows a cholesterol gradient and extracts the lipid from epithelial membranes.
Figure 2: H. pylori converts epithelial cholesterol into cholesteryl glucosides and destroys lipid rafts.
Figure 3: Cholesterol promotes phagocytosis, T cell activation and protection against H. pylori infection.
Figure 4: Cholesteryl-glucosides protect H. pylori from phagocytosis.
Figure 5: Cholesteryl α-glucoside is essential for phagocytosis escape of H. pylori.

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Acknowledgements

We thank K. Hoffmann and M. Dabrinka for technical assistance; M. Pompaiah and E. Belogolova for experimental help; L. Fehlig for image editing; A. Galmiche for providing the GPI-CD55-GFP plasmid; and T. Aebischer, T. Fowler, R. Krishnaraj and G.H. Patterson for critical suggestions on the manuscript. This work was supported in part through grants from the Deutsche Forschungsgemeinschaft (KFO104/1-1 and SFB470, respectively) to T.F.M. and D.W. and from the European Union (FP6 INCA project LSHC-CT-2005-018704) to T.F.M.

Author information

Author notes

  1. Christian Wunder

    Present address: Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, 20892, USA

  2. Michael Vieth

    Present address: Institute of Pathology, Klinikum Bayreuth, 95445, Bayreuth, Germany

  3. Christian Wunder, Yuri Churin and Florian Winau: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, Berlin, 10117, Germany

    Christian Wunder, Yuri Churin & Thomas F Meyer

  2. Department of Immunology, Max Planck Institute for Infection Biology, Charitéplatz 1, Berlin, 10117, Germany

    Florian Winau

  3. Biozentrum Klein Flottbek, University of Hamburg, Ohnhorststrasse 18, Hamburg, 22609, Germany

    Dirk Warnecke & Ernst Heinz

  4. Institute of Pathology, Otto von Guericke University, Leipziger Strasse 44, Magdeburg, 39120, Germany

    Michael Vieth

  5. Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, 23845, Germany

    Buko Lindner & Ulrich Zähringer

  6. Core Facility Microarray, Max Planck Institute for Infection Biology, Charitéplatz 1, Berlin, 10117, Germany

    Hans-Joachim Mollenkopf

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Contributions

C.W. and Y.C. made initial observations and performed main experiments. F.W. designed and performed T-cell assays. D.W. and E.H. identified hp0421 as a functional transferase and purified glycolipids. M.V. analyzed histological samples. U.Z. and B.L. performed NMR spectroscopy and MS glycolipid analysis. H.J.M. performed transcriptome analysis. F.W. and C.W. wrote the manuscript versions. T.F.M. supervised experimentation and coordinated the project.

Corresponding authors

Correspondence to Christian Wunder or Thomas F Meyer.

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Competing interests

(1) This work is the basis of a European patent application filed by the Max Planck Society and the University of Hamburg (Y.C., T.F.M., D.W, and C.W.). (2) The manuscript form the basis of forthcoming institutional grant applications (T.F.M. and D.W.). (3) Some of the authors act as advisors of relevant industrial companies (T.F.M. and M.V.).

Supplementary information

Supplementary Fig. 1

Chemotactic response of H. pylori. (PDF 58 kb)

Supplementary Fig. 2

H. pylori takes up cholesterol from epithelial cells. (PDF 214 kb)

Supplementary Fig. 3

H. pylori fails to incorporate cholesterol from supernatant of epithelial cells. (PDF 48 kb)

Supplementary Fig. 4

H. pylori colocalizes with GM1. (PDF 69 kb)

Supplementary Fig. 5

H. pylori incorporates and glucosylates eukaryotic cholesterol. (PDF 84 kb)

Supplementary Fig. 6

Increase in endogenous H. pylori cholesterol intensifies phagocytosis. (PDF 236 kb)

Supplementary Table 1

Transcriptome of gastric mucosa of cholesterol-treated infected animals. (PDF 254 kb)

Supplementary Methods (PDF 141 kb)

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Wunder, C., Churin, Y., Winau, F. et al. Cholesterol glucosylation promotes immune evasion by Helicobacter pylori. Nat Med 12, 1030–1038 (2006). https://doi.org/10.1038/nm1480

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