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Cholesterol glucosylation promotes immune evasion by Helicobacter pylori


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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  1. Falush, D. et al. Traces of human migrations in Helicobacter pylori populations. Science 299, 1582–1585 (2003).

    Article  CAS  Google Scholar 

  2. Marshall, B.J., Armstrong, J.A., McGechie, D.B. & Glancy, R.J. Attempt to fulfil Koch's postulates for pyloric Campylobacter. Med. J. Aust. 142, 436–439 (1985).

    CAS  PubMed  Google Scholar 

  3. Peek, R.M., Jr. & Blaser, M.J. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat. Rev. Cancer 2, 28–37 (2002).

    Article  CAS  Google Scholar 

  4. Simons, K. & Vaz, W.L. Model systems, lipid rafts, and cell membranes. Annu. Rev. Biophys. Biomol. Struct. 33, 269–295 (2004).

    Article  CAS  Google Scholar 

  5. Dixon, M.F., Genta, R.M., Yardley, J.H. & Correa, P. Histological classification of gastritis and Helicobacter pylori infection: an agreement at last? The International Workshop on the Histopathology of Gastritis. Helicobacter. 2 (Suppl. 1), S17–S24 (1997).

    Article  Google Scholar 

  6. Hirai, Y. et al. Unique cholesteryl glucosides in Helicobacter pylori: composition and structural analysis. J. Bacteriol. 177, 5327–5333 (1995).

    Article  CAS  Google Scholar 

  7. Kawakubo, M. et al. Natural antibiotic function of a human gastric mucin against Helicobacter pylori infection. Science 305, 1003–1006 (2004).

    Article  CAS  Google Scholar 

  8. Testerman, T.L., McGee, D.J. & Mobley, H.L. Helicobacter pylori growth and urease detection in the chemically defined medium Ham's F-12 nutrient mixture. J. Clin. Microbiol. 39, 3842–3850 (2001).

    Article  CAS  Google Scholar 

  9. O'Toole, P.W., Kostrzynska, M. & Trust, T.J. Non-motile mutants of Helicobacter pylori and Helicobacter mustelae defective in flagellar hook production. Mol. Microbiol. 14, 691–703 (1994).

    Article  CAS  Google Scholar 

  10. Schreiber, S. et al. The spatial orientation of Helicobacter pylori in the gastric mucus. Proc. Natl. Acad. Sci. USA 101, 5024–5029 (2004).

    Article  CAS  Google Scholar 

  11. Song, K.S. et al. Co-purification and direct interaction of Ras with caveolin, an integral membrane protein of caveolae microdomains. Detergent-free purification of caveolae microdomains. J. Biol. Chem. 271, 9690–9697 (1996).

    Article  CAS  Google Scholar 

  12. Foster, L.J., De Hoog, C.L. & Mann, M. Unbiased quantitative proteomics of lipid rafts reveals high specificity for signaling factors. Proc. Natl. Acad. Sci. USA 100, 5813–5818 (2003).

    Article  CAS  Google Scholar 

  13. Harder, T., Scheiffele, P., Verkade, P. & Simons, K. Lipid domain structure of the plasma membrane revealed by patching of membrane components. J. Cell Biol. 141, 929–942 (1998).

    Article  CAS  Google Scholar 

  14. Legler, D.F. et al. Differential insertion of GPI-anchored GFPs into lipid rafts of live cells. FASEB J. 19, 73–75 (2005).

    Article  CAS  Google Scholar 

  15. Amieva, M.R. et al. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 300, 1430–1434 (2003).

    Article  CAS  Google Scholar 

  16. Censini, S. et al. cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc. Natl. Acad. Sci. USA 93, 14648–14653 (1996).

    Article  CAS  Google Scholar 

  17. Hatakeyama, M. Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nat. Rev. Cancer 4, 688–694 (2004).

    Article  CAS  Google Scholar 

  18. Montecucco, C. & Rappuoli, R. Living dangerously: how Helicobacter pylori survives in the human stomach. Nat. Rev. Mol. Cell Biol. 2, 457–466 (2001).

    Article  CAS  Google Scholar 

  19. Smart, E.J., Ying, Y.S., Conrad, P.A. & Anderson, R.G. Caveolin moves from caveolae to the Golgi apparatus in response to cholesterol oxidation. J. Cell Biol. 127, 1185–1197 (1994).

    Article  CAS  Google Scholar 

  20. Allen, L.A., Schlesinger, L.S. & Kang, B. Virulent strains of Helicobacter pylori demonstrate delayed phagocytosis and stimulate homotypic phagosome fusion in macrophages. J. Exp. Med. 191, 115–128 (2000).

    Article  CAS  Google Scholar 

  21. Odenbreit, S., Gebert, B., Puls, J., Fischer, W. & Haas, R. Interaction of Helicobacter pylori with professional phagocytes: role of the cag pathogenicity island and translocation, phosphorylation and processing of CagA. Cell. Microbiol. 3, 21–31 (2001).

    Article  CAS  Google Scholar 

  22. Haque, M., Hirai, Y., Yokota, K. & Oguma, K. Steryl glycosides: a characteristic feature of the Helicobacter spp.? J. Bacteriol. 177, 5334–5337 (1995).

    Article  CAS  Google Scholar 

  23. Kanehisa, M. & Goto, S. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 28, 27–30 (2000).

    Article  CAS  Google Scholar 

  24. Gomez-Duarte, O.G. et al. Protection of mice against gastric colonization by Helicobacter pylori by single oral dose immunization with attenuated Salmonella typhimurium producing urease subunits A and B. Vaccine 16, 460–471 (1998).

