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Mobley HLT, Mendz GL, Hazell SL, editors. Helicobacter pylori: Physiology and Genetics. Washington (DC): ASM Press; 2001.

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Helicobacter pylori: Physiology and Genetics.

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Chapter 8Molecular Structure, Biosynthesis, and Pathogenic Roles of Lipopolysaccharides

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Department of Microbiology, National University of Ireland, Galway, Ireland

Like the cell envelopes of other gram-negative bacteria, that of Helicobacter pylori contains lipopolysaccharides (LPSs), which are a family of toxic phosphorylated glycolipids that are also termed endotoxins (57). In general, LPSs are essential for the physical integrity and functioning of the bacterial outer membrane (34) and, as the main surface antigens (O-antigens) of gram-negative bacteria, play an important role in the interaction of these bacteria with their environment and with higher organisms (34, 57, 93). LPSs are potent immunomodulating and immunostimulating compounds, due principally to their lipid component, lipid A (93, 94). This family of compounds also harbors binding sites for antibodies and nonimmunoglubulin serum factors (34, 93). Generally, LPSs possess a broad spectrum of endotoxic properties, e.g., pyrogenicity and lethal toxicity, which contribute to the pathogenic potential of gram-negative bacteria (57, 93, 94). Moreover, variation in the structure of the saccharide component of LPS may prevent efficient complement activation and phagocytosis, thereby contributing to the virulence of bacterial strains (44, 93). Despite the established importance of LPSs in bacterial pathogenesis, those of H. pylori have received more limited attention compared with LPSs of other bacterial pathogens. Evidence has accumulated that, although possessing properties similar to those of other gram-negative bacteria, the LPSs of H. pylori also possess unique biological properties. In this chapter the attributes and structure of H. pylori LPSs, especially the relationship between molecular structure and pathogenesis, are reviewed.

General Architecture of LPS

The LPSs of various bacterial species share a common architecture of three principal domains (Fig. 1): the O-specific polysaccharide chain, the core oligosaccharide, and the lipid moiety called lipid A (34, 93, 94). Each of these domains has different structural and functional properties. The outermost O-specific polysaccharide chain is a polymer of identical repeating units that may contain up to seven different sugars, depending on the bacterial species and strain (34, 93). The O-chain contributes to the antigenicity and serospecificity of native LPS (93). The second region is the core oligosaccharide composed of a short series of about 10 to 15 sugars (34, 93, 94). This region of LPS mediates binding of activated T lymphocytes and is essential for the permeation properties of the outer membrane (34, 93). The innermost lipid A component anchors the LPS molecule in the outer membrane (34, 57). Lipid A endows LPS with its range of immunological and endotoxic activities, although the degree of bioactivity of lipid A may be modulated by the saccharide portion of LPS (57, 93, 94). In each bacterial species, the structure of lipid A is highly conserved, whereas that of the core oligosaccharide is more variable, and that of the O-specific chain can be highly variable.

Figure 1. Schematic representation of the three major domains of the LPS molecule.

Figure 1

Schematic representation of the three major domains of the LPS molecule.

Macromolecular Nature of H. pylori LPS

Fresh clinical isolates of H. pylori produce high-molecular-weight, smooth-form LPS (S-LPS) (66). In contrast to fresh clinical isolates, H. pylori culture collection strains that have been subcultured many times on solid media in vitro produce low-molecular-weight, rough-form LPS (R-LPS) without O-polysaccharide chains (58, 66). Although a preliminary study had reported the production of R-LPS by some H. pylori clinical isolates (87), it has been demonstrated that strains may undergo a phenotypic change from S- to R-LPS when grown on conventional solid media (66, 78). This suggests that changes can be induced in LPS expression by growth conditions in vitro that could have major implications for biological studies on LPS. However, this phase shift can be reversed, and the expression of S-LPS stabilized in vitro, when strains are grown in liquid media, irrespective of composition (77, 112). Thus, care should be taken with bacterial growth conditions when performing LPS studies in order not to induce production of an aberrant molecular form.

Unlike enterobacterial LPS, H. pylori produces O-chains of relatively constant chain length as determined in electrophoretic and immunoblotting analyses (58, 66). Despite the relative homogeneity of O-chain length, interstrain variations in the banding pattern, mobility, and staining properties of H. pylori LPS in electrophoresis have been observed and indicate potential structural differences in the LPS (66). Supporting this, antigenic and structural differences in the LPS of different strains have been detected by immunoblotting, passive hemagglutination, lectin binding, and enzyme-linked immunosorbent assays and indicate sufficient diversity for use as the basis of a strain typing scheme (35, 53, 99).

