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Helicobacter pylori adhesion and patho-adaptation: the role of BabA and SabA adhesins in persistent infection and chronic inflammation
Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Helicobacter pylori (H. pylori) is a human-specific gastric pathogen which is responsible for a spectrum of diseases ranging from superficial gastritis to gastric and duodenal ulceration, and which is also highly associated with gastric cancer. The pathogenesis of severe gastric disorders caused by H. pylori is multifactorial and involves complex interactions between the microbe and the gastric mucosa. H. pylori expresses several adhesion proteins. These molecules have important roles in the establishment of persistent infection and chronic inflammation, which cause tissue damage.

The aim of this thesis was to study the attachment of this bacterium to human gastric epithelium, mediated by blood group antigens in both health and disease. One of the bestcharacterized H. pylori adhesins is the histo-blood group antigen binding adhesin (BabA), which binds specifically to the Lewis b antigen (Leb) in the gastric mucosa.

A protective mucus layer lines the stomach. The mucosal glycosylation patterns (GPs) vary between different cell lineages, different locations along the gastrointestinal (GI) tract and different developmental stages. In addition, GPs undergo changes during malignant transformation. MUC5AC is a mucin molecule produced by the surface epithelium. Three distinctly different types of human gastrointestinal tissue were studied by bacterial adherence analysis in situ. MUC5AC is the most important carrier of Leb and the new results demonstrate that it forms major receptors for H. pylori adherence.

By analysing an H. pylori babA-deletion mutant, a novel adhesin-receptor binding mode was found. Surprisingly, the mutant bound efficiently to both human gastric mucosa and to gastric mucosa of Leb transgenic mice. The sialylated and fucosylated blood group antigen, sialyl-dimeric-Lewis x (sdiLex), was structurally identified as the new receptor. A positive correlation was found between adherence of H. pylori to sialyl-Lewis x (sLex) and elevated levels of inflammation response in the human gastric mucosa. These results were supported by detailed analysis of sialylated and fucosylated blood group antigen glycosylation patterns and, in addition, in situ bacterial adherence to gastric mucosa of experimentally challenged Rhesus monkey. The cognate sialic acid-binding adhesin (SabA) was purified by the retagging technique, and the corresponding sabA-gene was identified.

H. pylori lipopolysaccharide (LPS) contains various Lewis blood group antigens such as Lewis x (Lex) and Lewis y (Ley). Additional bacterial adherence modes, which are independent of the BabA and/or SabA adhesins, could possibly be mediated by Lex interactions. Adherence of a clinical isolate and its corresponding Lex mutant to human gastric mucosa with various gastric pathologies was studied in situ. The results suggest that H. pylori LPS plays a distinct but minor role in promotion of bacterial adhesion.

Taken together, the results suggest mechanisms for continuous selection of H. pylori strains, involving capacity to adapt to changes in the local environment such as shifts in cell differentiation and associated glycosylation patterns. Adherence of H. pylori is dependent on both the BabA and the SabA adhesin. Multi-step dependent attachment mechanisms may direct the microbes to distinct ecological niches during persistent infections, driving the chronic inflammation processes further toward the development of peptic ulcer disease and/or malignant transformation.

Key words: H. pylori, BabA, adhesin, Lewis b, MUC5AC, sialyl-dimeric-Lewis x, chronic inflammation, SabA, Lewis x, LPS.

Place, publisher, year, edition, pages
2004.
Series
Umeå University odontological dissertations, ISSN 0345-7532 ; 83
Keyword [en]
H. pylori, BabA, adhesin, Lewis b, MUC5AC, sialyl-dimeric-Lewis x, chronic inflammation, SabA, Lewis x, LPS
Research subject
Odontology
Identifiers
URN: urn:nbn:se:umu:diva-271ISBN: 91-7305-548-4 (print)OAI: oai:DiVA.org:umu-271DiVA: diva2:142899
Public defence
2004-06-01, Föreläsningssal E04, Byggnad 6E, NUS, Umeå, 13:00 (English)
Opponent
Available from: 2004-05-10 Created: 2004-05-10 Last updated: 2010-08-06Bibliographically approved
List of papers
1. The MUC5AC glycoprotein is the primary receptor for Helicobacter pylori in the human stomach
Open this publication in new window or tab >>The MUC5AC glycoprotein is the primary receptor for Helicobacter pylori in the human stomach
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2003 (English)In: Helicobacter, ISSN 1083-4389, E-ISSN 1523-5378, Vol. 8, no 5, 521-532 p.Article in journal (Refereed) Published
Abstract [en]

Background and objectives. Helicobacter pylori shows a characteristic tropism for the mucusproducing gastric epithelium. In infected patients, H. pylori colocalizes in situ with the gastric secretory mucin MUC5AC. The carbohydrate blood-group antigen Lewis B (LeB) was deemed responsible for the adherence of H. pylori to the gastric surface epithelium. We sought to determine if MUC5AC is the carrier of LeB, and thus if MUC5AC is the underlying gene product functioning as the main receptor for H. pylori in the stomach.

