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Clinical isolates of Helicobacter pylori demonstrates alternative BabA-mediated adherence to human gastric mucosa
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.ORCID-id: 0000-0003-1615-0583
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
Vise andre og tillknytning
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
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.

Emneord [en]
Adhesion, recombination, adaptation
HSV kategori
Identifikatorer
URN: urn:nbn:se:umu:diva-60724OAI: oai:DiVA.org:umu-60724DiVA, id: diva2:562554
Tilgjengelig fra: 2012-10-25 Laget: 2012-10-24 Sist oppdatert: 2021-11-01bibliografisk kontrollert
Inngår i avhandling
1. Helicobacter pylori: multitalented adaptation of binding properties
Åpne denne publikasjonen i ny fane eller vindu >>Helicobacter pylori: multitalented adaptation of binding properties
2012 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Umeå: Umeå university, 2012. s. 52
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1524
Emneord
Helicobacter pylori, adherence, receptor specificity, adaptation, pH, BabA, Leb, recombination, secretor phenotype, recombinant cell lines
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-60751 (URN)978-91-7459-487-4 (ISBN)
Disputas
2012-11-16, KB3A9, KBC-huset, Umeå, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2012-10-26 Laget: 2012-10-25 Sist oppdatert: 2021-11-01bibliografisk kontrollert

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