Molecular Structure of H. pylori LPS

Lipid A

The lipid A component of H. pylori LPS contains d-glucosamine (GlcN), phosphate, ethanolamine, and the fatty acids hexadecanoic (16:0), 3-hydroxyhexadecanoic [16:0(3-OH)], and 3-hydroxyoctadecanoic [16:0(3-OH)] acids, with minor amounts of dodecanoic (12:0) and tetradecanoic (14:0) acids (66, 71). This lipid A is characterized by the absence of 3-hydroxytetradecanoic (β-hydroxymyristic) acid [14:0(3-OH)], which occurs in lipid A of many bacterial species (57, 93). The detailed structure of H. pylori lipid A has been investigated independently (71, 102), and both studies found underphosphorylation and underacylation of the lipid A, in agreement with preliminary reports (58, 72). However, one of these studies reported a lipid A with only three fatty acid substituents (102), whereas in the other investigation when milder isolation conditions were used, a lipid A backbone carrying four fatty acids was observed as the major molecular species (71). Thus, the latter represents the more intact form of the molecule (Fig. 2A). In contrast to H. pylori R-LPS, which contains only this tetraacyl lipid A, detailed analysis has shown the presence of hexaacyl lipid A (Fig. 2B) as a minor constituent, with tetraacyl lipid A predominating in H. pylori S-LPS (71).

Figure 2. Proposed chemical structures of (A) the predominant lipid A molecular structure found in H.

Figure 2

Proposed chemical structures of (A) the predominant lipid A molecular structure found in H. pylori R-LPS and S-LPS and (B) a minor lipid A species found in H. pylori S-LPS (71). Numbers in circles refer to the number of carbon atoms in acyl chains. Further (more...)

A structural comparison of the predominant lipid A molecular species of H. pylori with that of Escherichia coli has been performed (61) and, collectively, the data allow the following conclusions. First, there is one less phosphate group (4′-phosphate is absent) on the backbone of H. pylori lipid A. Second, only four fatty acids are present in H. pylori lipid A (two fatty acids are absent at postion 3′), compared with six in E. coli. Third, the average length of the fatty acid chains in H. pylori lipid A is longer (16 to 18 carbons) than in E. coli (12 to 14 carbons). Hence, there are major differences between the structures of these two lipid A molecules, which, based on established, structure-bioactivity relationships of lipid A molecules (34, 57, 93, 94), are likely to translate into differences in biological activities (61).

Core oligosaccharide

Compared with other bacterial species, the core regions of H. pylori strains exhibit an unusual conformation as determined by chemical structural studies. As exemplified by the core oligosaccharide of H. pylori NCTC 11637 (10) (Fig. 3), a branching occurs from the d-glycero-d-manno-heptose (DD-Hep) residue in the inner core through a second such residue to which the first repeating unit of the O-polysaccharide chain is attached (8, 10, 39). However, strain differences in substitution of the intervening DD-Hep between the core oligosaccharide and O-chain occur, whereby heptan and glycan chains may be present, adding to structural complexity (12) (Fig. 3). Moreover, preliminary serological analysis has shown the presence of epitopes in the core that are common with other bacterial species, whereas others are specific to H. pylori (111).

Figure 3. Proposed chemical structure of the polysaccharide moiety of LPS of H.

Figure 3

Proposed chemical structure of the polysaccharide moiety of LPS of H. pylori NCTTC 11637 (10). Further substitution of the lateral DD-Hep (indicated by arrow) by heptose and glucose occurs in some other H. pylori strains. Abbreviations: Fuc, fucose; Gal, (more...)

O-chains

Biochemically related to the ABO blood groups, the Lewis (Le) blood group antigen system is composed of type 1 antigens, Lewis a (Leb) and Lewis b (Leb), and type 2 antigens, Lewis x (Lex) and Lewis y (Ley) (Fig. 4). In 1994, Aspinall et al. (9) first reported the expression of Lex in the O-chain of the H. pylori type strain NCTC 11637. Subsequently, several structural studies on LPS of H. pylori strains have shown mimicry of Lex and/or Ley blood group determinants (8, 10, 11, 39, 55, 56) that are formed by mono- or difucosylated N-acetyl-β-lactosamine units attached to the LPS core (Fig. 5). Generally, the O-polysaccharide chains have a poly-(N-acetyl-β-lactosamine) chain decorated with multiple lateral α-l-fucose residues (811, 39) or in some strains, with additional glucose or galactose residues (7, 56) (Fig. 5). Also, Lea, Leb, and H type 1 antigenic determinants (55) and sialyl-Lex (54) have been found in the O-chains of other H. pylori strains (Fig. 4).

Figure 4. Structural relationship between A, B, H, and Lewis (Le) blood group determinants.

