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Gideonsson, Pär
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Publications (10 of 11) Show all publications
Skoog, E. C., Padra, M., Åberg, A., Gideonsson, P., Obi, I., Quintana-Hayashi, M. P., . . . Linden, S. K. (2017). BabA dependent binding of Helicobacter pylori to human gastric mucins cause aggregation that inhibits proliferation and is regulated via ArsS. Scientific Reports, 7, Article ID 40656.
Open this publication in new window or tab >>BabA dependent binding of Helicobacter pylori to human gastric mucins cause aggregation that inhibits proliferation and is regulated via ArsS
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 40656Article in journal (Refereed) Published
Abstract [en]

Mucins in the gastric mucus layer carry a range of glycan structures, which vary between individuals, can have antimicrobial effect or act as ligands for Helicobacter pylori. Mucins from various individuals and disease states modulate H. pylori proliferation and adhesin gene expression differently. Here we investigate the relationship between adhesin mediated binding, aggregation, proliferation and adhesin gene expression using human gastric mucins and synthetic adhesin ligand conjugates. By combining measurements of optical density, bacterial metabolic activity and live/dead stains, we could distinguish bacterial aggregation from viability changes, enabling elucidation of mechanisms behind the anti-prolific effects that mucins can have. Binding of H. pylori to Leb-glycoconjugates inhibited the proliferation of the bacteria in a BabA dependent manner, similarly to the effect of mucins carrying Leb. Furthermore, deletion of arsS lead to a decrease in binding to Leb-glycoconjugates and Leb-decorated mucins, accompanied by decreased aggregation and absence of anti-prolific effect of mucins and Leb-glycoconjugates. Inhibition of proliferation caused by adhesin dependent binding to mucins, and the subsequent aggregation suggests a new role of mucins in the host defense against H. pylori. This aggregating trait of mucins may be useful to incorporate into the design of adhesin inhibitors and other disease intervention molecules.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-132309 (URN)10.1038/srep40656 (DOI)000392344400001 ()28106125 (PubMedID)
Available from: 2017-04-07 Created: 2017-04-07 Last updated: 2018-06-09Bibliographically approved
Hansen, L. M., Gideonsson, P., Canfield, D. R., Borén, T. & Solnick, J. V. (2017). Dynamic Expression of the BabA Adhesin and Its BabB Paralog during Helicobacter pylori Infection in Rhesus Macaques. Infection and Immunity, 85(6), Article ID e00094.
Open this publication in new window or tab >>Dynamic Expression of the BabA Adhesin and Its BabB Paralog during Helicobacter pylori Infection in Rhesus Macaques
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2017 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 85, no 6, article id e00094Article in journal (Refereed) Published
Abstract [en]

Most Helicobacter pylori strains express the BabA adhesin, which binds to ABO/Leb blood group antigens on gastric mucin and epithelial cells and is found more commonly in strains that cause peptic ulcers or gastric cancer, rather than asymptomatic infection. We and others have previously reported that in mice, gerbils, and rhesus macaques, expression of babA is lost, either by phase variation or by gene conversion, in which the babB paralog recombines into the babA locus. The functional significance of loss of babA expression is unknown. Here we report that in rhesus monkeys, there is independent selective pressure for loss of babA and for overexpression of BabB, which confers a fitness advantage. Surprisingly, loss of babA by phase variation or gene conversion is not dependent on the capacity of BabA protein to bind Leb, which suggests that it may have other, unrecognized functions. These findings have implications for the role of outer membrane protein diversity in persistent H. pylori infection.

Place, publisher, year, edition, pages
AMER SOC MICROBIOLOGY, 2017
Keywords
Helicobacter pylori, adhesin, babA, rhesus
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-138236 (URN)10.1128/IAI.00094-17 (DOI)000405937200005 ()
Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2018-06-09Bibliographically approved
Bugaytsova, J. A., Björnham, O., Chernov, Y. A., Gideonsson, P., Henriksson, S., Mendez, M., . . . Boren, T. (2017). Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence. Cell Host and Microbe, 21(3), 376-389
Open this publication in new window or tab >>Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence
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2017 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 21, no 3, p. 376-389Article in journal (Refereed) Published
Abstract [en]

The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.

