ReviewRelevance of fucosylation and Lewis antigen expression in the bacterial gastroduodenal pathogen Helicobacter pylori
Graphical abstract
Introduction
Helicobacter pylori is a Gram-negative bacterium that colonizes human gastric mucosa, and is one of the most common bacterial pathogens worldwide, with a prevalence of up to 90% in developing countries.1 Infection once established can persist for life if left untreated, and although only 30% of those infected are clinically symptomatic, infection is associated with active inflammation in the gastric mucosa.1, 2 Infection outcome is diverse and includes the development and recurrence of gastritis, gastric and duodenal ulcers, and an increased risk of gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma.3 The cell envelope of H. pylori, like those of other Gram-negative bacteria, contains lipopolysaccharides (LPSs) which are important pathogenic and virulence factors of H. pylori with properties contributing to the severity and chronicity of this infection.4 In general, LPSs are a family of phosphorylated lipoglycans found in the outer membrane of Gram-negative bacteria, generally possessing potent immunomodulating and immunostimulating properties.5, 6 Although components of the outer membrane, these molecules can be released by multiplying or disintegrating bacteria, as well as by the blebbing of outer membrane vesicles from the cell surface of H. pylori.7
As surface antigens (O-antigens) of H. pylori, these molecules are capable of inducing an antibody response, structural variation can be used as the basis for serotyping strains.8, 9 In addition, this structural variation can be detected using non-immunoglobin factors such as lectins to allow strain differentiation in a lectin typing scheme.10, 11 Like members of the Enterobacteriaceae, exemplified by Escherichia coli, H. pylori produces high-molecular mass (smooth form) LPS composed of an outermost saccharide moiety, divided into the O-chain and core oligosaccharide (OS) regions, covalently linked to a lipid moiety, termed lipid A, that anchors the molecule in the outer leaflet of the outer membrane.6, 12, 13, 14 Each of these domains has differing structural and biological properties.6, 12, 14, 15
Extensive studies on the bioactivities of H. pylori LPS have revealed significantly lower endotoxic and immunological activities when compared with enterobacterial LPS as the gold standard.4, 16, 17 Consistent with the hypothesis that the structure of lipid A endows H. pylori LPS with low immuno-activities,18 detailed structural studies have found underphosphorylation, underacylation and substitution by long chain fatty acids in this lipid A,13, 19, 20 which based on established structure–bioactivity relationships of lipid A molecules5, 12 are likely to translate into reduced immunological activities. As to the core OS, in conjunction with a 25 kDa protein adhesin,21 that has been confirmed to be produced in vivo,22H. pylori LPS can bind laminin which is an important extracellular matrix glycoprotein found in the basement membrane.23 Moreover, the LPS-laminin binding may inhibit recognition of the glycoprotein by the laminin receptor (67 kDa integrin) on gastric epithelial cells.24 This interaction and also that of H. pylori with other extracellular matrix proteins25 can play an important role in the loss of gastric mucosal integrity,26 and along with other soluble factors of H. pylori contribute to development of gastric leakiness.27 In addition, H. pylori isolates, particularly those isolated from duodenal ulcer patients, stimulate pepsinogen secretion,28, 29 a precursor of the enzyme pepsin, which is considered an aggressive mucolytic factor in the development of duodenal ulcer disease. Of note, the serological response against the core OS of LPS is more developed in duodenal ulcer patients than gastritis patients, reflecting the availability of core structures for the above interactions.30 The identity of the structures within the core OS of LPS required for these interactions has been determined.31, 32, 33
The expression of Lewis (Le) and related blood group antigens in the O-chains of H. pylori LPS16, 17, 33, 34 has led to intensive investigations of the biosynthesis of these human antigens by H. pylori and the implications of their expression for pathogenesis and virulence of the bacterium. The aim of the present report is to review the structural and biological relevance of fucosylation and expression of these antigens by H. pylori.
Section snippets
Le antigens in humans
Le antigens are biochemically related to the ABH blood groups of humans that are formed by the sequential addition of fucose, galactose and N-acetylgalactosamine to the backbone carbohydrate chains of both lipids and proteins. These antigens are constituted from two types of backbone structures, containing galactose (Gal) and N-acetylglucosamine (GlcNAc), so-called type 1 chains [composed of Gal-β(1,3)-GlcNAc] giving rise to Lewisa (Lea), sialyl-Lea and Lewisb (Leb), and type 2 chains [composed
FucTs
FucTs belong to the glycosyltransferase superfamily, in the category of Carbohydrate-Active enZYmes (CAZY) (http://www.CAZY.org/fam/acc_GT.html), and catalyse the reactions in which a fucose residue is transferred from the donor-activated sugar (GDP-fucose) to the acceptor molecule. Based on the site of Fuc addition, FucTs are classified as α(1,2)-, α(1,3/4)-, α(1,6)- and O-FucTs, and are expressed in prokaryotes and eukaryotes.76
Roles of LPS-expressed Le antigens in H. pylori pathogenesis
Biologically, H. pylori Le expression has been implicated in evading the immune response upon initial infection and in influencing bacterial colonization and adhesion,16, 17, 33 and with the progress of chronic infection it has been suggested to contribute to gastric autoimmunity that leads to gastric atrophy, a precursor state of gastric cancer.7, 101, 102, 103 Although the latter has been considered controversial,16, 17, 104 more recent evidence supports a contributing role of Le
Concluding remarks and future directions
H. pylori has a well-established ability to evade and even subvert innate and adaptive immune responses during long-term infection2, 4 and certain properties of H. pylori LPS, including those associated with the O-chain, contribute to these. Similar to H. pylori, many colonizers of the gut, including commensals and pathogens, have developed mechanisms to vary LPS structure and thus may subvert recognition by innate immune receptors.136 This underlines the importance of LPS as a surface
Acknowledgements
A.P.M. was the recipient of a Sir Allan Sewell Fellowship from Griffith University. The financial support from the Irish Research Council for Science Engineering and Technology, Higher Education Authority PRTL-3 Programme of the National Development Plan and EU Marie Curie Programme (Grant No. MTKD-CT-2005-029774) for studies in the author’s laboratory is gratefully acknowledged.
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