Figure 4

Structural relationship between A, B, H, and Lewis (Le) blood group determinants. Except for fucose, which is in the l-form, all sugars possess the d-configuration. Abbreviations: Fuc, fucose; Gal, galactose; GalNAc, N-acetylgalactosamine; Glc, glucose; (more...)

Figure 5. Modular structures of the polysaccharide component of some examples of H.

Figure 5

Modular structures of the polysaccharide component of some examples of H. pylori LPS. For an explanation of sugar abbreviations, see the legend to Fig. 3.

Of H. pylori strains, 80 to 90% express Lex and/or Ley antigens when screened serologically (32, 50, 99, 115). However, such analysis may underestimate Lex and Ley expression since strains nontypeable with anti-Lewis antibodies have been shown by chemical analysis to express these antigens (39). On the other hand, expression of blood group A by LPS has been detected in some H. pylori strains (67). Moreover, detailed chemical structural analysis has shown that some strains possess O-chains composed of 3-C-methyl-d-mannose, a novel sugar not found previously in nature (40, 68), thus confirming that not all H. pylori strains express Lewis antigen mimicry.

LPS Biosynthesis Genes

The first LPS biosynthesis gene to be identified and cloned from H. pylori was an rfaC homolog encoding heptosyl transferase I involved in core oligosaccharide synthesis (29). However, attempts to produce knockout mutants of the gene in H. pylori have, to date, proven unsuccessful. Excepting technical difficulties, this indicates that such mutations are lethal, underlining the importance of the unusual conformation found in the H. pylori core oligosaccharide. Despite such mutational difficulties, the availability of two complete genome sequences of H. pylori strains (26695 and J99) and their comparative analysis (1, 106) have given further insights into putative LPS biosynthesis genes in H. pylori.

At least 27 genes likely to be involved in LPS biosynthesis have been found in H. pylori (106), but unlike in other bacteria, these genes are scattered throughout the genome, not clustered at one locus. This may reflect the synthetic mechanism of H. pylori LPS, particularly of the O-chain, by sequential addition of monosaccharides to the growing chain rather than the polymerization of repeating units (12, 14). H. pylori has homologs to all enzymes required for lipid A synthesis, including lpxA, lpxB, lpxD, and envA orthologs (24, 49). In addition, orthologs of genes involved in core oligosaccharide synthesis were identified: rfaF, rfaE, rfaD, and rfaC for synthesis of the inner core; kdsA, kdsB, and rpe for the 3-deoxy-d-manno-2-octulsonic acid (Kdo) region of the inner core; and three copies of rfaJ, pgi, and galU for outer core synthesis (49).

With respect to O-chain synthesis, each genome has two α(1,3)-fucosyltransferase genes that differ in the number of a seven-amino acid sequence repeat (1, 106). DNA motifs near the 5′ end of these genes at two distinct polynucleotide repeats have been deduced to indicate regulation through slipped-strand repair (1). No putative gene for α(1,2)-fucosyltransferase was identified in the genomes, but a truncated gene with a C14 tract was found and in silico insertion of a C-G pair yielded a full-length protein with strong homology to α(1,2)-fucosyltransferases (14). Due to the potential biological importance of Le antigen mimicry in H. pylori O-chains, attention has focused on cloning and sequencing first the α(1,3)-fucosyltransferase gene involved in Lex synthesis (28, 51), then the α(1,2)-fucosyltransferase gene involved in Ley synthesis (113), as well as the β(1,4)-galactosyltransferase gene required for synthesis of N-acetyllactosamine in the backbone of Le antigens (46). Also, an enzyme with both α(1,3)- and α(1,4)-fucosyltransferase activity involved in both Lex and Lea synthesis, respectively, has been cloned and sequenced (91).

Three genes in the sequenced genomes that are homologs of the α(1,2)-glucosyltransferase gene (rfaJ) have been found, but no α(1,2)-linked glucose has been described in H. pylori LPS (14, 49). It has been suggested that these genes encode β(1,4)-galactosyltransferase and/or β(1,3)-N-acetylglucosaminyltransferase functions required for Lewis antigen synthesis (14). Also, a homolog of GDP-d-mannose dehydratase from Vibrio cholerae and homologs of galactosyltransferases from Klebsiella pneumoniae have been suggested to be involved in O-chain synthesis (49). Although of low homology, an ortholog of neuA, which codes for CMP-N-acetylneuraminic (sialic) acid synthetase (106), was suggested to be involved in sialyl-Lex expression (14), which has been verified chemically to occur in H. pylori LPS (54). Mutants expressing truncated LPS structures have been generated by insertional mutagenesis of galE and rfbM genes that encode UDP-galactose-4-epimerase and GDP-d-mannose pyrophosphorylase, a key enzyme in the synthesis of GDP-fucose, respectively (25, 41). Since galactose is essential for linking the O-chain polysaccharide to the core of H. pylori LPS, construction of an isogenic H. pylori galE mutant results in expression of R-LPS without an O-chain (25, 41). As expected, construction of an rfbM mutant results in expression of S-LPS with an O-chain but without fucosylation (25).

