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Adaptation of Helicobacter pylori Adherence Properties in Promotion of Host Tropism and Inflammatory Disease
Umeå University, Faculty of Medicine, Odontology, Oral Microbiology.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Being among the most prevalent of persistent infectious agents in humans worldwide, Helicobacter pylori induces chronic inflammation (gastritis), which may progress to peptic ulceration and stomach cancer. The ability to adhere to the gastric mucosa is considered to be both a colonization and virulence property of H. pylori. For adherence, H. pylori expresses surface-located attachment proteins (adhesins) that bind to specific receptors in the gastric mucosa. The best characterized H. pylori adhesin-receptor interaction is that between the blood group antigen binding adhesin (BabA) and the fucosylated blood group antigens, which are glycans highly expressed in the gastric mucosa.

Our recent results have changed the view of the blood group antigen-specific binding mode of H. pylori. We have tested clinical isolates of H. pylori from human populations worldwide for their ability to bind to ABO blood group antigens. The results revealed that more than 95% of isolates from Sweden, Germany, Spain, Japan and Alaska that bind fucosylated blood group antigens, bind both the Lewis b antigen (Leb) (of blood group O) and the blood group A-related antigen A-Lewis b, i.e. they exhibit a generalist type of binding mode. In contrast, the majority of strains (62%) from South American Amerindians bound best to Leb, i.e. they exhibit a specialist blood group “O antigen” binding mode. This specialization in binding coincides with the unique predominance of blood group O in the South American Amerindian populations. Furthermore, we also showed that H. pylori could switch from specialist to generalist binding modes by chromosomal integration of foreign babA gene fragments.

A mutant strain lacking the babA gene turned out to adhere to inflamed gastric epithelium, despite the fact that it did not bind Leb. We identified the receptor to which the mutant binds to as the sialyl-dimeric-Lewis x antigen (sdiLex) and found its expression to be associated with persistent H. pylori infection and chronic inflammation, both in humans and Rhesus monkeys. The cognate sialic acid binding adhesin (SabA) was identified by our ReTagging technique. Deletion of sabA caused loss of H. pylori binding to sialylated glycans, and screening of single colony isolates revealed a high frequency of spontaneous on⇒off phase variation in sLex binding.

Using erythrocytes as a model for sialyl dependent cell adhesion, we could show that SabA is the sought-after H. pylori sialyl-dependent hemagglutinin. Swedish clinical H. pylori isolates were analyzed for sialyl-dependent hemagglutination (sia-HA), and the sia-HA titers were found to be highly correlated to the levels of sLex binding. Clinical isolates were shown to exhibit several distinct binding modes for sialylated glycans, which suggest that SabA exhibit polymorphism in binding. We also found that SabA binds to sialylated glycans on neutrophil surfaces by mechanisms involving “selectin mimicry”, and that SabA plays an important role in nonopsonic activation of neutrophils.

In the human stomach, H. pylori is exposed to selective pressures such as immune and inflammatory responses, and this is reflected by changes in mucosal glycosylation patterns. The high mutation and recombination rates of H. pylori in combination with bio selection will continuously generate clones that are adapted to changes in individual gastric mucosa. Such adaptive selection contributes to the remarkable diversity in binding modes and to the extraordinary chronicity of H. pylori infections worldwide.

Place, publisher, year, edition, pages
2004. , 68 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 87
Keyword [en]
H. pylori, BabA, SabA, adhesin, blood group antigens, sialylated, phase variation, hemagglutination, selectin, adaptation
Research subject
URN: urn:nbn:se:umu:diva-388ISBN: 91-7305-736-3OAI: diva2:143355
Public defence
2004-11-30, KB3A9, KBC-huset, Umeå, 13:00 (English)
Available from: 2004-12-21 Created: 2004-12-21 Last updated: 2009-12-08Bibliographically approved
List of papers
1. Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin.
Open this publication in new window or tab >>Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin.
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2004 (English)In: Science, ISSN 0036-8075, Vol. 305, no 5683, 519-522 p.Article in journal (Refereed) Published
Abstract [en]

Adherence by Helicobacter pylori increases the risk of gastric disease. Here, we report that more than 95% of strains that bind fucosylated blood group antigen bind A, B, and O antigens (generalists), whereas 60% of adherent South American Amerindian strains bind blood group O antigens best (specialists). This specialization coincides with the unique predominance of blood group O in these Amerindians. Strains differed about 1500-fold in binding affinities, and diversifying selection was evident in babA sequences. We propose that cycles of selection for increased and decreased bacterial adherence contribute to babA diversity and that these cycles have led to gradual replacement of generalist binding by specialist binding in blood group O-dominant human populations.