Place, publisher, year, edition, pages
CELL PRESS, 2017
National Category
Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-132788 (URN)10.1016/j.chom.2017.02.013 (DOI)000396375600023 ()28279347 (PubMedID)
Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2019-05-24Bibliographically approved
Kable, M. E., Hansen, L. M., Styer, C. M., Deck, S. L., Rakhimova, O., Shevtsova, A., . . . Solnick, J. V. (2017). Host Determinants of Expression of the Helicobacter pylori BabA Adhesin. Scientific Reports, 7, Article ID 46499.
Open this publication in new window or tab >>Host Determinants of Expression of the Helicobacter pylori BabA Adhesin
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 46499Article in journal (Refereed) Published
Abstract [en]

Expression of the Helicobacter pylori blood group antigen binding adhesin A (BabA) is more common in strains isolated from patients with peptic ulcer disease or gastric cancer, rather than asymptomatic colonization. Here we used mouse models to examine host determinants that affect H. pylori BabA expression. BabA expression was lost by phase variation as frequently in WT mice as in RAG2-/- mice that do not have functional B or T cells, and in MyD88-/-, TLR2-/- and TLR4-/- mice that are defective in toll like receptor signaling. The presence of other bacteria had no effect on BabA expression as shown by infection of germ free mice. Moreover, loss of BabA expression was not dependent on Le(b) expression or the capacity of BabA to bind Leb. Surprisingly, gender was the host determinant most associated with loss of BabA expression, which was maintained to a greater extent in male mice and was associated with greater bacterial load. These results suggest the possibility that loss of BabA expression is not driven by adaptive immunity or toll-like receptor signaling, and that BabA may have other, unrecognized functions in addition to serving as an adhesin that binds Le(b).

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-134722 (URN)10.1038/srep46499 (DOI)000399367000001 ()28418004 (PubMedID)
Available from: 2017-05-19 Created: 2017-05-19 Last updated: 2018-06-09Bibliographically approved
Gideonsson, P. (2016). Helicobacter pylori: molecular insights into regulation of adhesion properties. (Doctoral dissertation). Umeå: Umeå universitet
Open this publication in new window or tab >>Helicobacter pylori: molecular insights into regulation of adhesion properties
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Helicobacter pylori infects the human stomach and triggers an inflammatory response that damages the gastric tissue. This host-pathogen interplay has dire consequences as up to 20 % of infected individuals develop peptic ulcer disease or gastric cancer. Given that half of the world’s population is infected, the number of afflicted humans is staggering and also tells that H. pylori is extremely efficient in spreading and maintaining infection. To enable persistent infection many factors play a role, but one important feature of H. pylori is its impressive ability to adhere to the slimy gastric mucus layer and the underlying epithelial cells. This occurs mainly via the BabA and SabA proteins that bind ABO/Leb- and sLex/sLea-antigens. I have in my thesis studied how these two proteins are utilized and regulated.

H. pylori transcription is in part controlled by two-component systems (TCSs) that use a sensor protein and a DNA-binding response regulator. We have studied how these systems control sabA and to some extent babA and indeed found a better map of how sabA and babA is regulated at the transcriptional level. We also found that variations in a polynucleotide T-tract located in the sabA promotor could fine-tune SabA expression/ sLex-binding. Thus we have exposed how strict regulation by TCSs combined with stochastic processes together shapes attachment in the bacterial population.

As the buffering mucus layer is constantly exfoliated, placing H. pylori in bactericidal acid, we hypothesized that low pH should abrogate adhesion. SabA expression was indeed repressed in low pH, however BabA expression remained unaffected. The BabA/ Leb-binding was instead directly reversibly hampered by low pH and the degree of pH sensitivity was strain dependent and encoded in the BabA sequence. We believe that the pH dependent loss of binding is one key factor H. pylori utilizes to maintain persistent infection.

BabA is divided in generalists that bind ABO antigens and specialists that only bind blood group (bg) O. We co-crystalized BabA bound to these receptors and established the structural basis for generalist vs. specialist discrimination. We furthermore found a disulfide-clasped loop (CL2) in the center of the binding domain crucial for binding. Breaking CL2 with N-Acetylcysteine (NAC) disrupted binding and H. pylori infection mice experiments revealed inflammatory reduction upon NAC-treatment.

In sum, I have in my thesis dissected how H. pylori controls its adhesive abilities and how intrinsic properties in binding can be exploited for therapeutic purposes.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2016. p. 53
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1813
Keywords
Helicobacter pylori
National Category
Microbiology in the medical area
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-120466 (URN)978-91-7601-493-6 (ISBN)
Public defence
2016-06-09, N300, Umeå universitet, Naturvetarhuset, Umeå, 09:00 (English)
Opponent
Supervisors
Funder
The Kempe Foundations
Available from: 2016-05-19 Created: 2016-05-16 Last updated: 2018-06-07Bibliographically approved
Moonens, K., Gideonsson, P., Subedi, S., Bugaytsova, J., Romao, E., Mendez, M., . . . Remaut, H. (2016). Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori. Cell Host and Microbe, 19(1), 55-66
Open this publication in new window or tab >>Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori
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2016 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 19, no 1, p. 55-66Article in journal (Refereed) Published
Abstract [en]