    Article  CAS  Google Scholar 

  25. Mombaerts, P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992).

    Article  CAS  Google Scholar 

  26. Haque, M., Hirai, Y., Yokota, K. & Oguma, K. Lipid profiles of Helicobacter pylori and Helicobacter mustelae grown in serum-supplemented and serum-free media. Acta Med. Okayama 49, 205–211 (1995).

    CAS  PubMed  Google Scholar 

  27. Lebrun, A.H. et al. Cloning of a cholesterol-α-glucosyltransferase from Helicobacter pylori. J. Biol. Chem., published online 14 July 2006.

  28. Oku, M. et al. Peroxisome degradation requires catalytically active sterol glucosyltransferase with a GRAM domain. EMBO J. 22, 3231–3241 (2003).

    Article  CAS  Google Scholar 

  29. Raggers, R.J., Pomorski, T., Holthuis, J.C., Kalin, N. & van Meer, G. Lipid traffic: the ABC of transbilayer movement. Traffic 1, 226–234 (2000).

    Article  CAS  Google Scholar 

  30. Simons, K. & Toomre, D. Lipid rafts and signal transduction. Nat. Rev. Mol. Cell Biol. 1, 31–39 (2000).

    Article  CAS  Google Scholar 

  31. Schaller, H. New aspects of sterol biosynthesis in growth and development of higher plants. Plant Physiol. Biochem. 42, 465–476 (2004).

    Article  CAS  Google Scholar 

  32. Parks, L.W. & Casey, W.M. Physiological implications of sterol biosynthesis in yeast. Annu. Rev. Microbiol. 49, 95–116 (1995).

    Article  CAS  Google Scholar 

  33. Mayberry, W.R. & Smith, P.F. Structures and properties of acyl diglucosylcholesterol and galactofuranosyl diacylglycerol from Acholeplasma axanthum. Biochim. Biophys. Acta 752, 434–443 (1983).

    Article  CAS  Google Scholar 

  34. Smith, P.F. Biosynthesis of cholesteryl glucoside by Mycoplasma gallinarum. J. Bacteriol. 108, 986–991 (1971).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Livermore, B.P., Bey, R.F. & Johnson, R.C. Lipid metabolism of Borrelia hermsi. Infect. Immun. 20, 215–220 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Peng, L., Kawagoe, Y., Hogan, P. & Delmer, D. Sitosterol-β-glucoside as primer for cellulose synthesis in plants. Science 295, 147–150 (2002).

    Article  CAS  Google Scholar 

  37. Ben Menachem, G., Kubler-Kielb, J., Coxon, B., Yergey, A. & Schneerson, R. A newly discovered cholesteryl galactoside from Borrelia burgdorferi. Proc. Natl. Acad. Sci. USA 100, 7913–7918 (2003).

    Article  CAS  Google Scholar 

  38. Shimomura, H., Hayashi, S., Yokota, K., Oguma, K. & Hirai, Y. Alteration in the composition of cholesteryl glucosides and other lipids in Helicobacter pylori undergoing morphological change from spiral to coccoid form. FEMS Microbiol. Lett. 237, 407–413 (2004).

    CAS  PubMed  Google Scholar 

  39. Tannaes, T. & Bukholm, G. Cholesteryl-6-O-acyl-α-D-glucopyranoside of Helicobacter pylori relate to relative lysophospholipid content. FEMS Microbiol. Lett. 244, 117–120 (2005).

    Article  CAS  Google Scholar 

  40. Burger, K., Gimpl, G. & Fahrenholz, F. Regulation of receptor function by cholesterol. Cell. Mol. Life Sci. 57, 1577–1592 (2000).

    Article  CAS  Google Scholar 

  41. Li, J. et al. Impaired phagocytosis in caveolin-1 deficient macrophages. Cell Cycle 4, 1599–1607 (2005).

    Article  CAS  Google Scholar 

  42. Wang, Y., Thiele, C. & Huttner, W.B. Cholesterol is required for the formation of regulated and constitutive secretory vesicles from the trans-Golgi network. Traffic 1, 952–962 (2000).

    Article  CAS  Google Scholar 

  43. Guillemin, K., Salama, N.R., Tompkins, L.S. & Falkow, S. Cag pathogenicity island-specific responses of gastric epithelial cells to Helicobacter pylori infection. Proc. Natl. Acad. Sci. USA 99, 15136–15141 (2002).

    Article  CAS  Google Scholar 

  44. Slonczewski, J.L., McGee, D.J., Phillips, J., Kirkpatrick, C. & Mobley, H.L. pH-dependent protein profiles of Helicobacter pylori analyzed by two-dimensional gels. Helicobacter 5, 240–247 (2000).

    Article  CAS  Google Scholar 

  45. Heuermann, D. & Haas, R. A stable shuttle vector system for efficient genetic complementation of Helicobacter pylori strains by transformation and conjugation. Mol. Gen. Genet. 257, 519–528 (1998).

    Article  CAS  Google Scholar 

  46. Schaible, U.E. et al. Parasitophorous vacuoles of Leishmania mexicana acquire macromolecules from the host cell cytosol via two independent routes. J. Cell Sci. 112, 681–693 (1999).

    CAS  PubMed  Google Scholar 

  47. Barrett, T. et al. NCBI GEO: mining millions of expression profiles—database and tools. Nucleic Acids Res. 33, D562–D566 (2005).

    Article  CAS  Google Scholar 

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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

Authors and Affiliations



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.

Ethics declarations

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).

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