LPS Expression under Acid Stress

Survival of H. pylori below pH 4 is dependent on urease activity, whereas urease-independent mechanisms, although less well characterized, operate at greater than pH 4. Even less studied are the mechanisms that play a role in H. pylori growth under constantly acidic conditions that prevail in the mucus layer. Expression of LPS appears to be involved in the ability of H. pylori to withstand acid shock since a wbcJ gene, encoding a protein homolog involved in the conversion of GDP-mannose to GDP-fucose for O-chain biosynthesis, was induced under acid shock conditions and during growth at pH 5 (52). Moreover, a wbcJ mutant did not survive an acid shock of pH 3.5 and was impaired in its survival of acid shock at pH 4. Further emphasizing the importance of the O-chain in the bacterial response to acid, detailed chemical studies have shown structural differences between the O-chain of H. pylori grown in liquid media at pH 7 and pH 5, whereas no differences were observed in the core and lipid A regions of LPS (69). Other changes may also occur in the bacterial cell wall since Bukholm et al. (16) observed that growth of H. pylori on solid media at pH 5.5 resulted in production of colonies with increased amounts of lysophosphatidyl ethanolamine and phosphatidyl serine as well as increased virulence, compared with those at pH 7. However, these changes in lipid composition can be induced independently of acidic conditions (63) and, thus, may simply reflect growth on solid media rather than an acidic environment.

Low Immunological Activity of LPS

Immunological and endotoxic properties

Based on the structure of H. pylori lipid A, the hypothesis was proposed that H. pylori LPS should have low biological activities (80) and, subsequently, this has been proven. The properties of H. pylori LPS, which are reviewed extensively elsewhere (58, 59, 62, 65), have revealed significantly lower endotoxic and immunological activities when compared with enterobacterial LPS as the gold standard. For example, the pyrogenicity and mitogenicity of H. pylori LPS is 1,000-fold lower, and lethal toxicity in mice, 500-fold lower, compared with Salmonella enterica serovar Typhimurium LPS (80). The induction of interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha (TNF-α) from activated human mononuclear cells by H. pylori LPS is significantly lower than that by E. coli LPS (15, 85). Also, the induction of IL-8 from neutrophils is 1,000-fold lower when induced by H. pylori LPS than by enterobacterial LPS (20), and only low-level secretion of IL-8 from epithelial cell lines occurs (21). Similar observations were made in other biological assays (13, 23, 83, 88, 103), including a 1,000-fold lower ability by H. pylori LPS to induce production of procoagulant activity (PCA), identified as tissue factor, and plasminogen activator inhibitor type 2 (PAI-2) by human mononuclear leukocytes (98).

Fine structure of lipid A

Studies using chemically defined synthetic analogs and partial structures of E. coli and Salmonella spp. lipid A have shown that E. coli hexaacyl lipid A optimally expresses the full spectrum of endotoxic activities associated with LPS (34, 93, 94). Slight modifications to this lipid A architecture, e.g., the addition or removal of chemical groups, or the presence of long or unusual fatty acids, result in a significant reduction in the immunological activities of lipid A, and hence of LPS (57, 93). These findings suggested that the unusual phosphorylation and acylation in H. pylori lipid A (Fig. 2) could, in part, explain the observed lower biological activities (58, 59, 80). In serum, LPS-binding protein (LBP) acts as a catalytic protein to present LPS to the monocyte-macrophage cell surface, where the newly formed LPS-LBP complex interacts with the CD14 surface receptor, which, independently or in association with a second receptor, leads to the induction of proinflammatory cytokines (57). H. pylori LPS binds more poorly with slower binding kinetics than E. coli LPS to LBP, and also exhibits poorer binding to CD14 (22). Collectively, as LBP binds LPS through its lipid A component, these findings are consistent with a proportionately lower ability of H. pylori LPS to activate monocytes and reflect the unusual phosphorylation and fatty acid substitution in this lipid A (61, 71).

In addition, modification and isolation of H. pylori LPS components with subsequent testing in immunological assays have given insights into the molecular basis for the observed lower immunological activities. With this approach, the phosphorylation pattern in H. pylori lipid A has been shown to influence induction of TNF-α, and the core oligosaccharide modulates this effect (85). A similar phenomenon was observed with induction of PCA and PAI-2 release from mononuclear leukocytes (98), and dephosphorylation of H. pylori LPS influences activity in the Limulus amebocyte lysate assay (85). In contrast, dephosphorylation does not alter the priming activity of H. pylori LPS on neutrophils to release toxic oxygen radicals, which suggests the lesser importance of phosphorylation compared with acylation pattern in priming (83). On the other hand, the lack of abolition of suppressor T-cell activity has been attributed to the presence of long-chain fatty acids in H. pylori lipid A (13). Thus, depending on the particular immunological activity examined, the phosphorylation or acylation pattern of H. pylori lipid A assumes importance.