The Helicobacter pylori adhesin BabA binds mucosal ABO/Le b blood group (bg) carbohydrates. BabA facilitates bacterial attachment to gastric surfaces, increasing strain virulence and forming a recognized risk factor for peptic ulcers and gastric cancer. High sequence variation causes BabA functional diversity, but the underlying structural-molecular determinants are unknown. We generated X-ray structures of representative BabA isoforms that reveal a polymorphic, three-pronged Le(b) binding site. Two diversity loops, DL1 and DL2, provide adaptive control to binding affinity, notably ABO versus O bg preference. H. pylori strains can switch bg preference with single DL1 amino acid substitutions, and can coexpress functionally divergent BabA isoforms. The anchor point for receptor binding is the embrace of an ABO fucose residue by a disulfide-clasped loop, which is inactivated by reduction. Treatment with the redox-active pharmaceutic N-acetylcysteine lowers gastric mucosal neutrophil infiltration in H. pylori-infected Le(b)-expressing mice, providing perspectives on possible H. pylori eradication therapies.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-117839 (URN)10.1016/j.chom.2015.12.004 (DOI)000369839900010 ()26764597 (PubMedID)
Available from: 2016-04-04 Created: 2016-03-04 Last updated: 2018-06-07Bibliographically approved
Åberg, A., Gideonsson, P., Vallström, A., Olofsson, A., Öhman, C., Rakhimova, L., . . . Arnqvist, A. (2014). A Repetitive DNA Element Regulates Expression of the Helicobacter pylori Sialic Acid Binding Adhesin by a Rheostat-like Mechanism. PLoS Pathogens, 10(7), Article ID e1004234.
Open this publication in new window or tab >>A Repetitive DNA Element Regulates Expression of the Helicobacter pylori Sialic Acid Binding Adhesin by a Rheostat-like Mechanism
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2014 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 10, no 7, article id e1004234Article in journal (Refereed) Published
Abstract [en]

During persistent infection, optimal expression of bacterial factors is required to match the ever-changing host environment. The gastric pathogen Helicobacter pylori has a large set of simple sequence repeats (SSR), which constitute contingency loci. Through a slipped strand mispairing mechanism, the SSRs generate heterogeneous populations that facilitate adaptation. Here, we present a model that explains, in molecular terms, how an intergenically located T-tract, via slipped strand mispairing, operates with a rheostat-like function, to fine-tune activity of the promoter that drives expression of the sialic acid binding adhesin, SabA. Using T-tract variants, in an isogenic strain background, we show that the length of the T-tract generates multiphasic output from the sabA promoter. Consequently, this alters the H. pylori binding to sialyl-Lewis x receptors on gastric mucosa. Fragment length analysis of post-infection isolated clones shows that the T-tract length is a highly variable feature in H. pylori. This mirrors the host-pathogen interplay, where the bacterium generates a set of clones from which the best-fit phenotypes are selected in the host. In silico and functional in vitro analyzes revealed that the length of the T-tract affects the local DNA structure and thereby binding of the RNA polymerase, through shifting of the axial alignment between the core promoter and UP-like elements. We identified additional genes in H. pylori, with T- or A-tracts positioned similar to that of sabA, and show that variations in the tract length likewise acted as rheostats to modulate cognate promoter output. Thus, we propose that this generally applicable mechanism, mediated by promoter-proximal SSRs, provides an alternative mechanism for transcriptional regulation in bacteria, such as H. pylori, which possesses a limited repertoire of classical trans-acting regulatory factors.

National Category
Physiology Physical Chemistry
Identifiers
urn:nbn:se:umu:diva-91641 (URN)10.1371/journal.ppat.1004234 (DOI)000340551000026 ()24991812 (PubMedID)
Available from: 2014-08-13 Created: 2014-08-13 Last updated: 2018-06-07Bibliographically approved
Bugaytsova, J., Chernov, Y. A., Gideonsson, P., Mendez, M., Henriksson, S., Mahdavi, J., . . . Borén, T.Acid Responsive Helicobacter pylori Adherence: Implications for Chronic Infection and Disease.
Open this publication in new window or tab >>Acid Responsive Helicobacter pylori Adherence: Implications for Chronic Infection and Disease
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(English)Manuscript (preprint) (Other academic)
Keywords
Helicobacter pylori
National Category
Microbiology in the medical area
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-120299 (URN)
Funder
Swedish Research CouncilSwedish Cancer SocietyThe Kempe FoundationsKnut and Alice Wallenberg Foundation
Available from: 2016-05-14 Created: 2016-05-14 Last updated: 2018-06-07
Bugaytsova, J., Björnhamn, O., Henriksson, S., Johansson, P., Mendez, M., Sjöström, R., . . . Borén, T. 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
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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:nbn:se:umu:diva-21487 (URN)
Available from: 2009-04-14 Created: 2009-04-14 Last updated: 2018-06-09Bibliographically approved
Öhman, C., Vallström, A., Olofsson, A., Johansson, P., Larsson, C., Aspholm, M. & Arnqvist, A.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.

Identifiers
urn:nbn:se:umu:diva-25929 (URN)
Available from: 2009-09-13 Created: 2009-09-13 Last updated: 2018-06-08Bibliographically approved
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