Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Helicobacter pylori: multitalented adaptation of binding properties
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
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 [en]
Helicobacter pylori, adherence, receptor specificity, adaptation, pH, BabA, Leb, recombination, secretor phenotype, recombinant cell lines
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-60751ISBN: 978-91-7459-487-4 (print)OAI: oai:DiVA.org:umu-60751DiVA: diva2:562583
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
List of papers
1. pH regulated H. pylori adherence: implications for persistent infection and disease
Open this publication in new window or tab >>pH regulated H. pylori adherence: implications for persistent infection and disease
Show others...
(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:nbn:se:umu:diva-21487 (URN)
Available from: 2009-04-14 Created: 2009-04-14 Last updated: 2016-05-27Bibliographically approved
2. Clinical isolates of Helicobacter pylori demonstrates alternative BabA-mediated adherence to human gastric mucosa
Open this publication in new window or tab >>Clinical isolates of Helicobacter pylori demonstrates alternative BabA-mediated adherence to human gastric mucosa
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Helicobacter pylori infection is life-long and can cause peptic ulcer disease and gastric cancer. The H. pylori BabA adhesin binds the ABO/Leb blood group (bg) antigens (Leb), which mediates attachment to the gastric epithelium. The prevalence of ABO binding is high worldwide and also in northern Europe. However, prevalence is reduced by 50% in Germany and is further reduced in Spain and Portugal. An inventory of strains from different European populations resulted in strains with high level of BabA expression but very little or no binding to Leb. The majority of such strains could not bind to human gastric mucosa in vitro. We further characterized a Spanish isolates, strain 812, that binds only weakly to soluble Leb-conjugate but still adheres firmly to gastric mucosa indicative of that it might bind to an alternative set of receptor. Receptor analysis by glycan arrays revealed higher binding of strain 812 to ALeb and Bleb glycans than to Leb, indicating that BabA from strain 812 has shifted its binding epitope somewhat away from the central Fuca1.2Gal bg domain and closer to the very terminal bg A and B determinants, i.e. GalNAca1.3Gal (bgA) or the Gala1.3Gal (bgB). By a colony screening approach we identified a subpopulation of 812 clones adapted for stronger Leb binding. Such affinity shifts comes from replacement of distinguishing amino acids by mechanisms of recombination with a BabA-related outer membrane protein.

Keyword
Adhesion, recombination, adaptation
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-60724 (URN)
Available from: 2012-10-25 Created: 2012-10-24 Last updated: 2012-10-26Bibliographically approved
3. Infection by Helicobacter pylori expressing the BabA adhesin is influenced by the secretor phenotype
Open this publication in new window or tab >>Infection by Helicobacter pylori expressing the BabA adhesin is influenced by the secretor phenotype
Show others...
2008 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 215, no 3, 308-316 p.Article in journal (Refereed) Published
Abstract [en]

Helicobacter pylori (Hp) infects half the world's population and causes diverse gastric lesions, from gastritis to gastric cancer. Our aim was to evaluate the significance of secretor and Lewis status in infection and in vitro adherence by Hp expressing BabA adhesin. We enrolled 304 Hp-infected individuals from Northern Portugal. Gastric biopsies, blood and saliva were collected. Polymerase chain reaction (PCR) and immunofluorescence were used to detect BabA+ Hp in gastric biopsies. In vitro adherence by a BabA expressing Hp strain to gastric biopsies was performed. Secretor status was identified by Ulex, a lectin that recognizes secretor-dependent glycan structures in saliva and in gastric mucosa, and by Lewis(a/b) antibodies, and indirectly by identification of an inactivating mutation in the FUT2 gene (G428A). BabA status of infecting Hp was associated with CagA and VacAs1 (p < 0.05), intercellular localization of Hp (p < 0.01) and the presence of intestinal metaplasia (p < 0.05) and degenerative alterations (p < 0.005) in the biopsies. BabA was associated (p < 0.05) with Ulex staining of gastric biopsies and, although not significantly, to absence of homozygosity for FUT2 G428A inactivating polymorphism. In vitro Hp adherence was higher in cases wild-type or heterozygous for FUT2 G428A mutation (p < 0.0001), cases staining for Ulex (p < 0.0001) and a(-)b+ and a(-)b(-) secretor phenotypes (p < 0.001). In conclusion, BabA+ Hp infection/adhesion is secretor-dependent and associated with the severity of gastric lesions.

