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Review
. 2009 Jan;10(1):29-40.
doi: 10.2174/138920009787048428.

Carbohydrate-dependent defense mechanisms against Helicobacter pylori infection

Motohiro Kobayashi  1 , Heeseob Lee, Jun Nakayama, Minoru Fukuda
Affiliations
Review

Carbohydrate-dependent defense mechanisms against Helicobacter pylori infection

Motohiro Kobayashi et al. Curr Drug Metab. 2009 Jan.

Abstract

Helicobacter pylori is a Gram-negative bacterium that infects over 50% of the world's population. This organism causes various gastric diseases such as chronic gastritis, peptic ulcer, and gastric cancer. H. pylori possesses lipopolysaccharide, which shares structural similarity to Lewis blood group antigens in gastric mucosa. Such antigenic mimicry could result in immune tolerance against antigens of this pathogen. On the other hand, H. pylori colonize gastric mucosa by utilizing adhesins, which bind Lewis blood group antigen-related carbohydrates expressed on gastric epithelial cells. In chronic gastritis, lymphocytes infiltrate the lamina propria, and such infiltration is facilitated by 6-sulfo sialyl Lewis X-capped O-glycans, peripheral lymph node addressin (PNAd), on high endothelial venule (HEV)-like vessels. The number of HEV-like vessels increases as chronic inflammation progresses. Furthermore, PNAd formed on HEV-like vessels disappear once H. pylori is eradicated. These results indicate that PNAd plays an important role in H. pylori-associated inflammation. H. pylori barely colonizes gland mucous cell-derived mucin where alpha1,4-GlcNAc-capped O-glycans exist. In vitro experiments show that alpha1,4-GlcNAc-capped O-glycans function as a natural antibiotic to inhibit H. pylori growth. We recently identified cholesterol alpha-glucosyltransferase (CHLalphaGcT) using an expression cloning strategy and showed that this enzyme is specifically inhibited by mucin-type O-glycans like those present in deeper portions of the gastric mucosa. These findings show that a battery of carbohydrates expressed in the stomach is closely associated with pathogenesis and also prevention of H. pylori-related diseases.

