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pH regulated H. pylori adherence: implications for persistent infection and disease
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Helicobacter pylori’s BabA adhesin binds strongly to gastric mucosal ABH/Leb glycans on the stomach epithelium and overlying mucus, materials continuously shed into the acidic gastric lumen. Here we report that this binding is acid labile, acid inactivation is fully reversible; and acid lability profiles vary with BabA sequence and correlate with disease patterns. Isogenic H. pylori strains from the gastric antrum and more acidic corpus were identified that differed in acid lability of receptor binding and in sequence near BabA’s carbohydrate binding domain. We propose that reversible acid inactivation of receptor binding helps H. pylori avoid clearance by mucosal shedding, and that strain differences in acid lability affect tissue tropism and the spectrum of associated gastric diseases.

National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-21487OAI: oai:DiVA.org:umu-21487DiVA: diva2:211328
Available from: 2009-04-14 Created: 2009-04-14 Last updated: 2016-05-27Bibliographically approved
In thesis
1. A study of bacterial adhesion on a single-cell level by means of force measuring optical tweezers and simulations
Open this publication in new window or tab >>A study of bacterial adhesion on a single-cell level by means of force measuring optical tweezers and simulations
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The intriguing world of microbiology is nowadays accessible for detailed exploration at a single–molecular level. Optical tweezers are a novel instrument that allows for non–invasive manipulation of single cells by the sole use of laser light and operates on the nano– and micrometer scale which corresponds to the same length scale as living cells. Moreover, forces within the field of microbiology are typically in the picoNewton range which is in accordance with the capability of force measuring optical tweezers systems. Both these conformabilities imply that force measuring optical tweezers is suitable for studies of single living cells. This thesis focuses on the mechanisms of bacterial attachments to host cells which constitute the first step in bacterial infection processes. Bacteria bind specifically to host receptors by means of adhesins that are expressed either directly on the bacterial membrane or on micrometer–long adhesion organelles that are called pili. The properties of single adhesin–receptor bonds that mediate adherence of the bacterium Helicobacter pylori are first examined at various acidities. Further on, biomechanical properties of P pili expressed by Escherichia coli are presented to which computer simulations, that capture the complex kinetics of the pili structure and precisely replicate measured data, are applied. Simulations are found to be a powerful tool for investigations of adhesive attributes of binding systems and are utilized in the analyses of the specific binding properties of P pili on a single–pilus level. However, bacterial binding systems generally involve a multitude of adhesin–receptor bonds. To explore bacterial attachments, the knowledge from single–pilus studies is brought into a full multipili attachment scenario which is analyzed by means of theoretical treatments and simulations. The results are remarkable in several aspects. Not only is it found that the intrinsic properties of P pili are composed in an optimal combination to promote strong multipili bindings. The properties of the pili structure itself are also found to be optimized with respect to its in vivo environment. Indeed, the true meaning of the attributes derived at a single–pilus level cannot be unraveled until a multipili–binding system is considered. Whereas detailed studies are presented for the helix–like P pili expressed by Gram–negative Escherichia coli, conceptual studies are presented for the open coil–like T4 pili expressed by Gram–positive Streptococcus pneumoniae. The structural and adhesive properties of these two types of pili differ considerably. These dissimilarities have far–reaching consequences on the adhesion possibilities at both single–pilus and multipili levels which are discussed qualitatively. Moreover, error analyses of conventional data processing methods in dynamic force spectroscopy as well as development of novel analysis methods are presented. These findings provide better understanding of how to perform refined force measurements on single adhesion organelles as well as how to improve the analyses of measurement data to obtain accurate parameter values of biomechanical entities. In conclusion, this thesis comprises a study of bacterial adhesion organelles and the way they cooperate to establish efficient attachment systems that can successfully withstand strong external forces that acts upon bacteria. Such systems can resist, for instance, rinsing effects and thereby allow bacteria to colonize their host. By understanding the complexity, and thereby possible weaknesses, of bacterial attachments, new targets for combating bacterial infections can be identified.