Keyword
Helicobacter pylori; blood-group antigen binding adhesin (BabA); Lewis antigens; secretor status; gastritis; intestinal metaplasia; stomach; immunofluorescence
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-22412 (URN)10.1002/path.2363 (DOI)18498114 (PubMedID)
Available from: 2009-05-07 Created: 2009-05-07 Last updated: 2012-10-26Bibliographically approved
4. Studies of Lewis antigens and H. pylori adhesion in CHO cell lines engineered to express Lewis b determinants
Open this publication in new window or tab >>Studies of Lewis antigens and H. pylori adhesion in CHO cell lines engineered to express Lewis b determinants
Show others...
2008 (English)In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 18, no 7, 494-501 p.Article in journal (Refereed) Published
Abstract [en]

Many microbes bind and adhere via adhesins to host cell carbohydrates as an initial step for infection. Therefore, cell lines expressing Lewis b (Le(b)) determinants were generated as a potential model system for Helicobacter pylori colonization and infection, and their expression of blood group Lewis determinants was characterized. CHO-K1 cells were stably transfected with selected glycosyltransferase cDNAs, and two Le(b) positive clones, 1C5 and 2C2, were identified. Expression of Lewis (Le(a), Le(b), Le(x), and Le(y)) determinants was analyzed by flow cytometry of intact cells, SDS-PAGE/Western blot of solubilized glycoproteins, and thin layer chromatography immunostaining of isolated glycolipids (GL). Binding of H. pylori to cells was examined by microscopy and quantified. Flow cytometry showed that 1C5 and 2C2 were Le(a) and Le(b) positive. 1C5 expressed Le(b) on O-linked, but not N-linked, glycans and only weakly on GLs. In contrast, 2C2 expressed Le(b) on N-, O-glycans, and GLs. Furthermore, both clones expressed Le(a) on N- and O-glycans but not on GLs. 2C2, but not 1C5, stained positively for Le(y) on N-linked glycans and GLs. Both clones, as well as the parental CHO-K1 cells, expressed Le(x) on GLs. A Le(b)-binding H. pylori strain bound to the 1C5 and 2C2 cells. In summary, two glycosyltransferase transfected CHO-K1 cell clones differed regarding Lewis antigen expression on N- and O-linked glycans as well as on GLs. Both clones examined supported adhesion of a Le(b)-binding H. pylori strain and may thus be a useful in vitro model system for H. pylori colonization/infection studies.

Keyword
Bacterial adhesion, fucosyltransferase, Helicobacter pylori, Lewis antigens
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-22627 (URN)10.1093/glycob/cwn030 (DOI)18400963 (PubMedID)
Available from: 2009-05-14 Created: 2009-05-14 Last updated: 2012-10-26Bibliographically approved

Open Access in DiVA

fulltext(1481 kB)1220 downloads
File information
File name FULLTEXT01.pdfFile size 1481 kBChecksum SHA-512
a1f394e7f8eaf1b566d2547da50bd1d1ad8f58c5957d6d1d8b43baf3891da37ea5b687ee4a0207382fa50830e0a473a783d94839cb07a486cf83cd0cd61abddb
Type fulltextMimetype application/pdf

Authority records BETA

Henriksson, Sara

Search in DiVA

By author/editor
Henriksson, Sara
By organisation
Department of Medical Biochemistry and Biophysics
Microbiology in the medical area

Search outside of DiVA

GoogleGoogle Scholar
Total: 1220 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 694 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf