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BETA
Boren, Thomas
Alternative names
Publications (10 of 72) Show all publications
Jin, C., Barone, A., Boren, T. & Sandberg, S. (2018). Helicobacter pylori-binding nonacid glycosphingolipids in the human stomach. Journal of Biological Chemistry, 293(44), 17248-17266
Open this publication in new window or tab >>Helicobacter pylori-binding nonacid glycosphingolipids in the human stomach
2018 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, no 44, p. 17248-17266Article in journal (Refereed) Published
Abstract [en]

Helicobacter pylori has a number of well-characterized carbohydrate-binding adhesins (BabA, SabA, and LabA) that promote adhesion to the gastric mucosa. In contrast, information on the glycoconjugates present in the human stomach remains unavailable. Here, we used MS and binding of carbohydrate-recognizing ligands to characterize the glycosphingolipids of three human stomachs from individuals with different blood group phenotypes (O(Rh-)P, A(Rh+)P, and A(Rh+)p), focusing on compounds recognized by H. pylori. We observed a high degree of structural complexity, and the composition of glycosphingolipids differed among individuals with different blood groups. The type 2 chain was the dominating core chain of the complex glycosphingolipids in the human stomach, in contrast to the complex glycosphingolipids in the human small intestine, which have mainly a type 1 core. H. pylori did not bind to the O(Rh-)P stomach glycosphingolipids, whose major complex glycosphingolipids were neolactotetraosylceramide, the Lex, Lea, and H type 2 pentaosylceramides, and the Ley hexaosylceramide. Several H. pylori-binding compounds were present among the A(Rh+)P and A(Rh+)p stomach glycosphingolipids. Ligands for BabA-mediated binding of H. pylori were the Leb hexaosylceramide, the H type 1 pentaosylceramide, and the A type 1/ALeb heptaosylceramide. Additional H. pylori-binding glycosphingolipids recognized by BabA-deficient strains were lactosylceramide, lactotetraosylceramide, the x2 pentaosylceramide, and neolactohexaosylceramide. Our characterization of human gastric receptors required for H. pylori adhesion provides a basis for the development of specific compounds that inhibit the binding of this bacterium to the human gastric mucosa.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2018
Keywords
Helicobacter pylori, mass spectrometry (MS), glycolipid structure, adhesin, carbohydrate structure, ycoconjugate, virulence factor, gastric mucosa, glycosphingolipid characterization, H, pylori BabA hesin, Human gastric glycosphingolipids, microbial adhesion
National Category
Biochemistry and Molecular Biology Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-153648 (URN)10.1074/jbc.RA118.004854 (DOI)000449466500024 ()30232154 (PubMedID)
Available from: 2018-11-27 Created: 2018-11-27 Last updated: 2018-11-27Bibliographically 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
Esberg, A., Sheng, N., Mårell, L., Claesson, R., Persson, K., Borén, T. & Strömberg, N. (2017). Streptococcus Mutans Adhesin Biotypes that Match and Predict Individual Caries Development. EBioMedicine, 24, 205-215
Open this publication in new window or tab >>Streptococcus Mutans Adhesin Biotypes that Match and Predict Individual Caries Development
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2017 (English)In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 24, p. 205-215Article in journal (Refereed) Published
Abstract [en]

Dental caries, which affects billions of people, is a chronic infectious disease that involves Streptococcus mutans, which is nevertheless a poor predictor of individual caries development. We therefore investigated if adhesin types of S.mutans with sucrose-independent adhesion to host DMBT1 (i.e. SpaP A, B or C) and collagen (i.e. Cnm, Cbm) match and predict individual differences in caries development. The adhesin types were measured in whole saliva by qPCR in 452 12-year-old Swedish children and related to caries at baseline and prospectively at a 5-year follow-up. Strains isolated from the children were explored for genetic and phenotypic properties. The presence of SpaP B and Cnm subtypes coincided with increased 5-year caries increment, and their binding to DMBT1 and saliva correlated with individual caries scores. The SpaP B subtypes are enriched in amino acid substitutions that coincided with caries and binding and specify biotypes of S. mutans with increased acid tolerance. The findings reveal adhesin subtypes of S. mutans that match and predict individual differences in caries development and provide a rationale for individualized oral care.

Keywords
Adhesion, Chronic infections, Dental caries, SpaP, Streptococcus mutans, Virulence
National Category
Dentistry
Identifiers
urn:nbn:se:umu:diva-140203 (URN)10.1016/j.ebiom.2017.09.027 (DOI)000414392900033 ()28958656 (PubMedID)
Funder
Swedish Research Council, 10906
Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2018-06-09Bibliographically approved
Saberi, S., Schmidt, A., Eybpoosh, S., Esmaili, M., Talebkhan, Y., Mohajerani, N., . . . Mohammadi, M. (2016). Helicobacter pylori Strains from Duodenal Ulcer Patients Exhibit Mixed babA/B Genotypes with Low Levels of BabA Adhesin and Lewis b Binding. Digestive Diseases and Sciences, 61(10), 2868-2877
Open this publication in new window or tab >>Helicobacter pylori Strains from Duodenal Ulcer Patients Exhibit Mixed babA/B Genotypes with Low Levels of BabA Adhesin and Lewis b Binding
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2016 (English)In: Digestive Diseases and Sciences, ISSN 0163-2116, E-ISSN 1573-2568, Vol. 61, no 10, p. 2868-2877Article in journal (Refereed) Published
Abstract [en]

BabA is a Helicobacter pylori cell surface adhesin, which binds to the ABO/Le(b) histo-blood group antigens (Le(b)) and serves as a virulence factor. H. pylori single colonies were isolated from 156 [non-ulcer dyspepsia (NUD) = 97, duodenal ulcer (DU) = 34, gastric cancer (GC) = 25)] patients. babA and babB genes were evaluated by gene/locus-specific PCR. BabA protein expression and Le(b) binding activity were determined by immunoblotting and ELISA, respectively. The combined categorization of H. pylori strains based on high, low or no levels of BabA expression and Le(b) binding, produced 4 groups: (I) BabA-high/Le(b)-high (36 %), (II) BabA-low/Le(b)-low (26 %), (III) BabA-neg/Le(b)-low (30 %) and (IV) BabA-neg/Le(b)-neg (8 %) strains. The majority (63 %) of the BabA-low/Le(b)-low strains exhibited mixed babA/B genotypes as compared to merely 18 % of the BabA-high/Le(b)-high, 15 % of the BabA-neg/Le(b)-neg and 11 % of the BabA-neg/Le(b)-low (P = 0.0001) strains. In contrast to NUD strains, the great majority (70 %) of DU strains were BabA-low/Le(b)-low (11 %, P = 0.0001), which compared to NUD strains, enhanced the risk of DU by 18.8-fold. In parallel, infection with babA/B mixed genotype strains amplified the risk of DU by 3.6-fold (vs. babA-positive: P = 0.01) to 6.9-fold (vs. babA-negative: P = 0.007). Here, we show higher prevalence of mixed babA/B genotypes among BabA-low/Le(b)-low clinical strains. Recombination of babA and babB genes across their loci may yield lower BabA expression and lower Le(b) binding activity. We conclude that H. pylori strains with lower Le(b) binding activity are better adapted for colonization of the gastric metaplastic patches in the duodenum and enhance the risk of duodenal ulcers.

Keywords
Helicobacter pylori, Duodenal ulcer, Mixed babA/B genotypes, BabA, Adhesin
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-127719 (URN)10.1007/s10620-016-4217-z (DOI)000384211900015 ()27318698 (PubMedID)
Available from: 2016-12-21 Created: 2016-11-18 Last updated: 2018-06-09Bibliographically approved
Magalhaes, A., Rossez, Y., Robbe-Masselot, C., Maes, E., Gomes, J., Shevtsova, A., . . . Reis, C. A. (2016). Muc5ac gastric mucin glycosylation is shaped by FUT2 activity and functionally impacts Helicobacter pylori binding. Scientific Reports, 6, Article ID 25575.
Open this publication in new window or tab >>Muc5ac gastric mucin glycosylation is shaped by FUT2 activity and functionally impacts Helicobacter pylori binding
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 25575Article in journal (Refereed) Published
Abstract [en]

The gastrointestinal tract is lined by a thick and complex layer of mucus that protects the mucosal epithelium from biochemical and mechanical aggressions. This mucus barrier confers protection against pathogens but also serves as a binding site that supports a sheltered niche of microbial adherence. The carcinogenic bacteria Helicobacter pylori colonize the stomach through binding to host glycans present in the glycocalyx of epithelial cells and extracellular mucus. The secreted MUC5AC mucin is the main component of the gastric mucus layer, and BabA-mediated binding of H. pylori to MUC5AC confers increased risk for overt disease. In this study we unraveled the O-glycosylation profile of Muc5ac from glycoengineered mice models lacking the FUT2 enzyme and therefore mimicking a non-secretor human phenotype. Our results demonstrated that the FUT2 determines the O-glycosylation pattern of Muc5ac, with Fut2 knock-out leading to a marked decrease in alpha 1,2-fucosylated structures and increased expression of the terminal type 1 glycan structure Lewis-a. Importantly, for the first time, we structurally validated the expression of Lewis-a in murine gastric mucosa. Finally, we demonstrated that loss of mucin FUT2-mediated fucosylation impairs gastric mucosal binding of H. pylori BabA adhesin, which is a recognized feature of pathogenicity.