Place, publisher, year, edition, pages
Umeå: Print & Media, 2009. 108 p.
National Category
Physical Sciences
Research subject
Physics; cellforskning; Molecular Cellbiology
Identifiers
urn:nbn:se:umu:diva-21493 (URN)978-91-7264-765-7 (ISBN)
Public defence
2009-05-08, N420, Naturvetarhuset, Umeå Universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2009-04-17 Created: 2009-04-14 Last updated: 2009-04-17Bibliographically approved
2. Helicobacter pylori: multitalented adaptation of binding properties
Open this publication in new window or tab >>Helicobacter pylori: multitalented adaptation of binding properties
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Helicobacter pylori infects and persistently colonizes the stomach, which results in gastritis and in some individuals peptic ulcer disease or gastric cancer. Adherence of H. pylori to the epithelium is an important factor for development of disease. Attachment is mediated by the adhesins BabA and SabA that binds the ABO/Leb blood group antigens and sialylated glycoconjugates respectively.  High-affinity attachment could be anticipated to be of disadvantage for H. pylori because epithelial cells have a fast turnover rate and the dislocated and shed epithelial cells would carry attached bacteria to the acidic gastric juice in the lumen. However, here we describe that H. pylori manage to adapt to this innate clearance mechanism by unique acid regulatory binding properties of its adhesins. We propose that pH regulated binding properties enable bacteria to detachment from host cells for chemotactic guided motility and successful return to the more neutral epithelium for a fresh restart of the infectious cycle. By comparison of BabA from different stomach loci we identified amino acid key position for acid regulated binding activity.

Previous studies found lower prevalence of Leb-binding among H. pylori isolates from southern Europe compared to Sweden. Here we tested if the reduced prevalence of Leb-binding could be explained by a novel binding mode; in among Spanish strains, we identified S812 that demonstrates preference for multivalent binding to ABO antigens in glycolipids; we found that 812 BabA had drifted in its preferred binding epitope away from the consensus a1,2fucosylation and towards the blood group A and B derivatives. Such epitope drift might in particular optimize binding to ABO antigens in densely packed lipid rafts.

In parallel, we studied the influence of BabA for disease progression by an inventory of gastric biopsies. BabA correlated both with the oncoprotein CagA, the VacAs1 toxin and, in addition, to severe disease progression. We further correlate BabA expression with positive secretor phenotype and stronger adhesion of H. pylori in vitro.

For functional adherence studies in vitro, we constructed a recombinant Leb-expressing cell lineage that supports BabA mediated H. pylori attachment.

Place, publisher, year, edition, pages
Umeå: Umeå university, 2012. 52 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1524
Keyword
Helicobacter pylori, adherence, receptor specificity, adaptation, pH, BabA, Leb, recombination, secretor phenotype, recombinant cell lines
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-60751 (URN)978-91-7459-487-4 (ISBN)
Public defence
2012-11-16, KB3A9, KBC-huset, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2012-10-26 Created: 2012-10-25 Last updated: 2012-10-26Bibliographically approved
3. Diversity and adaptation in the adherence properties of Helicobacter pylori
Open this publication in new window or tab >>Diversity and adaptation in the adherence properties of Helicobacter pylori
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2014. 39 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1602
Keyword
Helicobacter pylori, transmission, phylogeny, native populations, bacterial adherence, BabA adhesin, receptor specificity, functional polymorphism, genetic diversity, adaptation
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-84597 (URN)978-91-7459-734-9 (ISBN)
Public defence
2014-01-24, Naturvetarhuset, N300, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2014-01-10 Created: 2014-01-10 Last updated: 2014-12-17Bibliographically approved

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Bugaytsova, JeannaBjörnhamn, OscarHenriksson, SaraJohansson, PärMendez, MelissaSjöström, RolfBrännström, KristofferAisenbrey, ChristopherShevtsova, AnnaBylund, GöranGröbner, GerhardSchedin, StaffanArnqvist, AnnaBorén, Thomas
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