Methods. We studied three types of human tissue producing MUC5AC: Barrett’s esophagus (BE), normal gastric tissue, and gastric metaplasia of the duodenum (GMD). Tissue sections were immunofluorescently stained for MUC5AC or LeB, and subsequently incubated with one of three strains of Texas red-labeled H. pylori , one of which was unable to bind to LeB. We determined the colocalization of MUC5AC or LeB with adherent H. pylori.

Results. The binding patterns for the two LeBbinding strains to all tissues were similar, whereas the strain unable to bind to LeB did not bind to any of the tissues. In normal gastric tissue, the LeBbinding strains always bound to MUC5AC- and LeBpositive epithelial cells. In four nonsecretor patients, colocalization of the LeB-binding strains was found to MUC5AC-positive gastric epithelial cells. In BE, the LeB-binding H. pylori strains colocalized very specifically to MUC5AC-positive cells. MUC5ACproducing cells in GMD contained LeB. Yet, LeBbinding H. pylori not only colocalized to MUC5AC or LeB present in GMD, but also bound to the LeBpositive brush border of normal duodenal epithelium. Conclusions. Mucin MUC5AC is the most important carrier of the LeB carbohydrate structure in normal gastric tissue and forms the major receptor for H. pylori.

Keyword
adhesion, helicobacter pylori, mucin, MUC5AC, Barrett’s esophagus, gastric metaplasia, Lewis B blood group antigen
National Category
Dentistry
Identifiers
urn:nbn:se:umu:diva-3971 (URN)10.1046/j.1523-5378.2003.00173.x (DOI)14535999 (PubMedID)
Available from: 2004-05-10 Created: 2004-05-10 Last updated: 2011-03-30Bibliographically approved
2. Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation
Open this publication in new window or tab >>Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation
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2002 (English)In: Science, ISSN 0036-8075, Vol. 297, no 5581, 573-578 p.Article in journal (Refereed) Published
Abstract [en]

Helicobacter pylori adherence in the human gastric mucosa involves specific bacterial adhesins and cognate host receptors. Here, we identify sialyl-dimeric-Lewis x glycosphingolipid as a receptor for H. pylori and show that H. pylori infection induced formation of sialyl-Lewis x antigens in gastric epithelium in humans and in a Rhesus monkey. The corresponding sialic acid-binding adhesin (SabA) was isolated with the "retagging" method, and the underlying sabA gene (JHP662/HP0725) was identified. The ability of many H. pylori strains to adhere to sialylated glycoconjugates expressed during chronic inflammation might thus contribute to virulence and the extraordinary chronicity of H. pylori infection.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-4319 (URN)10.1126/science.1069076 (DOI)12142529 (PubMedID)
Available from: 2004-12-21 Created: 2004-12-21 Last updated: 2011-03-22Bibliographically approved
3. Effects of Helicobacter pylori inoculation on host glycosylation and H. pylori adhesion sites in rhesus monkey
Open this publication in new window or tab >>Effects of Helicobacter pylori inoculation on host glycosylation and H. pylori adhesion sites in rhesus monkey
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(English)Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:umu:diva-3973 (URN)
Available from: 2004-05-10 Created: 2004-05-10 Last updated: 2011-03-30Bibliographically approved
4. Limited role of lipopolysaccharide Lewis antigens in adherence of Helicobacter pylori to the human gastric epithelium
Open this publication in new window or tab >>Limited role of lipopolysaccharide Lewis antigens in adherence of Helicobacter pylori to the human gastric epithelium
2003 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 71, no 5, 2876-2880 p.Article in journal (Refereed) Published
Abstract [en]

In vitro and in vivo studies from various groups have suggested that Helicobacter pylori lipopolysaccharide (LPS) Lewis x (Lex) antigens mediate bacterial adhesion. We have now reevaluated this hypothesis by studying the adherence in situ of H. pylori strain 11637 and its corresponding Lex-negative rfbM mutant to human gastric mucosa from patients (n 22) with various gastric pathologies. Significant binding of the parent strain was observed in only 8 out of 22 sections; in four out of eight patients, the Lex-negative mutant bound less well. One of these four patients displayed no gastric abnormalities, and the other three showed dysplasia, metaplasia, and adenocarcinoma, respectively; hence, we are unable to define the circumstances under which LPS-mediated adhesion takes place. We conclude that H. pylori LPS plays a distinct but minor role in adhesion.

National Category
Dentistry
Identifiers
urn:nbn:se:umu:diva-3974 (URN)10.1128/IAI.71.5.2876-2880.2003 (DOI)12704161 (PubMedID)
Available from: 2004-05-10 Created: 2004-05-10 Last updated: 2010-08-06Bibliographically approved

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