Implications for the host-parasite relationship

H. pylori LPS, which is an essential component of the bacterial outer membrane, by inducing a low immunological response may prolong H. pylori infection for longer than that by more aggressive and short-lived pathogens. Thus, we have suggested that H. pylori LPS, and its lipid A component in particular, have evolved their present structure as a consequence of adaptation to the ecological niche in the gastric mucosa (58, 59). In an analogous manner, the long-term human commensal bacterium Bacteroides fragilis, a member of the normal gut microbiota, produces a lipid A bearing some structural similarity to H. pylori lipid A and which possesses low immunological activities (114). Since the primary role of H. pylori LPS is to provide a functional macromolecular matrix in the outer membrane through which the bacterium interacts with its environment (57, 59, 80), the LPS molecule has retained this role but has been modified to reduce the immunological response, hence aiding persistence of the bacterium and thereby aiding development of a chronic infection.

Despite the low immunological activity of H. pylori LPS, H. pylori colonization of the human antral mucosa is associated with inflammation. H. pylori can activate mononuclear cells by an LPS-independent, as well as an LPS-dependent mechanism (48), and other bacterial surface molecules can induce an immunological response contributing to pathology (61). Nevertheless, as a consequence of enzymatic degradation of LPS by phagocytes, some LPS and/or lipid A partially modified structures can be excreted by exocytosis. These compounds, retaining some immunological activity, could play a role as subliminal, low-grade, persistent stimuli involved in H. pylori pathogenesis during long-term chronic infection contributing to gastric damage, and potentially to extragastric sequelae (62, 65). Consistent with this, H. pylori LPS and derivatives can induce PCA and PAI-2 production by human mononuclear leukocytes, influencing coagulation and fibrin formation (98), and can induce nitric oxide synthase in an in vivo animal model, thereby contributing to gastric damage (42, 43).

LPS and Lectin-Like Interactions in Laminin Binding

Bacterial interactions with extracellular and basement membrane proteins play an important role in the pathogenesis and virulence of a number of infections (45). H. pylori strains bind a number of extracellular matrix components and, especially, exhibit high-affinity binding to laminin (45, 70, 107, 108). This glycoprotein is not alone a component of the extracellular matrix, but plays an important role in the structure of the basement membrane. Preliminary studies indicated the involvement of both a lectin-like interaction (108) and LPS (70) in laminin binding by H. pylori.

The interaction of H. pylori with laminin is complex and that mediated by LPS involves two mechanisms operating in strains that can be divided into hemagglutinating and nonhemagglutinating strains (109). A phosphorylated structure in the core oligosaccharide of LPS mediates the interaction of a hemagglutinating strain, whereas a conserved nonphosphorylated structure in the core oligosaccharide mediates the interaction of a poorly hemagglutinating strain. However, the amino acid domain on the laminin molecule for LPS interaction has not, to date, been identified. Although these interactions are mediated by the core of LPS, as a serological response against this LPS domain occurs in H. pylori-positive patients (86), structures within this domain can be exposed on the bacterial surface (62). Moreover, the serological response against the core domain, and hence the availability of the core structures for interaction with laminin, is more developed in duodenal ulcer patients than gastritis patients (86), which may reflect the role of the LPS-laminin interaction in the development of peptic ulcers (see below). The lectin-like adhesin involved in laminin binding is sialic acid-specific, recognizes α(2,3)-sialyllactose, is conserved in H. pylori strains, and has been identified as a 25-kDa protein (110). A serological response against this protein occurs in H. pylori-infected individuals, confirming that the adhesin is produced in vivo (63). Conceptually, the binding of H. pylori to laminin illustrates a dual recognition system, whereby sugars in the core of LPS interact with a peptide sequence of laminin, and a protein on H. pylori (with lectin-like properties) recognizes a stretch of sugars in laminin. It has been proposed that the initial binding of laminin by H. pylori is mediated by LPS and that this is followed by the specific lectin binding (45, 110).