ABO Blood-Group System/*metabolism, Adaptation; Biological, Adhesins; Bacterial/chemistry/*genetics/immunology/*metabolism, Alleles, Bacterial Adhesion, Base Sequence, Binding Sites, Evolution; Molecular, Fucose/metabolism, Gastric Mucosa/microbiology, Helicobacter Infections/microbiology, Helicobacter pylori/genetics/immunology/*physiology, Humans, Indians; South American, Lewis Blood-Group System/metabolism, Molecular Sequence Data, Mutation, Peru, Phenotype, Phylogeny, Protein Binding, Selection (Genetics), Transformation; Bacterial
urn:nbn:se:umu:diva-6649 (URN)10.1126/science.1098801 (DOI)15273394 (PubMedID)
Available from: 2008-01-08 Created: 2008-01-08 Last updated: 2011-03-22Bibliographically 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
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. The Helicobacter pylori SabA Adhesin Exhibits Polymorphism in Binding and is the Same as the Sialic Acid Specific Hemagglutinin
Open this publication in new window or tab >>The Helicobacter pylori SabA Adhesin Exhibits Polymorphism in Binding and is the Same as the Sialic Acid Specific Hemagglutinin
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(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
urn:nbn:se:umu:diva-4320 (URN)
Available from: 2004-12-21 Created: 2004-12-21 Last updated: 2012-05-04Bibliographically approved
4. The sialic acid binding SabA adhesin of Helicobacter pylori is essential for nonopsonic activation of human neutrophils.
Open this publication in new window or tab >>The sialic acid binding SabA adhesin of Helicobacter pylori is essential for nonopsonic activation of human neutrophils.
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2005 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 280, no 15, 15390-15397 p.Article in journal (Refereed) Published
Abstract [en]

Infiltration of neutrophils and monocytes into the gastric mucosa is a hallmark of chronic gastritis caused by Helicobacter pylori. Certain H. pylori strains nonopsonized stimulate neutrophils to production of reactive oxygen species causing oxidative damage of the gastric epithelium. Here, the contribution of some H. pylori virulence factors, the blood group antigen-binding adhesin BabA, the sialic acid-binding adhesin SabA, the neutrophil-activating protein HP-NAP, and the vacuolating cytotoxin VacA, to the activation of human neutrophils in terms of adherence, phagocytosis, and oxidative burst was investigated. Neutrophils were challenged with wild type bacteria and isogenic mutants lacking BabA, SabA, HP-NAP, or VacA. Mutant and wild type strains lacking SabA had no neutrophil-activating capacity, demonstrating that binding of H. pylori to sialylated neutrophil receptors plays a pivotal initial role in the adherence and phagocytosis of the bacteria and the induction of the oxidative burst. The link between receptor binding and oxidative burst involves a G-protein-linked signaling pathway and downstream activation of phosphatidylinositol 3-kinase as shown by experiments using signal transduction inhibitors. Collectively our data suggest that the sialic acid-binding SabA adhesin is a prerequisite for the nonopsonic activation of human neutrophils and, thus, is a virulence factor important for the pathogenesis of H. pylori infection.

1-Phosphatidylinositol 3-Kinase/metabolism, Adhesins; Bacterial/chemistry/metabolism/*physiology, Animals, Bacterial Adhesion, Bacterial Proteins/chemistry, Chromatography; High Pressure Liquid, Chromatography; Thin Layer, Cytotoxins/chemistry, Electrophoresis; Polyacrylamide Gel, Granulocytes/metabolism, Helicobacter pylori/*metabolism, Humans, Hydrogen Peroxide/pharmacology, Magnetic Resonance Spectroscopy, N-Acetylneuraminic Acid/*metabolism, Neutrophils/chemistry/*metabolism/*microbiology, Oligonucleotides/chemistry, Oxidative Stress, Phagocytosis, Protein Binding, Reactive Oxygen Species, Respiratory Burst, Signal Transduction, Time Factors
urn:nbn:se:umu:diva-6647 (URN)10.1074/jbc.M412725200 (DOI)15689619 (PubMedID)
Available from: 2007-12-16 Created: 2007-12-16 Last updated: 2011-03-30Bibliographically approved

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