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Figures

Fig. (1)
Fig. (1)
Gastric mucosa of different degrees of chronic inflammation and association of HEV-like vessels with progression of inflammation. (A) (Upper) Gastric mucosa at a mild stage barely expresses HEV-like vessels with minimum recruitment of lymphocytes. (Lower) Gastric mucosa at a marked stage expresses a significant number of recruited lymphocytes (arrowheads) around HEV-like vessels. (B) The number of MECA-79+ or HECA-452+ vessels is positively correlated with the progression of chronic inflammation. Each group consists of 11 (normal), 42 (mild), 67 (moderate), and 23 (marked) patients. (C) The number of patients exhibiting greater than 1% MECA-79+ or HECA-452+ vessels is highly correlated with progression of chronic inflammation. *, P<0.05; **, P<0.01;, P<0.001; NS, not significant. Bar = 50 μm. Adapted with permission from Kobayashi, M.; Mitoma, J.; Nakamura, N.; Katsuyama, T.; Nakayama, J.; Fukuda, M. Proc. Natl. Acad. Sci. U. S. A., 2004, 101(51), 17807–17812, Copyright 2004 National Academy of Science, USA.
Fig. (2)
Fig. (2)
Disappearance of HEV-like vessels in the gastric mucosa after eradication of H. pylori. Gastric mucosa infected with H. pylori was examined before and 2 months after treatment to eradicate H. pylori. (A) Before treatment, HEV-like vessels detected by MECA-79 and HECA-452 antibodies were abundant, and large numbers of mononuclear cells (lymphocytes) were present around these vessels. (B) After eradication of H. pylori, HEV-like vessels were no longer present and very few mononuclear cells were present. CD34 was used for a marker of vascular endothelial cells. HE, hematoxylin and eosin, Bar = 100 μm. Adapted with permission from Kobayashi, M.; Mitoma, J.; Nakamura, N.; Katsuyama, T.; Nakayama, J.; Fukuda, M. Proc. Natl. Acad. Sci. USA, 2004, 101(51), 17807–17812, Copyright 2004 National Academy of Science, USA.
Fig. (3)
Fig. (3)
Growth curve of H. pylori incubated with soluble CD43 having α1,4-GlcNAc-capped O-glycan (αGlcNAc (+)) and soluble CD43 lacking this O-glycan (αGlcNAc (−)). One milliunit (mU) of αGlcNAc (+) is defined as 1 μg of GlcNAcα-PNP. The protein concentration of αGlcNAc (−) is the same as that of 31.2 mU/ml of αGlcNAc (+). Adapted with permission from Kawakubo, M.; Ito, Y.; Okimura, Y.; Kobayashi, M.; Sakura, K.; Kasama, S.; Fukuda, M.N.; Fukuda, M.; Katsuyama, T.; Nakayama, J. Science, 2004, 305(5686), 1003–1006.
Fig. (4)
Fig. (4)
Morphology of H. pylori incubated with 31.2 mU/ml of soluble CD43 having α1,4-GlcNAc-capped O-glycan (αGlcNAc (+)) and the same protein concentration of soluble CD43 lacking this O-glycan (αGlcNAc (−)). Bar = 1 μm. Adapted with permission from Kawakubo, M.; Ito, Y.; Okimura, Y.; Kobayashi, M.; Sakura, K.; Kasama, S.; Fukuda, M.N.; Fukuda, M.; Katsuyama, T.; Nakayama, J. Science, 2004, 305(5686), 1003–1006.
Fig. (5)
Fig. (5)
Comparison of amino acid sequences of cloned H. pylori CHLαGcT (Hp), H. felis CHLαGcT (Hf), and putative CHLαGcTs from H. hepaticus (Hh), H. mustelae (Hm), and H. acinonychis (Ha). Identical amino acid residues are indicated by closed boxes. Adapted from Lee, H.; Kobayashi, M.; Wang, P.; Nakayama, J.; Seeberger, P.H.; Fukuda, M. Biochem. Biophys. Res. Commun., 2006, 349(4), 1235–1241.
Fig. (6)
Fig. (6)
Expression and purification of CHLαGcT. (A) SDS-polyacrylamide gel electrophoresis of proteins in both soluble and membrane fractions (lanes 1–3: pTKNd6xH vector only; 2, pTKNd6xH-CHLαGcT; 3, pTKNd6xH-CHLαGcT + pRARE (Novagen), and of protein purified from the soluble fraction using Ni-NTA column (lane 4). (B) Distribution of CHLαGcT activity in samples shown in (A). The amount of protein in lane 4 was approximately one-third of that in lane 3 of the membrane fraction. Adapted from Lee, H.; Kobayashi, M.; Wang, P.; Nakayama, J.; Seeberger, P.H.; Fukuda, M. Biochem. Biophys. Res. Commun., 2006, 349(4), 1235–1241.
Fig. (7)
Fig. (7)
Catalytic mechanisms of CHLαGcT. The kinetic data are consistent with an ordered Bi-Bi reaction mechanism. UDP-Glc binds to CHLαGcT (E) prior to cholesterol binding, and α-glucosyl cholesterol (Glc-CHL) is released prior to UDP release from the enzyme-UDP complex. The arrows indicate the directions of reactions. kp represents a kinetic constant to form a product, Glc-CHL. Adapted from Lee, H.; Wang, P.; Hoshino, H.; Ito, Y.; Kobayashi, M.; Nakayama, J.; Seeberger, P.H.; Fukuda, M. Glycobiology, 2008, 18(7), 549–558.
Fig. (8)
Fig. (8)
Inhibition of H. pylori growth by synthetic oligosaccharides and monosaccharides. H. pylori was cultured for 5 days in Mueller-Hinton broth supplemented with 5.5% horse serum containing various amounts of synthetic oligosaccharides and monosaccharides. Bacterial growth was measured at O.D. 600 nm, and the absorbance for control experiments at time 0 was subtracted from absorbance at later time points. Oligosaccharide and monosaccharide concentrations are 1 mM (red), 0.75 mM (orange), 0.5 mM (blue), 0.25 mM (green), 0.125 mM (brown), and control (closed circle). Two mM GlcNAc was also added in B (magenta). Oligosaccharides and monosaccharides were initially dissolved in DMSO, and the final DMSO concentration in the culture medium was 1%. The growth curve in the absence of DMSO is shown as a dotted line (A). Adapted from Lee, H.; Wang, P.; Hoshino, H.; Ito, Y.; Kobayashi, M.; Nakayama, J.; Seeberger, P.H.; Fukuda, M. Glycobiology, 2008, 18(7), 549–558.
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