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Helicobacter pylori: molecular mechanisms for variable adherence properties
Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics. Umeå University, Faculty of Medicine, Odontology, Oral Microbiology.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

More than half of all people worldwide are infected with H. pylori. The infection always cause a gastric inflammation that may develop into peptic ulcer disease or gastric cancer. Attachment proteins, adhesins, mediate specific adherence of H. pylori to receptor structures on the human gastric mucosa. The best-characterized H. pylori adhesin-receptor interactions are the BabA adhesin and the binding to the fucosylated blood group antigens ABO/Lewis b (Leb) and the SabA adhesin and its binding to the inflammation associated sialyl-Lewis x antigen. During H. pylori infection the availability of receptor structures on the human gastric mucosa changes as a consequence of the host inflammatory and immune responses. Consequently the bacterial population need to adjust its adherence properties to stay colonized. This thesis describes mechanisms that generate H. pylori populations with variable adherence properties and mechanisms for adjustment of adhesin expression levels.In H. pylori strains devoid of Leb-binding, we found bacterial cells with Leb-binding. Isolation of such H. pylori clones demonstrated that the change in receptor binding phenotype was obtained via the mechanisms of homologous recombination and slipped strand mispairing (SSM). Disease presentation in relation to BabA expression was studied in H. pylori infected Mongolian gerbils. We showed that BabA was not essential for colonization but caused severe injury to the gastric mucosa and was turned off during long-term infection by nucleotide changes within the babA gene. Gerbils infected with BabA-weak-expressing strains maintained BabA expressing clones for a longer period than gerbils that were infected with BabA-high-expressing strains. Studies of the gerbil gastric mucosal glycosylation showed that gerbils respond in a similar way as humans and Rhesus monkeys which support gerbils to be a model suitable for studying H. pylori infection and disease outcome in relation to adherence.We studied the SSM mechanism of SabA phase variation and the cognate shift in sLex-binding phenotype and we show sLex-binding activity to be growth phase dependent. H. pylori vesicles were characterized for the major phosholipid and protein components. Virulence factors e.g., VacA, and CagA were identified and both the BabA and the SabA adhesins was shown to be located on the vesicle surface and to mediate specific binding to their cognate receptors present on the human gastric mucosa. H. pylori generate bacterial cells with different receptor binding phenotypes via the mechanisms of homologous recombination, SSM and nucleotide changes. These mechanisms will probably contribute to bacterial fitness by the generation of quasi species populations where some of the clones will be better adapted to the environmental chances during persistent infection.