The capacity of H. pylori strains to bind laminin is unlikely to be involved in the initial colonization of gastric mucosal cells, since H. pylori possesses adhesins that putatively recognize receptors in the mucus layer and on the epithelial cell surface (58, 60, 75, 76). Importantly, H. pylori is observed associating with intercellular junctions, and laminin binding may explain its association with this microenvironment (59) and have pathological consequences (59, 62). An integrin, a 67-kDa protein receptor for laminin on gastric epithelial cells, has been isolated and H. pylori LPS has been shown to interfere with its specific interaction with laminin in vitro (101). Therefore, the binding of H. pylori to laminin mediated by LPS could disrupt epithelial cell-basement membrane interactions, contributing to the disruption of gastric mucosal integrity and the development of gastric leakiness associated with the bacterium. Interestingly, H. pylori exhibits a significant penetration between cells, and infection is associated with a weakening of adhesion of the tight junctions between cells, which could explain the origin of gastric leakiness. Certain cyto-protective anti-ulcer drugs, e.g., nitecapone, sucralfate, ebrotidine, and sulglycotide, have been reported to counteract the anti-adhesive effect of LPS on integrin action (see references 59, 101), but further studies are required to verify this hypothesis, since other soluble factors of H. pylori have been identified as contributing to gastric leakiness (105).

Pepsinogen Stimulation by LPS

Elevated pepsinogen, a precursor of mucolytic and barrier-breaking pepsin, is considered a marker for the development and recurrence of duodenal ulcers. Young et al. (119), using gastric mucosa from guinea pigs in Ussing chambers, observed a 50-fold stimulation of pepsinogen secretion with H. pylori LPS compared with only a 12-fold increase with E. coli LPS. Microscopic examination confirmed the structural integrity of chief cells, indicating the absence of a nonspecific toxic effect induced by H. pylori LPS. Importantly, degranulation of zymogen granules in H. pylori LPS-treated tissue suggested a specific mechanism of pepsinogen release. Other investigations using guinea pig mucosa have confirmed these observations (65, 118). Although the pepsinogen stimulatory effect was comparatively lower, stimulation of pepsinogen was induced in isolated rabbit gastric glands by cell sonicates of H. pylori (18), but this may reflect the stimulatory effect of a lower concentration of LPS in the tested cell sonicates (59). Using guinea pig mucosa, comparison of the stimulatory effect of LPS derived from two duodenal ulcer patients and two asymptomatic individuals showed that the former preparations induced 50-fold stimulation, whereas the latter induced levels like those of controls (79). Hence, strain-dependent differences in LPS-induced pepsinogen secretion induction are related to pathogenesis. Nevertheless, studies using isolated human gastric mucosa have, to date, not been undertaken.

Experiments using LPS components, dephosphorylated LPS, and polymyxin B inhibition studies have indicated the involvement of structures in the core oligosaccharide of H. pylori LPS from duodenal ulcer patients in pepsinogen induction (79, 118). As discussed above, the LPS cores of H. pylori strains exhibit an unusual conformation compared with those of other bacterial species (62, 65). Structural investigations of the LPS cores of pepsinogen-inducing and noninducing strains have identified differences in substitution in the outer core–O-chain domain (7). Thus, core structures are present that may explain the activation of pepsinogen by H. pylori LPS.

Mimicry of Lewis Blood Group Antigens

Lewis antigen expression and phase variation mechanisms

Phase variation is the reversible on-and-off switching of surface epitopes, including those of LPS, and can be genetically paralleled by the on-and-off switching of the specific glycosyltransferase genes involved in LPS biosynthesis (97). In H. pylori, Lex is not a stable trait and LPS can display a high frequency of phase variation, resulting in the occurrence of several LPS variants in one bacterial cell population in vitro (5). Thus, phase variation could contribute to the phenotypic heterogeneity of H. pylori and may explain the isolation from one individual of several highly related isolates that differ in Le expression (116).

For synthesis of an O-chain containing Lex polymer terminated with a Ley unit, H. pylori requires a series of enzymes including α(1,3)- and α(1,2)-fucosyltransferases that link fucose to C-3 of N-acetylglucosamine (GlcNAc) and C-2 of galactose (Gal), respectively; and GlcNAc and Gal transfersases that form the polylactosamine O-chain backbone to which fucose is attached (Fig. 4). Three main groups of variants have been reported in H. pylori LPS: one variant group had loss of α(1,3)-linked fucose resulting in nonsubstituted polylactosamine O-chains, producing an i-antigen chain; another had loss of the polymeric chain resulting in expression of a truncated LPS with monomeric Ley; and a third arose by acquisition of α(1,2)-fucose, which expressed polymeric Lex plus terminal Ley (5). Nevertheless, these structural deductions were solely based on serology and require chemical structural validation.