National Category
Microbiology in the medical area Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-121550 (URN)10.1038/srep25575 (DOI)000375437900001 ()27161092 (PubMedID)
Available from: 2016-07-01 Created: 2016-06-03 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
Magalhaes, A., Marcos-Pinto, R., Gomes, J., Nairn, A. V., Rossez, Y., Robbe-Masselot, C., . . . Reis, C. A. (2016). The glycan receptors of Helicobacter pylori: decoding the pathways underlying gastric glycophenotype modulation. Paper presented at Annual Meeting of the Society-for-Glycobiology, Nov 19-22, 2016, New Orleans, LA. Glycobiology, 26(12), 1401-1402
Open this publication in new window or tab >>The glycan receptors of Helicobacter pylori: decoding the pathways underlying gastric glycophenotype modulation
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2016 (English)In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 26, no 12, p. 1401-1402Article in journal, Meeting abstract (Refereed) Published
Abstract [en]

The gastrointestinal tract is covered by a complex extracellular mucus layer that protects the gastric epithelium fromexternal aggressions such as chemical agents, microorganismsand shear stress. Although this mucus barrier confers protec-tion against certain pathogens, it may also provide a niche formicrobial binding.Helicobacter pyloriexploits the host glycoconjugates present in the gastric mucus layer and lining thesurface epithelium of the gastric mucosa to colonize the stomach. Infection can persist for decades promoting chronicinflammation, and in a subset of individuals lesions cansilently progress to cancer. The secreted MUC5AC mucin isthe main component of the gastric mucus layer, andH. pyloriBabA-mediated binding to MUC5AC confers increased riskfor overt disease. We have shown that FUT2 determines theO-glycosylation pattern of Muc5ac, with Fut2 knock-outleading to a marked decrease inα1,2-fucosylated structuresand increased expression of the terminal type 1 glycan structure Lewisa. Importantly, for thefirst time, we structurallyvalidated the expression of Lewisain murine gastric mucosa(1). We further demonstrated that loss of mucin FUT2-mediated fucosylation impairs gastric mucosal binding ofH.pyloriBabA adhesin, which is a recognized feature of patho-genicity. UponH. pyloriinfection,concomitantly with tissueinflammation, there is a remodeling of the gastric glycopheno-type. We showed that increased expression of sialyl-Lewisa/xantigens is due to transcriptional up-regulation of theB3GNT5,B3GALT5,andFUT3genes. In addition, weobserved thatH. pyloriinfected individuals present a markedgastric local pro-inflammatory signature with significantlyhigher TNF-αlevels and demonstrated that TNF-induced activation of the NF-kappaB pathway results in B3GNT5 up-regulation (2). Furthermore, we showed that this gastric glycosylation shift, characterized by increased sialylation pat-terns, favors SabA-mediatedH. pyloriattachment to humaninflamed gastric mucosa. Our data provides clinically relevantinsights into the regulatory mechanisms underlyingH. pylorimodulation of host glycosylation machinery, and phenotypicalterations crucial for life-long infection and gastric disease.

National Category
Microbiology in the medical area Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-131886 (URN)10.1093/glycob/cww110 (DOI)000392935600073 ()
Conference
Annual Meeting of the Society-for-Glycobiology, Nov 19-22, 2016, New Orleans, LA
Available from: 2017-02-24 Created: 2017-02-24 Last updated: 2018-06-09Bibliographically approved
Liu, H., Fero, J. B., Mendez, M., Carpenter, B. M., Servetas, S. L., Rahman, A., . . . Dubois, A. (2015). Analysis of a single Helicobacter pylori strain over a 10-year period in a primate model. International Journal of Medical Microbiology, 305(3), 392-403
Open this publication in new window or tab >>Analysis of a single Helicobacter pylori strain over a 10-year period in a primate model
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2015 (English)In: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 305, no 3, p. 392-403Article in journal (Refereed) Published
Abstract [en]

Helicobacter pylori from different individuals exhibits substantial genetic diversity. However, the kinetics of bacterial diversification after infection with a single strain is poorly understood. We investigated evolution of H. pylori following long-term infection in the primate stomach; Rhesus macaques were infected with H. pylori strain USU101 and then followed for 10 years. H. pylori was regularly cultured from biopsies, and single colony isolates were analyzed. At 1-year, DNA fingerprinting showed that all output isolates were identical to the input strain; however, at 5-years, different H. pylori fingerprints were observed. Microarray-based comparative genomic hybridization revealed that long term persistence of USU101 in the macaque stomach was associated with specific whole gene changes. Further detailed investigation showed that levels of the BabA protein were dramatically reduced within weeks of infection. The molecular mechanisms behind this reduction were shown to include phase variation and gene loss via intragenomic rearrangement, suggesting strong selective pressure against BabA expression in the macaque model. Notably, although there is apparently strong selective pressure against babA, babA is required for establishment of infection in this model as a strain in which babA was deleted was unable to colonize experimentally infected macaques.

Keywords
Evolution, babA, Helicobacter pylori, Colonization, Outer membrane protein
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-106142 (URN)10.1016/j.ijmm.2015.03.002 (DOI)000354583900014 ()25804332 (PubMedID)
Available from: 2015-07-13 Created: 2015-07-09 Last updated: 2018-06-07Bibliographically approved
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