Place, publisher, year, edition, pages
Umeå: Umeå university , 2009. , 57 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1280
Keyword [en]
H. pylori, adherence, BabA, SabA, Leb, sLex, phase variation, recombination, vesicles
URN: urn:nbn:se:umu:diva-25931ISBN: 978-91-7264-820-3OAI: diva2:235107
Oral mikrobiologi, 901 87, Umeå
Public defence
2009-10-09, KBC3A9, plan 3, KBC-huset, Umeå Universitet, Umeå, 09:00 (English)
Available from: 2009-09-21 Created: 2009-09-13 Last updated: 2009-09-21Bibliographically approved
List of papers
1. Metastability of Helicobacter pylori bab adhesin genes and dynamics in Lewis b antigen binding
Open this publication in new window or tab >>Metastability of Helicobacter pylori bab adhesin genes and dynamics in Lewis b antigen binding
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2004 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, no 48, 16923-16928 p.Article in journal (Refereed) Published
Adhesins; Bacterial/*genetics/immunology, Base Sequence, Blotting; Northern, Blotting; Southern, Helicobacter pylori/*genetics, Lewis Blood-Group System/*immunology, Microscopy; Fluorescence, Molecular Sequence Data, RNA; Messenger/genetics, Recombinant Fusion Proteins/immunology
urn:nbn:se:umu:diva-6648 (URN)10.1073/pnas.0404817101 (DOI)15557006 (PubMedID)
Available from: 2007-12-16 Created: 2007-12-16 Last updated: 2011-03-22Bibliographically approved
2. Effects of BabA expression during H. pylori infection of Mongolian gerbils
Open this publication in new window or tab >>Effects of BabA expression during H. pylori infection of Mongolian gerbils
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective: Helicobacter pylori outer membrane proteins, such as the BabA adhesin are associated with severe pathological outcome.  However, the in vivo role of the BabA adhesin during long-term infection is not clear.  Design and Setting: Mongolian gerbils were inoculated with the H. pylori TN2GF4 and were necropsied at 1, 3, 6, and 18 months.  Main outcome measures: Bacterial clones recovered from the infected gerbils were evaluated by immunoblot for BabA expression, radioimmunoassay for Leb-binding, and bacterial binding to gastric tissue.  H1 antigen expression and the increase in sialylation levels were monitored by immunohistochemistry.  Results: BabA expression increased, then progressively decreased, and was completely absent by 6 months post-infection.  Loss of BabA expression was caused by nucleotide changes/deletions within the babA gene that resulted in a truncated BabA.  Infection with a BabA-expressing H. pylori caused severe mucosal injury, whereas infection with a BabA non-expressing strain caused only mild inflammation.  In response to the infection, changes in the epithelial glycosylation pattern were observed, similar to responses observed in humans and monkeys.  Conclusion: Down-regulation of BabA is probably a result of adaptation to the host response during long-term H. pylori infection.  BabA expression is most likely not essential for colonisation, but for the obtained gerbil host response, which confirms the role of BabA adhesin as a virulence factor and its impact in the induction of a severe inflammatory response.  The changes in glycosylation of gastric mucosa demonstrate the relevance of the Mongolian gerbil as a model for H. pylori infection and host responses.

urn:nbn:se:umu:diva-25930 (URN)
Available from: 2009-09-13 Created: 2009-09-13 Last updated: 2011-03-22Bibliographically approved
3. Phase variation and expression mechanisms of the sialic acid binding adhesin SabA in Helicobacter pylori
Open this publication in new window or tab >>Phase variation and expression mechanisms of the sialic acid binding adhesin SabA in Helicobacter pylori
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Bacterial attachment to host epithelial surfaces by means of bacterial adhesion proteins is a key event in colonization. Phase variation is a mechanism used by bacteria that mediates frequent and reversible gains and losses in expression of proteins. In the inflamed stomach, H. pylori adherence to sialyl Lewis antigens (sLex) is mediated by the sialic acid binding adhesin (SabA). Instability in sLex-binding was previously reported and here we show that this is caused by the high frequency of ON/OFF switching in SabA expression. Our data shows that SabA phase variation is due to slippages in the number of CT repeat sequences in the 5’ end of the sabA gene (i.e. slipped strand mispairing). The sabA operon was defined and the sabA transcriptional start site was determined. Changes in the number of thymine bases present in a mononucleotide stretch upstream of the sabA gene and in close proximity to a -35-like promoter element did not affect the ON/OFF phase variation. Instead, we show that changes in intrinsic DNA properties are likely to influence SabA expression. The effect of growth phase on sLex-binding properties and SabA expression was also analyzed. SabA expression and sLex-binding increased as H. pylori entered late logarithmic phase. Our data show the ability of H. pylori to cycle between an adherent and non-adherent phenotype by phase variation mechanisms and adjustment of receptor binding activity. These data increase our understanding of how H. pylori adjust adherence properties during persistent infection.

urn:nbn:se:umu:diva-25929 (URN)
Available from: 2009-09-13 Created: 2009-09-13 Last updated: 2011-03-22Bibliographically approved
4. Characterization of Helicobacter pylori vesicles and their cognate properties for intimate host interactions
Open this publication in new window or tab >>Characterization of Helicobacter pylori vesicles and their cognate properties for intimate host interactions
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(English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351XArticle in journal (Refereed) Submitted
urn:nbn:se:umu:diva-25737 (URN)
Available from: 2009-09-01 Created: 2009-09-01 Last updated: 2011-03-22Bibliographically approved

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