It is well established in LPS of Neisseria spp. and Haemophilus influenzae that on-off switching occurs during replication because of a slip-strand mechanism that changes the length of nucleotide repeats that introduce translational frameshifts, leading to the production of inactive truncated gene products (97). Subsequent changes during replication may switch the gene back on by restoring the reading frame and hence production of an active gene product. Interestingly, the α(1,3)- and α(1,2)-fucosyltransferase genes of H. pylori contain poly(C) tracts and the α(1,3)-fucosyltransferase genes contain oligonucleotide repeats at the 3′-end (1, 106). Moreover, the poly(C) tracts of the α(1,3)-fucosyltransferase genes have been demonstrated to shorten and lengthen randomly in H. pylori laboratory strains, and changes in Le expression deduced to be a direct result of reversible frameshifting and inactivation of gene products (3). However, the length of C repeats in α(1,3)-fucosyltransferase genes did not correlate with Lex or Ley expression in H. pylori clinical isolates (95), indicating that posttranslational events and the availability of sugar intermediates, in addition to active enzyme, are important in determining the Le phenotype expressed.

Camouflage, colonization, and bacterial adherence

The Lex, Ley, and related blood group antigens are present in the human gastric mucosa (96). Surface and foveolar epithelia coexpress either Lea and Lex in Le(a+, b−) individuals (nonsecretors), or Leb and Ley in Le(a−, b+) individuals (secretors), whereas glandular epithelium lacks type 1 antigens (Lea and Leb) but expresses Lex and Ley (type 2 antigens) irrespective of the secretor phenotype. Therefore, it has been speculated that bacterial expression of Lex and Ley antigens identical to those in the gastric mucosa may camouflage H. pylori in its ecological niche, particularly in the early phases of infection (59, 60, 64). Because Lea and Leb that are expressed in the foveolar epithelium are isoforms of Lex and Ley (Fig. 4), Wirth et al. (117) extended the original hypothesis and reported, using erythrocyte Lewis (a, b) phenotyping, that the relative proportion of bacterial expression of Lex and Ley corresponded to the host Le(a+,b−) and Le(a−,b+) blood group phenotypes, respectively. However, in contrast, similar studies in Irish and Canadian patient populations did not find this correlation (31, 32, 104). The discrepancies between these results may be influenced by the characteristics of the study populations. Of considerable importance is that 26% of the study population of Wirth et al. (117) were of the recessive Lewis phenotype, Le(a−,b−), which is higher than that usually observed for a Caucasian or European population, and reflects the heterogeneous origin of their patients. Distribution of this recessive phenotype group of patients to their true secretor or nonsecretor phenotype by salivary testing would influence the outcome of the obtained results. Importantly, in the other studies, no patients of a recessive phenotype were observed (31).

Loss of O-chain and Lewis antigen expression by H. pylori strains results in a lack of ability to infect mouse models of colonization (36, 74). Construction of an isogenic H. pylori galE mutant, expressing R-LPS without an O-chain, results in loss of ability to colonize mice compared with the Lex-expressing parental strain (62, 74). Similarly, mutation of a gene encoding a (1,4)-galactosyltransferase affecting synthesis of the O-chain backbone resulted in less efficient colonization of the murine stomach (46). These observations may be attributable to camouflage but also to the involvement of bacterial expression Lex in adherence to the gastric mucosa (62). In adherence studies to gastric antral mucosa in situ in which an H. pylori galE mutant and another mutant in which rfbM had undergone insertional mutagenesis, yielding an LPS with an O-chain but without fucosylation and hence without Lex expression, no tropic binding of either mutant to the mucosa was observed (25). Furthermore, Lex-binding polypeptides in the range of 16 to 29 kDa are found in gastric epithelial cells, but their identity is, to date, unknown (17).

Lewis antigens and the inflammatory response

In patient studies, although it has become apparent that bacterial colonization density and the ensuing inflammatory response can be influenced by host expression of ABO and Lea blood group determinants (33), bacterial Lex expression is associated with peptic ulcer disease (50) and is statistically related to neutrophil infiltration (32). This is consistent with the role of Lex in adherence, aiding bacterial interaction and delivery of secreted products to the mucosa (60, 92), hence influencing the inflammatory response. Alternatively, it has been speculated that recognition and cross-linking of CD15 by H. pylori-induced anti-Lex autoantibodies could directly potentiate polymorph adhesiveness to the endothelium (6, 61, 73), but this remains a question for further investigation.

On the other hand, one study showed that H. pylori isolates positive for both Lex and Ley were predominantly cagA positive and that a cagA-ablated strain had diminished expression of Lex (115). It was concluded that expression of host Lewis antigens by the bacterium could aid the persistence of cagA-positive H. pylori proinflammatory strains. Although small numbers of isolates from different countries were examined, predominantly the isolates were from North America. In contrast, investigations of H. pylori isolates from a geographically distinct Irish population have shown the lack of an association between cagA status and Lewis antigen expression (32, 50). These differing results reflect the adaptation of H. pylori strains with differing attributes to differing human populations (50).

Lewis antigens and putative autoimmune mechanisms

Expression of Lex and Ley antigens has been implicated in the pathogenesis of atrophic gastritis by the induction of autoreactive antibodies (4, 6, 64, 73), but this pathogenic mechanism has not been unequivocally established (2). The presence of antigastric autoantibodies in H. pylori-infected individuals has been correlated with the degree of gastric infiltration, with the numbers of inflammatory cells, and with glandular atrophy (27, 82). In mouse immunization studies, H. pylori isolates from patients with severe atrophy, which expressed Lex and Ley antigens, yielded a strong gastric autoantibody response, whereas isolates from individuals with near-normal mucosa, which often lacked Lewis antigen expression, were less able to induce autoantibodies (82). Moreover, growth in mice of an H. pylori-induced, anti-Ley-secreting hybridoma resulted in gastritis-like histopathological changes (6, 81).

The oligosaccharide of the β-chain of the gastric proton pump (H+, K+-ATPase) of parietal cell canaliculi, which is similar in chemical structure to Lewis antigens, has been implicated in pathogenic autoimmune responses. Anti-Ley H. pylori-induced autoreactive antibodies react with the human and murine β-chain (6). In addition, anti-Lewis and related antigen-parietal cell antibodies were induced in a transgenic mouse model of H. pylori infection in which gastric pathology developed (30). Collectively, these data have been taken to indicate that Lewis antigen mimicry plays a role in the induction of autoimmunity in H. pylori-associated disease. Nevertheless, this interpretation remains controversial.

Contradictory results have been obtained from experiments attempting to abolish the binding of anticanalicular serum autoantibodies by absorption with H. pylori. In one such series (81) using Lewis-positive lysates of H. pylori, a decrease was observed, but no significant reduction was observed in another (26), and anti-H+, K+-ATPase serum autoantibodies were not absorbed with H. pylori whole cells in another study (47). Furthermore, patient sera reacted with recombinant H+, K+-ATPase expressed in Xenopus oocytes, which was deduced not to express Lewis antigens (19). Because of these findings, it has been concluded that H. pylori-associated autoimmunity parallels the classical model for induction of organ-specific autoimmunity, with a central role for increased autoantigen presentation resulting in loss of tolerance, and anti-Lewis antibodies only reflecting gastric damage (2, 26). However, the outer membrane of H. pylori undergoes blebbing, producing vesicles, the membranes of which contain LPS, and the associated Lewis antigens, which can be demonstrated by immunoelectron microscopy (37, 62). Thus, the Lewis antigens of H. pylori can be presented to the immune system in this format, rather than on whole bacterial cells. Because the use of whole cells or lysates of H. pylori may not be optimal to remove H. pylori-induced anti-Lewis antibodies and it is unclear as to what type of glycosylation occurs in the Xenopus oocytes, further studies are required to resolve these issues.

Future Outlook

In addition to the biological properties detailed above, a number of other biological activities that are less well characterized have been attributed to H. pylori LPS. A shift from high- to low-molecular-weight mucin production coupled with an inhibitory effect on the process of mucus glycosylation and sulfation by H. pylori LPS in segments of rat stomach has been observed (100). Moreover, H. pylori LPS inhibited mucin binding to a 97-kDa protein receptor that was isolated from gastric epithelial cells (90). Both these in vitro phenomena require independent verification and further evaluation since such mechanisms could profoundly influence the nature and integrity of the mucus perimeter in vivo. H. pylori LPS has been reported to inhibit acid secretion in pylorus-ligated conscious rats (84), and the LPS has been shown to influence enterochromaffin-like cell secretion and proliferation that may contribute to the abnormalities in gastric acid secretion associated with H. pylori infection (38). Furthermore, induction of apoptosis in gastric epithelia of rats by H. pylori LPS has been shown to contribute to the gastric mucosal injury (89). Although of potential pathogenic importance, the molecular structures within H. pylori LPS responsible for these properties, and hence the structural-bioactivity relationships in the LPS, need to be identified before these phenomena can be unequivocally accepted.

Despite the assignment of roles to putative open reading frames as LPS biosynthetic genes in the sequenced H. pylori genomes (1, 106), interpretation should be performed with caution, particularly since the putative functions have not been subjected to mutational and biochemical analyses. For future studies, mutational analysis of the genes should be followed by chemical verification of the LPS structures present. Subsequent testing of the validated mutants in animal models and other relevant biological test systems may provide further useful tools for gaining deeper insights into the role of LPS in H. pylori pathogenesis.

Acknowledgments

This work was supported by grants from the Irish Health Research Board and the Millennium Research Fund. The author thanks his many colleagues for their continued support.

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